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Rashid MHO, Yasui F, Sanada T, Kono R, Honda T, Kitab B, Akter L, Utsunomiya M, Sato R, Yoshida O, Hiasa Y, Oda Y, Goh Y, Miyazaki T, Kohara M, Tsukiyama-Kohara K. Immunogenicity of an Intranasal Dual (Core and Surface)-Antigen Vaccine Against Hepatitis B Virus Enhanced by Carboxyl-Vinyl Polymer Excipients. Vaccines (Basel) 2025; 13:464. [PMID: 40432076 PMCID: PMC12115510 DOI: 10.3390/vaccines13050464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2025] [Revised: 04/18/2025] [Accepted: 04/24/2025] [Indexed: 05/29/2025] Open
Abstract
Background: Hepatitis B virus (HBV) is a major cause of morbidity and mortality globally, and chronic infections are associated with cirrhosis and hepatocellular carcinoma. Issues with conventional treatments and vaccines mean there is a need for new therapeutic vaccines, which must elicit a strong and sustainable immune response. Here, we evaluated the immunogenicity of dual-antigen vaccines containing hybrid surface (hy-LHBs) and core (HBc) antigens, combined with a carboxyl-vinyl polymer (CVP) as a mucoadhesive excipient, following intranasal administration in mice. Methods: Mice were intranasally administered a mixed vaccine (10 µg of hy-LHBs and 2.5 or 10 µg of HBc) with or without a CVP excipient, and they were assessed for their immune response (levels of IgGs or IgA antibodies in an ELISA, IFN-γ level in splenocytes in an ELISpot assay, and cytokine/chemokine levels in a BioPlex assay). A protein stability assay was also conducted for vaccine formulations with and without excipients. Results: Significantly enhanced IgG production was noted targeting hy-LHBs and (less markedly) HBc at 10 µg/antigen, but only a non-significant elevation was noted with the vaccine containing 2.5 µg HBc. The BioPlex assay showed a significant increase in IL-2 (#00-07, 0B), IL-12(p40)(#00), eotaxin (#00), MIP1α (#00, #00-07, 0B), and MCP-1 (#00-07, 0B) in mice that received treatment compared to those of untreated mice. The endpoint titers of IgG1 and IgG2a were measured, which were higher with CVP excipients than without. From the IgG2a/IgG1 ratio, a higher IgG1 response was induced by CVPs to hy-LHBs and a higher IgG2a response was induced to HBc. Th2-dominant phenotype to hy-LHBs was induced with CVP#00 in an ELISpot assay. The highest anti-hy-LHBs antibody titer was noted with the conventional CVP#00 excipient. Consistent with these results, a higher amount of neutralizing antibodies of HBV was induced with CVP#00 treatment and followed by #00-03 and #14-00. Conclusions: We consider that the addition of CVP excipients to vaccine formulation enhances immunogenicity and HBV antigen stability for intranasal vaccines. This effect was seen for both humoral and cell-mediated immune responses, indicating the potential of CVPs as excipients in intranasal HBV vaccines.
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Affiliation(s)
- Md Haroon Or Rashid
- Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima 890-0065, Japan; (M.H.O.R.); (B.K.); (L.A.); (M.U.); (R.S.)
| | - Fumihiko Yasui
- Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan; (F.Y.); (T.S.); (R.K.); (T.H.); (M.K.)
| | - Takahiro Sanada
- Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan; (F.Y.); (T.S.); (R.K.); (T.H.); (M.K.)
| | - Risa Kono
- Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan; (F.Y.); (T.S.); (R.K.); (T.H.); (M.K.)
| | - Tomoko Honda
- Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan; (F.Y.); (T.S.); (R.K.); (T.H.); (M.K.)
| | - Bouchra Kitab
- Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima 890-0065, Japan; (M.H.O.R.); (B.K.); (L.A.); (M.U.); (R.S.)
| | - Lipi Akter
- Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima 890-0065, Japan; (M.H.O.R.); (B.K.); (L.A.); (M.U.); (R.S.)
| | - Masashi Utsunomiya
- Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima 890-0065, Japan; (M.H.O.R.); (B.K.); (L.A.); (M.U.); (R.S.)
| | - Risa Sato
- Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima 890-0065, Japan; (M.H.O.R.); (B.K.); (L.A.); (M.U.); (R.S.)
| | - Osamu Yoshida
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon 791-0295, Japan; (O.Y.); (Y.H.)
| | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon 791-0295, Japan; (O.Y.); (Y.H.)
| | - Yasunori Oda
- Beacle Co., Ltd., Kyoto 606-8305, Japan; (Y.O.); (Y.G.)
| | - Yasumasa Goh
- Beacle Co., Ltd., Kyoto 606-8305, Japan; (Y.O.); (Y.G.)
| | | | - Michinori Kohara
- Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan; (F.Y.); (T.S.); (R.K.); (T.H.); (M.K.)
| | - Kyoko Tsukiyama-Kohara
- Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima 890-0065, Japan; (M.H.O.R.); (B.K.); (L.A.); (M.U.); (R.S.)
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Shechter O, Sausen DG, Dahari H, Vaillant A, Cotler SJ, Borenstein R. Functional Cure for Hepatitis B Virus: Challenges and Achievements. Int J Mol Sci 2025; 26:3633. [PMID: 40332208 PMCID: PMC12026623 DOI: 10.3390/ijms26083633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2025] [Revised: 03/31/2025] [Accepted: 04/04/2025] [Indexed: 05/08/2025] Open
Abstract
The Hepatitis B Virus (HBV) presents a formidable global health challenge, impacting hundreds of millions worldwide and imposing a considerable burden on healthcare systems. The elusive nature of the virus, with its ability to establish chronic infection and evade immune detection, and the absence of curative agents have prompted efforts to develop novel therapeutic approaches beyond current antiviral treatments. This review addresses the challenging concept of a functional cure for HBV, a state characterized by the suppression of HBV and HBsAg, mitigating disease progression and transmission without a complete cure. We provide an overview of HBV epidemiology and its clinical impact, followed by an exploration of the current treatment landscape and its limitations. The immunological basis of a functional cure is then discussed, exploring the intricate interplay between the virus and the host immune response. Emerging therapeutic approaches, such as RNA interference-based interventions, entry inhibitors, nucleic acid polymers, and therapeutic vaccines, are discussed with regard to their success in achieving a functional cure. Lastly, the review underscores the urgent need for innovative strategies to achieve a functional cure for HBV.
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Affiliation(s)
- Oren Shechter
- Eastern Virginia Medical School, Norfolk, VA 23501, USA;
| | | | - Harel Dahari
- The Program for Experimental and Theoretical Modeling, Division of Hepatology, Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA; (H.D.); (S.J.C.)
| | - Andrew Vaillant
- Replicor Inc., 6100 Royalmount Ave., Montreal, QC H4P 2R2, Canada;
| | - Scott J. Cotler
- The Program for Experimental and Theoretical Modeling, Division of Hepatology, Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA; (H.D.); (S.J.C.)
| | - Ronen Borenstein
- The Program for Experimental and Theoretical Modeling, Division of Hepatology, Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA; (H.D.); (S.J.C.)
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Rana D, Prajapati A, Karunakaran B, Vora L, Benival D, Jindal AB, Patel R, Joshi V, Jamloki A, Shah U. Recent Advances in Antiviral Drug Delivery Strategies. AAPS PharmSciTech 2025; 26:73. [PMID: 40038154 DOI: 10.1208/s12249-025-03053-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Accepted: 01/23/2025] [Indexed: 03/06/2025] Open
Abstract
Viral infectious diseases have long posed significant challenges to public health, leading to substantial morbidity and mortality worldwide. Recent outbreaks, including those caused by coronaviruses, have highlighted the urgent need for more effective antiviral treatments. Existing therapies, while numerous, face limitations such as drug resistance, toxicity, poor bioavailability, and non-specific targeting, which hinder their effectiveness against new and emerging viruses. This review focuses on the latest advances in nanoplatform technologies designed to enhance drug solubility, provide sustained or targeted delivery, and improve the efficacy of antiviral therapies. Additionally, we explore how these technologies can be integrated with novel strategies like genetic modulation to combat viral infections more effectively. The review also discusses the potential of these innovations in addressing the challenges posed by current antiviral therapies and their implications for future clinical applications.
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Affiliation(s)
- Dhwani Rana
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research- Ahmedabad (NIPER-A), 382355, Palaj, India
| | - Arvee Prajapati
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research- Ahmedabad (NIPER-A), 382355, Palaj, India
| | - Bharathi Karunakaran
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research- Ahmedabad (NIPER-A), 382355, Palaj, India
| | - Lalitkumar Vora
- School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK
| | - Derajram Benival
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research- Ahmedabad (NIPER-A), 382355, Palaj, India
| | - Anil B Jindal
- Department of Pharmacy, Birla Institute of Technology and Science Pilani (BITS PILANI), Pilani Campus, Pilani, Rajasthan, 333031, India.
| | - Rikin Patel
- Intas Pharmaceuticals Ltd., Matoda, Gujarat, 382210, India
| | - Vishvesh Joshi
- Chartwell Pharmaceuticals LLC, 77 Brenner Dr, Congers, New York, 10920, USA
| | - Ashutosh Jamloki
- Faculty of Pharmacy, Nootan Pharmacy College, Sankalchand Patel University, Visnagar, Gujarat, India
| | - Ujashkumar Shah
- Faculty of Pharmacy, Nootan Pharmacy College, Sankalchand Patel University, Visnagar, Gujarat, India
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Liang M, Liu L, Liu J, Yang Z, Wang M, Xie Y, Cai Y, Xue P, Chen Y, Zhan P, Jia H. Design, synthesis and anti-HBV activity study of novel HBV capsid assembly modulators. Bioorg Med Chem Lett 2024; 112:129913. [PMID: 39111727 DOI: 10.1016/j.bmcl.2024.129913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 08/02/2024] [Accepted: 08/02/2024] [Indexed: 08/18/2024]
Abstract
Capsid assembly modulators (CAMs) have the potential to cure chronic hepatitis B, as demonstrated in clinical trials. Lead compounds NVR3-778 and 5a were found to exist in normal and flipped conformations through induced fit docking. Therefore, we designed and synthesized series I and II compounds by interchanging the amide and sulfonamide bonds of 5a to modify both the tolerance region and solvent-opening region. Among them, compound 4a (EC50 = 0.24 ± 0.10 μM, CC50 > 100 μM) exhibited potent anti-HBV activity with low toxicity, surpassing the lead compounds NVR3-778 (EC50 = 0.29 ± 0.03 μM, CC50 = 20.78 ± 2.29 μM) and 5a (EC50 = 0.50 ± 0.07 μM, CC50 = 48.16 ± 9.15 μM) in HepAD38 cells. Additionally, compared with the lead compound, 4a displayed a stronger inhibitory effect on HBV capsid protein assembly. Molecular dynamics (MD) simulations confirmed that the normal conformation of 4a had relatively stable conformation at different frames of binding modes. Furthermore, 4a showed better metabolic stability in human plasma than positive control drugs. Therefore, compound 4a could be further structurally modified as a potent lead compound.
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Affiliation(s)
- Minghui Liang
- School of Pharmacy, Shandong Second Medical University, Weifang, China
| | - Linyue Liu
- School of Pharmacy, Shandong Second Medical University, Weifang, China; Binzhou Hospital of Traditional Chinese Medicine, Binzhou, China
| | - Jun Liu
- School of Nursing, Shandong Second Medical University, Weifang, China
| | - Zechun Yang
- School of Pharmacy, Shandong Second Medical University, Weifang, China
| | - Mei Wang
- School of Pharmacy, Shandong Second Medical University, Weifang, China; Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, China
| | - Yong Xie
- State Key Laboratory of Anti-Infective Drug Development (NO. 2015DQ780357), Sunshine Lake Pharma Co., Ltd, Dongguan 523871, China
| | - Yuqing Cai
- School of Public Health, Shandong Second Medical University, Weifang, China
| | - Peng Xue
- School of Public Health, Shandong Second Medical University, Weifang, China
| | - Yunfu Chen
- State Key Laboratory of Anti-Infective Drug Development (NO. 2015DQ780357), Sunshine Lake Pharma Co., Ltd, Dongguan 523871, China.
| | - Peng Zhan
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, China.
| | - Haiyong Jia
- School of Pharmacy, Shandong Second Medical University, Weifang, China.
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Xu X, Liu J, Li X, Feng Q, Su Y. Integrated network pharmacology and metabolomics to study the potential mechanism of Jiawei Yinchenhao decoction in chronic hepatitis B. Heliyon 2024; 10:e36267. [PMID: 39224343 PMCID: PMC11367511 DOI: 10.1016/j.heliyon.2024.e36267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Revised: 08/01/2024] [Accepted: 08/13/2024] [Indexed: 09/04/2024] Open
Abstract
Chronic hepatitis B infection (CHB) is a major risk factor for the development of hepatocellular carcinoma (HCC) globally and continues to pose a significant global health challenge. Jiawei Yinchenhao decoction (JWYCH) is a modified version of Yinchenhao decoction (YCHD), which is widely used to treat liver diseases including icteric hepatitis, cholelithiasis, and hepatic ascites. However, the effectiveness and underlying mechanism of JWYCH on CHB are still unclear. This study aimed to investigate the impact of JWYCH on CHB and explore the underlying mechanism via network pharmacology and metabolomics. C57BL/6 mice were administered rAAV-HBV1.3 via hydrodynamic injection (HDI) to establish the CHB model. The infected mice were orally administered JWYCH for 4 weeks. HBsAg, HBeAg, HBV DNA, the serum liver function index, and histopathology were detected. In addition, network pharmacology was used to investigate potential targets, whereas untargeted metabolomics analysis was employed to explore the hepatic metabolic changes in JWYCH in CHB mice and identify relevant biomarkers and metabolic pathways. JWYCH was able to reduce HBeAg levels and improve liver pathological changes in mice with CHB. Additionally, metabolomics analysis indicated that JWYCH can influence 105 metabolites, including pipecolic acid, alpha-terpinene, adenosine, and L-phenylalanine, among others. Bile acid metabolism, arachidonic acid metabolism, and retinol metabolism are suggested to be potential targets of JWYCH in CHB. In conclusion, JWYCH demonstrated a hepatoprotective effect on a mouse model of CHB, suggesting a potential alternative therapeutic strategy for CHB. The effect of JWYCH is associated mainly with regulating the metabolism of bile acid, arachidonic acid, and retinol. These differentially abundant metabolites may serve as potential biomarkers and therapeutic targets for CHB.
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Affiliation(s)
- Xinyi Xu
- College of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Jin Liu
- College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Xue Li
- College of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - QuanSheng Feng
- College of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Yue Su
- College of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
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El Messaoudi S, Brichler S, Fougerou-Leurent C, Gordien E, Gerber A, Kortebi A, Lagadic G, Subic-Levrero M, Metivier S, Pol S, Minello A, Ratziu V, Leroy V, Mathurin P, Alric L, Coulibaly F, Pawlotsky JM, Zoulim F, de Lédinghen V, Guedj J, the ANRS HD EP01 BULEDELTA Study Group. Effect of Peg-IFN on the viral kinetics of patients with HDV infection treated with bulevirtide. JHEP Rep 2024; 6:101070. [PMID: 39100818 PMCID: PMC11295569 DOI: 10.1016/j.jhepr.2024.101070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 03/12/2024] [Accepted: 03/14/2024] [Indexed: 08/06/2024] Open
Abstract
Background & Aims Bulevirtide is a first-in-class entry inhibitor antiviral treatment for chronic hepatitis D. The viral kinetics during bulevirtide therapy and the effect of combining bulevirtide with pegylated-interferon (Peg-IFN) are unknown. Methods We used mathematical modelling to analyze the viral kinetics in two French observational cohorts of 183 patients receiving bulevirtide with or without Peg-IFN for 48 weeks. Results The efficacy of bulevirtide in blocking cell infection was estimated to 90.3%, whereas Peg-IFN blocked viral production with an efficacy of 92.4%, albeit with large inter-individual variabilities. The addition of Peg-IFN to bulevirtide was associated with a more rapid virological decline, with a rate of virological response (>2 log of decline or undetectability) at week 48 of 86.9% (95% prediction interval [PI] = [79.7-95.0]), compared with 56.1% (95% PI = [46.4-66.7]) with bulevirtide only. The model was also used to predict the probability to achieve a cure of viral infection, with a rate of 8.8% (95% PI = [3.5-13.2]) with bulevirtide compared with 18.8% (95% PI = [11.6-29.0]) with bulevirtide + Peg-IFN. Mathematical modelling suggests that after 144 weeks of treatment, the rates of viral cure could be 42.1% (95% PI = [33.3-52.6]) with bulevirtide and 66.7% (95% PI = [56.5-76.8]) with bulevirtide + Peg-IFN. Conclusions In this analysis of real-world data, Peg-IFN strongly enhanced the kinetics of viral decline in patients treated with bulevirtide. Randomized clinical trials are warranted to assess the virological and clinical benefit of this combination, and to identify predictors of poor response to treatment. Impact and implications Bulevirtide has been approved for chronic HDV infection by regulatory agencies in Europe based on its good safety profile and rapid virological response after treatment initiation, but the optimal duration of treatment and the chance to achieve a sustained virological response remain unknown. The results presented in this study have a high impact for clinicians and investigators as they provide important knowledge on the long-term virological benefits of a combination of Peg-IFN and bulevirtide in patients with CHD. Clinical trials are now warranted to confirm those predictions.
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Affiliation(s)
| | - Ségolène Brichler
- National Reference Center for Viral Hepatitis B, C, and D, Department of Clinical Microbiology, Hôpital Avicenne AP-HP, Université Sorbonne Paris Nord, Bobigny, INSERM U955, Créteil, France
| | - Claire Fougerou-Leurent
- Clinical Pharmacology Department, CHU Rennes, Rennes, France
- CIC 1414 (Clinical Investigation Center), INSERM, Rennes, France
| | - Emmanuel Gordien
- National Reference Center for Viral Hepatitis B, C, and D, Department of Clinical Microbiology, Hôpital Avicenne AP-HP, Université Sorbonne Paris Nord, Bobigny, INSERM U955, Créteil, France
| | - Athenaïs Gerber
- National Reference Center for Viral Hepatitis B, C, and D, Department of Clinical Microbiology, Hôpital Avicenne AP-HP, Université Sorbonne Paris Nord, Bobigny, INSERM U955, Créteil, France
| | - Amal Kortebi
- Clinical Pharmacology Department, CHU Rennes, Rennes, France
- CIC 1414 (Clinical Investigation Center), INSERM, Rennes, France
| | - Garance Lagadic
- Clinical Pharmacology Department, CHU Rennes, Rennes, France
- CIC 1414 (Clinical Investigation Center), INSERM, Rennes, France
| | - Miroslava Subic-Levrero
- Department of Hepatology, Hospices Civils de Lyon, INSERM Unit 1052, Université Claude Bernard Lyon 1, France
| | | | - Stanislas Pol
- Department of Hepatology, Hôpital Cochin, AP-HP, Université Paris-René Descartes, INSERM U1016, Paris, France
| | - Anne Minello
- Department of Hepatology and Gastroenterology, University hospital Dijon, INSERM UMR 1231, France
| | - Vlad Ratziu
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié Salpêtrière, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
| | - Vincent Leroy
- Department of Hepatology and Gastroenterology, Centre Hospitalo-Universitaire, INSERM U1209, Université Grenoble Alpes, Grenoble, France
| | - Philippe Mathurin
- Service des maladies de l’appareil digestif, Université Lille 2 and Inserm U795, Lille, France
| | - Laurent Alric
- Department of Internal Medicine and Digestive Diseases, UMR-152, Toulouse III University, Toulouse, France
| | - Fatoumata Coulibaly
- Clinical research department, ANRS Maladies infectieuses émergentes, Paris, France
| | - Jean-Michel Pawlotsky
- National Reference Center for Viral Hepatitis B, C, and D, Department of Virology, Hôpital Henri Mondor, Université Paris-Est, Inserm U955, Créteil, France
| | - Fabien Zoulim
- Department of Hepatology, Hospices Civils de Lyon, INSERM Unit 1052, Université Claude Bernard Lyon 1, France
| | - Victor de Lédinghen
- Centre d'Investigation de la Fibrose Hépatique, Bordeaux University Hospital, Pessac, France; INSERM U1312, Bordeaux University, Bordeaux, France
| | | | - the ANRS HD EP01 BULEDELTA Study Group
- Université Paris Cité, IAME, Inserm, Paris, France
- National Reference Center for Viral Hepatitis B, C, and D, Department of Clinical Microbiology, Hôpital Avicenne AP-HP, Université Sorbonne Paris Nord, Bobigny, INSERM U955, Créteil, France
- Clinical Pharmacology Department, CHU Rennes, Rennes, France
- CIC 1414 (Clinical Investigation Center), INSERM, Rennes, France
- Department of Hepatology, Hospices Civils de Lyon, INSERM Unit 1052, Université Claude Bernard Lyon 1, France
- Department of Hepatology, CHU Rangueil, Toulouse, France
- Department of Hepatology, Hôpital Cochin, AP-HP, Université Paris-René Descartes, INSERM U1016, Paris, France
- Department of Hepatology and Gastroenterology, University hospital Dijon, INSERM UMR 1231, France
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié Salpêtrière, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
- Department of Hepatology and Gastroenterology, Centre Hospitalo-Universitaire, INSERM U1209, Université Grenoble Alpes, Grenoble, France
- Service des maladies de l’appareil digestif, Université Lille 2 and Inserm U795, Lille, France
- Department of Internal Medicine and Digestive Diseases, UMR-152, Toulouse III University, Toulouse, France
- Clinical research department, ANRS Maladies infectieuses émergentes, Paris, France
- National Reference Center for Viral Hepatitis B, C, and D, Department of Virology, Hôpital Henri Mondor, Université Paris-Est, Inserm U955, Créteil, France
- Centre d'Investigation de la Fibrose Hépatique, Bordeaux University Hospital, Pessac, France; INSERM U1312, Bordeaux University, Bordeaux, France
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Liu X, Pang X, Wan Z, Zhao J, Gao Z, Deng H. Dopamine Inhibits the Expression of Hepatitis B Virus Surface and e Antigens by Activating the JAK/STAT Pathway and Upregulating Interferon-stimulated Gene 15 Expression. J Clin Transl Hepatol 2024; 12:443-456. [PMID: 38779516 PMCID: PMC11106351 DOI: 10.14218/jcth.2024.00051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 04/16/2024] [Accepted: 04/17/2024] [Indexed: 05/25/2024] Open
Abstract
Background and Aims Hepatitis B virus (HBV) infection is a major risk factor for cirrhosis and liver cancer, and its treatment continues to be difficult. We previously demonstrated that a dopamine analog inhibited the packaging of pregenomic RNA into capsids. The present study aimed to determine the effect of dopamine on the expressions of hepatitis B virus surface and e antigens (HBsAg and HBeAg, respectively) and to elucidate the underlying mechanism. Methods We used dopamine-treated HBV-infected HepG2.2.15 and NTCP-G2 cells to monitor HBsAg and HBeAg expression levels. We analyzed interferon-stimulated gene 15 (ISG15) expression in dopamine-treated cells. We knocked down ISG15 and then monitored HBsAg and HBeAg expression levels. We analyzed the expression of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway factors in dopamine-treated cells. We used dopamine hydrochloride-treated adeno-associated virus/HBV-infected mouse model to evaluate HBV DNA, HBsAg, and HBeAg expression. HBV virus was collected from HepAD38.7 cell culture medium. Results Dopamine inhibited HBsAg and HBeAg expression and upregulated ISG15 expression in HepG2.2.15 and HepG2-NTCP cell lines. ISG15 knockdown increased HBsAg and HBeAg expression in HepG2.2.15 cells. Dopamine-treated cells activated the JAK/STAT pathway, which upregulated ISG15 expression. In the adeno-associated virus-HBV murine infection model, dopamine downregulated HBsAg and HBeAg expression and activated the JAK-STAT/ISG15 axis. Conclusions Dopamine inhibits the expression of HBsAg and HBeAg by activating the JAK/STAT pathway and upregulating ISG15 expression.
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Affiliation(s)
- Xiaoquan Liu
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou Guangdong, China
| | - Xiuqing Pang
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou Guangdong, China
| | - Zhiping Wan
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou Guangdong, China
| | - Jinhua Zhao
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou Guangdong, China
| | - Zhiliang Gao
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou Guangdong, China
- Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong, China
| | - Hong Deng
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou Guangdong, China
- Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong, China
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8
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Zhang Y, Wu D, Tian X, Chen B. From hepatitis B virus infection to acute-on-chronic liver failure: The dynamic role of hepatic macrophages. Scand J Immunol 2024; 99:e13349. [PMID: 38441398 DOI: 10.1111/sji.13349] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Revised: 11/15/2023] [Accepted: 12/11/2023] [Indexed: 03/07/2024]
Abstract
Acute-on-chronic liver failure (ACLF) is a progressive disease that is associated with rapid worsening of clinical symptoms and high mortality. A multicentre prospective study from China demonstrated that patients with hepatitis B virus-related ACLF (HBV-ACLF) exhibited worse clinical characteristics and higher mortality rates compared to non-HBV-ACLF patients. Immune dysregulation is closely linked to the potential mechanisms of initiation and progression of ACLF. Innate immune response, which is represented by monocytes/macrophages, is up-regulated across ACLF development. This suggests that monocytes/macrophages play an essential role in maintaining the immune homeostasis of ACLF. Information that has been published in recent years shows that the immune status and function of monocytes/macrophages vary in ACLF precipitated by different chronic liver diseases. Monocytes/macrophages have an immune activation effect in hepatitis B-precipitated-ACLF, but they exhibit an immune suppression in cirrhosis-precipitated-ACLF. Therefore, this review aims to explain whether this difference affects the clinical outcome in HBV-ACLF patients as well as the mechanisms involved. We summarize the novel findings that highlight the dynamic polarization phenotype and functional status of hepatic macrophages from the stage of HBV infection to ACLF development. Moreover, we discuss how different HBV-related liver disease tissue microenvironments affect the phenotype and function of hepatic macrophages. In summary, increasing developments in understanding the differences in immune phenotype and functional status of hepatic macrophages in ACLF patients will provide new perspectives towards the effective restoration of ACLF immune homeostasis.
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Affiliation(s)
- Yu Zhang
- Department of Hepatology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan Province, China
| | - Dongsheng Wu
- Department of Anorectal Surgical, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan Province, China
| | - Xiaoling Tian
- Department of Hepatology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan Province, China
| | - Bin Chen
- Department of Hepatology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan Province, China
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9
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Yamasaki M, Sawa R, Muramatsu H, Yamamoto Y, Umekita M, Kubota Y, Kanegae Y, Igarashi M. Catenulopyrizomicins, new anti-Hepatitis B virus compounds, from the rare actinomycete Catenuloplanes sp. MM782L-181F7. J Antibiot (Tokyo) 2024; 77:85-92. [PMID: 38008738 DOI: 10.1038/s41429-023-00681-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 10/31/2023] [Accepted: 11/01/2023] [Indexed: 11/28/2023]
Abstract
Hepatitis B virus (HBV) causes chronic hepatitis in humans, and current antiviral therapies rarely treat viral infections. To improve the treatment efficacy, novel therapeutic agents, especially those with different mechanisms of action, need to be developed for use in combination with the current antivirals. Here, we isolated new anti-HBV compounds, named catenulopyrizomicins A-C, from the fermentation broth of rare actinomycete Catenuloplanes sp. MM782L-181F7. Structural analysis revealed that these compounds contained a structure that is composed of thiazolyl pyridine moiety. The catenulopyrizomicins reduced the amount of intracellular viral DNA in HepG2.2.15 cells with EC50 values ranging from 1.94 to 2.63 µM with small but notable selectivity. Mechanistic studies indicated that catenulopyrizomicin promotes the release of immature virion particles that fail to be enveloped through alterations in membrane permeability.
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Affiliation(s)
- Manabu Yamasaki
- Institute of Microbial Chemistry (BIKAKEN), Shinagawa-ku, Tokyo, Japan.
| | - Ryuichi Sawa
- Institute of Microbial Chemistry (BIKAKEN), Shinagawa-ku, Tokyo, Japan
| | | | - Yui Yamamoto
- Institute of Microbial Chemistry (BIKAKEN), Shinagawa-ku, Tokyo, Japan
| | - Maya Umekita
- Institute of Microbial Chemistry (BIKAKEN), Shinagawa-ku, Tokyo, Japan
| | - Yumiko Kubota
- Institute of Microbial Chemistry (BIKAKEN), Shinagawa-ku, Tokyo, Japan
| | - Yumi Kanegae
- Core Research Facilities of Basic Science, Research Center for Medical Science, The Jikei University School of Medicine, Minato-ku, Tokyo, Japan
| | - Masayuki Igarashi
- Institute of Microbial Chemistry (BIKAKEN), Shinagawa-ku, Tokyo, Japan
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10
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Wen X, Li D, Chen P, Tan M, Zhang H, Liu Y, Ren J, Cheng S. Gambogic acid inhibits HBx-mediated hepatitis B virus replication by targeting the DTX1-Notch signaling pathway. Virus Res 2024; 339:199273. [PMID: 38029800 PMCID: PMC10714370 DOI: 10.1016/j.virusres.2023.199273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 11/04/2023] [Accepted: 11/16/2023] [Indexed: 12/01/2023]
Abstract
BACKGROUND & AIMS Current antiviral drugs, including nucleoside analogs and interferon, fail to eliminate the HBV covalently closed circular DNA (cccDNA), which serves as a transcript template in infected hepatocytes. Silencing the HBV X protein, which plays a crucial role in cccDNA transcription, is a promising approach to inhibit HBV replication. Therefore, the identification of novel compounds that can inhibit HBx-mediated cccDNA transcription is critical. METHODS Initially, a compound library consisting of 715 monomers derived from traditional Chinese medicines known for their liver-protecting properties was established. Then, MTT assays were used to determine the cytotoxicity of each compound. The effect of candidates on Flag-HBx expression was examined by real-time PCR and western blotting in Flag-HBx transfected HepG2-NTCP cells. Ultimately, the antiviral effect of gambogic acid (GA) on HBV was observed in HBV-infected HepG2-NTCP cells. Mechanistically, the functional role of DTX1 in GA-induced HBV inhibition was examined using RNA-seq. Finally, the antiviral effect of GA was estimated in vivo. RESULTS Gambogic acid (GA), a natural bioactive compound with a myriad of biological activities, markedly reduced Flag-HBx expression. Potent and dose-dependent reductions in extracellular HBV RNAs, HBV DNA, HBsAg, HBeAg and HBc protein were discovered three days after GA treatment in HBV-infected cells, accompanied by the absence of significant cytotoxicity. Furthermore, our research revealed that GA exhibited a dose-dependent inhibition of HBx expression, which is a pleiotropic protein required for HBV infection in vivo. We explored the mechanisms underlying GA-mediated inhibition of HBV and confirmed that this inhibition is accomplished by upregulating the expression of the DTX1 gene and boosting the Notch signaling pathway. Finally, the inhibitory effect of GA on HBV replication was tested in vivo using a mouse model of hepatitis B virus recombinant cccDNA. CONCLUSIONS Herein, we discovered GA, which is a natural bioactive compound that targets HBx to inhibit hepatitis B virus replication by activating the DTX1-Notch signaling pathway.
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Affiliation(s)
- Xu Wen
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Clinical Laboratory, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China; Department of Laboratory Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Dian Li
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Clinical Laboratory, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Peng Chen
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Clinical Laboratory, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Ming Tan
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Clinical Laboratory, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Hui Zhang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Clinical Laboratory, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Yuting Liu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Clinical Laboratory, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Jihua Ren
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Clinical Laboratory, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Shengtao Cheng
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Clinical Laboratory, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
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11
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Ogunnaike M, Das S, Raut SS, Sultana A, Nayan MU, Ganesan M, Edagwa BJ, Osna NA, Poluektova LY. Chronic Hepatitis B Infection: New Approaches towards Cure. Biomolecules 2023; 13:1208. [PMID: 37627273 PMCID: PMC10452112 DOI: 10.3390/biom13081208] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 07/24/2023] [Accepted: 07/28/2023] [Indexed: 08/27/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection leads to the development of cirrhosis and hepatocellular carcinoma. Lifelong treatment with nucleotides/nucleoside antiviral agents is effective at suppressing HBV replication, however, adherence to daily therapy can be challenging. This review discusses recent advances in the development of long-acting formulations for HBV treatment and prevention, which could potentially improve adherence. Promising new compounds that target distinct steps of the virus life cycle are summarized. In addition to treatments that suppress viral replication, curative strategies are focused on the elimination of covalently closed circular DNA and the inactivation of the integrated viral DNA from infected hepatocytes. We highlight promising long-acting antivirals and genome editing strategies for the elimination or deactivation of persistent viral DNA products in development.
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Affiliation(s)
- Mojisola Ogunnaike
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA; (M.O.); (S.D.); (S.S.R.); (A.S.); (M.U.N.); (M.G.)
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Srijanee Das
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA; (M.O.); (S.D.); (S.S.R.); (A.S.); (M.U.N.); (M.G.)
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Samiksha S. Raut
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA; (M.O.); (S.D.); (S.S.R.); (A.S.); (M.U.N.); (M.G.)
| | - Ashrafi Sultana
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA; (M.O.); (S.D.); (S.S.R.); (A.S.); (M.U.N.); (M.G.)
| | - Mohammad Ullah Nayan
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA; (M.O.); (S.D.); (S.S.R.); (A.S.); (M.U.N.); (M.G.)
| | - Murali Ganesan
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA; (M.O.); (S.D.); (S.S.R.); (A.S.); (M.U.N.); (M.G.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Benson J. Edagwa
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA; (M.O.); (S.D.); (S.S.R.); (A.S.); (M.U.N.); (M.G.)
| | - Natalia A. Osna
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA; (M.O.); (S.D.); (S.S.R.); (A.S.); (M.U.N.); (M.G.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Larisa Y. Poluektova
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA; (M.O.); (S.D.); (S.S.R.); (A.S.); (M.U.N.); (M.G.)
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12
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Qin B, Shen S, Lai J, Yang W, Feng L, Ding J. Inhibition of Hepatitis B Virus (HBV) replication and antigen expression by Brucea javanica (L.) Merr. oil emulsion. Front Cell Infect Microbiol 2023; 13:1193775. [PMID: 37560319 PMCID: PMC10408445 DOI: 10.3389/fcimb.2023.1193775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Accepted: 07/03/2023] [Indexed: 08/11/2023] Open
Abstract
Introduction The seeds of Brucea javanica (L.) Merr. (BJ) have been traditionally used to treat various types of cancers for many years in China. In this study, we systematically investigated a BJ oil emulsion (BJOE) produced from BJ seeds with the purpose of evaluating its antiviral effect against hepatitis B virus (HBV). Methods HepG2.215 (a wild-type HBV cell line), HepG2, and Huh7, transfected with wildtype (WT) or lamivudine-resistance mutant (LMV-MT) HBV replicon plasmids, were treated with different doses of BJOE and then used for pharmacodynamic evaluation. Cell viability was determined using CCK8 assay. The levels of HBsAg/HBeAg in cell cultured supernatant, HBcAg in cell lysis solution, and HBV DNA in both were evaluated. Results BJOE at ≤5 mg/ml was nontoxic to carcinoma cell lines, but could significantly inhibit WT/LMV-MT HBV replication and HBs/e/c antigen expression in a dose-dependent manner by upregulating interleukin-6 (IL-6), demonstrating that it possesses moderate anti-HBV activity. As one of the major components of BJOE, bruceine B was found to play a dominant role in IL-6 induction and HBV inhibition. Discussion Our results demonstrated that BJOE suppressed HBV replication by stimulating IL-6, indicating that it has promising clinical therapeutic potential for both WT and LMV-MT HBV.
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Affiliation(s)
- Bo Qin
- Clinical Laboratory, Shaoxing Maternity and Child Health Care Hospital, Shaoxing, China
- Obstetrics and Gynecology Hospital of Shaoxing University, Shaoxing, China
| | - Shu Shen
- Obstetrics and Gynecology Hospital of Shaoxing University, Shaoxing, China
- Department of Gynecology, Shaoxing Maternity and Child Health Care Hospital, Shaoxing, China
| | - Juan Lai
- GeneMind Biosciences Company Limited, Shenzhen, China
| | - Wei Yang
- GeneMind Biosciences Company Limited, Shenzhen, China
| | - Lili Feng
- Obstetrics and Gynecology Hospital of Shaoxing University, Shaoxing, China
- Department of Anesthesiology, Shaoxing Maternity and Child Health Care Hospital, Shaoxing, China
| | - Jiefeng Ding
- Clinical Laboratory, Shaoxing Maternity and Child Health Care Hospital, Shaoxing, China
- Obstetrics and Gynecology Hospital of Shaoxing University, Shaoxing, China
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13
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Jin Y, Wang S, Xu S, Zhao S, Xu X, Poongavanam V, Menéndez-Arias L, Zhan P, Liu X. Targeting hepatitis B virus cccDNA levels: Recent progress in seeking small molecule drug candidates. Drug Discov Today 2023; 28:103617. [PMID: 37196762 DOI: 10.1016/j.drudis.2023.103617] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 03/29/2023] [Accepted: 05/10/2023] [Indexed: 05/19/2023]
Abstract
Hepatitis B virus (HBV) infection is a major global health problem that puts people at high risk of death from cirrhosis and liver cancer. The presence of covalently closed circular DNA (cccDNA) in infected cells is considered to be the main obstacle to curing chronic hepatitis B. At present, the cccDNA cannot be completely eliminated by standard treatments. There is an urgent need to develop drugs or therapies that can reduce HBV cccDNA levels in infected cells. We summarize the discovery and optimization of small molecules that target cccDNA synthesis and degradation. These compounds are cccDNA synthesis inhibitors, cccDNA reducers, core protein allosteric modulators, ribonuclease H inhibitors, cccDNA transcriptional modulators, HBx inhibitors and other small molecules that reduce cccDNA levels.
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Affiliation(s)
- Yu Jin
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, PR China
| | - Shuo Wang
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, PR China
| | - Shujing Xu
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, PR China
| | - Shujie Zhao
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, PR China
| | - Xiangrui Xu
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, PR China
| | - Vasanthanathan Poongavanam
- Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense M DK-5230, Denmark
| | - Luis Menéndez-Arias
- Centro de Biología Molecular 'Severo Ochoa' (Consejo Superior de Investigaciones Científicas & Universidad Autónoma de Madrid), 28049 Madrid, Spain.
| | - Peng Zhan
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, PR China.
| | - Xinyong Liu
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, PR China.
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14
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Yu H, Deng W, Chen S, Qin B, Yao Y, Zhou C, Guo M. Strongylocentrotus nudus egg polysaccharide (SEP) suppresses HBV replication via activation of TLR4-induced immune pathway. Int J Biol Macromol 2023:125539. [PMID: 37355064 DOI: 10.1016/j.ijbiomac.2023.125539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 06/17/2023] [Accepted: 06/21/2023] [Indexed: 06/26/2023]
Abstract
Chronic hepatitis B virus (HBV) infection is a worldwide public health problem that causes significant liver-related morbidity and mortality. In our previous study, Strongylocentrotus nudus eggs polysaccharide (SEP), extracted from sea urchins, had immunomodulatory and antitumor effects. Whether SEP has anti-HBV activity is still obscure. This study demonstrated that SEP decreased the secretion of hepatitis B surface antigen (HBsAg) and e antigen (HBeAg), as well as the replication and transcription of HBV both in vitro and in vivo. Immunofluorescence and immunohistochemistry results showed that the level of HBV core antigen (HBcAg) was clearly reduced by SEP treatment. Mechanistically, RT-qPCR, western blot, and confocal microscopy analysis showed that SEP significantly increased the expression of toll-like receptor 4 (TLR4) and co-localization with TLR4. The downstream molecules of TLR4, including NF-κb and IRF3, were activated and the expression of IFN-β, TNF-α, IL-6, OAS, and MxA were also increased, which could suppress HBV replication. Moreover, SEP inhibited other genotypes of HBV and hepatitis C virus (HCV) replication in vitro. In summary, SEP could be investigated as a potential anti-HBV drug capable of modulating the innate immune.
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Affiliation(s)
- Haifei Yu
- State Key Laboratory of Natural Medicines, School of Life Science & Technolgy, China Pharmaceutical University, Nanjing 211198, Jiangsu province, China
| | - Wanyu Deng
- College of life science, Shangrao Normal University, Shangrao 334001, Jiangxi province, China
| | - Shuo Chen
- State Key Laboratory of Natural Medicines, School of Life Science & Technolgy, China Pharmaceutical University, Nanjing 211198, Jiangsu province, China
| | - Bo Qin
- Shaoxing Women and Children's Hospital, Shaoxing 312000, Zhejiang, China
| | - Yongxuan Yao
- Guangzhou Institute of Pediatrics, Guangzhou Women and Children Medical Center, Guangzhou 510623, China.
| | - Changlin Zhou
- State Key Laboratory of Natural Medicines, School of Life Science & Technolgy, China Pharmaceutical University, Nanjing 211198, Jiangsu province, China.
| | - Min Guo
- State Key Laboratory of Natural Medicines, School of Life Science & Technolgy, China Pharmaceutical University, Nanjing 211198, Jiangsu province, China.
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15
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Boora S, Sharma V, Kaushik S, Bhupatiraju AV, Singh S, Kaushik S. Hepatitis B virus-induced hepatocellular carcinoma: a persistent global problem. Braz J Microbiol 2023; 54:679-689. [PMID: 37059940 PMCID: PMC10235410 DOI: 10.1007/s42770-023-00970-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 04/05/2023] [Indexed: 04/16/2023] Open
Abstract
Hepatitis B virus (HBV) infections are highly prevalent globally, representing a serious public health problem. The diverse modes of transmission and the burden of the chronic carrier population pose challenges to the effective management of HBV. Vaccination is the most effective preventive measure available in the current scenario. Still, HBV is one of the significant health issues in various parts of the globe due to non-response to vaccines, the high number of concealed carriers, and the lack of access and awareness. Universal vaccination programs must be scaled up in neonates, especially in the developing parts of the world, to prevent new HBV infections. Novel treatments like combinational therapy, gene silencing, and new antivirals must be available for effective management. The prolonged infection of HBV, direct and indirect, can promote the growth of hepatocellular carcinoma (HCC). The present review emphasizes the problems and probable solutions for better managing HBV infections, causal risk factors of HCC, and mechanisms of HCC.
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Affiliation(s)
- Sanjit Boora
- Centre for Biotechnology, Maharshi Dayanand University, 124001, Haryana, Rohtak, India
| | - Vikrant Sharma
- Centre for Biotechnology, Maharshi Dayanand University, 124001, Haryana, Rohtak, India
| | | | | | - Sandeep Singh
- Department of Biochemistry, Maharshi Dayanand University, Rohtak, India
| | - Samander Kaushik
- Centre for Biotechnology, Maharshi Dayanand University, 124001, Haryana, Rohtak, India.
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16
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Bhat S, Ahanger IA, Kazim SN. Forthcoming Developments in Models to Study the Hepatitis B Virus Replication Cycle, Pathogenesis, and Pharmacological Advancements. ACS OMEGA 2023; 8:14273-14289. [PMID: 37125123 PMCID: PMC10134252 DOI: 10.1021/acsomega.2c07154] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 02/08/2023] [Indexed: 05/03/2023]
Abstract
Hepatitis, liver cirrhosis, and hepatocellular carcinoma are all manifestations of chronic hepatitis B. Its pathogenesis and molecular mechanism remain mysterious. As medical science progresses, different models are being used to study the disease from the physiological and molecular levels. Animal models have played an unprecedented role in achieving in-depth knowledge of the disease while posing no risk of harming humans throughout the study. The scarcity of acceptable animal models has slowed progress in hepatitis B virus (HBV) research and preclinical testing of antiviral medicines since HBV has a narrow species tropism and exclusively infects humans and higher primates. The development of human chimeric mice was supported by a better understanding of the obstacles to interspecies transmission, which has substantially opened the way for HBV research in vivo and the evaluation of possible chronic hepatitis B therapeutics. Animal models are cumbersome to handle, not accessible, and expensive. Hence, it is herculean to investigate the HBV replication cycle in animal models. Therefore, it becomes essential to build a splendid in vitro cell culture system to demonstrate the mechanisms attained by the HBV for its multiplication and sustenance. We also addressed the advantages and caveats associated with different models in examining HBV.
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Affiliation(s)
- Sajad
Ahmad Bhat
- Centre
for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Ishfaq Ahmad Ahanger
- Centre
for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
- Clinical
Biochemistry University of Kashmir, Srinagar, India
| | - Syed Naqui Kazim
- Centre
for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
- Phone: +91 9953621758.
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17
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Wang L, Zhu Q, Zhang JD, Zhang Y, Ni X, Xiang K, Jiang J, Li B, Yu Y, Hu H, Zhang M, Wu W, Zeng J, Yan Z, Dai J, Sun K, Zhang X, Chen D, Feng S, Sach-Peltason L, Young JAT, Gao L. Discovery of a first-in-class orally available HBV cccDNA inhibitor. J Hepatol 2023; 78:742-753. [PMID: 36587899 DOI: 10.1016/j.jhep.2022.12.014] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 11/25/2022] [Accepted: 12/13/2022] [Indexed: 12/31/2022]
Abstract
BACKGROUND & AIMS The persistence of covalently closed circular DNA (cccDNA) in infected hepatocytes is the major barrier preventing viral eradication with existing therapies in patients with chronic hepatitis B. Therapeutic agents that can eliminate cccDNA are urgently needed to achieve viral eradication and thus HBV cure. METHODS A phenotypic assay with HBV-infected primary human hepatocytes (PHHs) was employed to screen for novel cccDNA inhibitors. A HBVcircle mouse model and a uPA-SCID (urokinase-type plasminogen activator-severe combined immunodeficiency) humanized liver mouse model were used to evaluate the anti-HBV efficacy of the discovered cccDNA inhibitors. RESULTS Potent and dose-dependent reductions in extracellular HBV DNA, HBsAg, and HBeAg levels were achieved upon the initiation of ccc_R08 treatment two days after the HBV infection of PHHs. More importantly, the level of cccDNA was specifically reduced by ccc_R08, while it did not obviously affect mitochondrial DNA. Additionally, ccc_R08 showed no significant cytotoxicity in PHHs or in multiple proliferating cell lines. The twice daily oral administration of ccc_R08 to HBVcircle model mice, which contained surrogate cccDNA molecules, significantly decreased the serum levels of HBV DNA and antigens, and these effects were sustained during the off-treatment follow-up period. Moreover, at the end of follow-up, the levels of surrogate cccDNA molecules in the livers of ccc_R08-treated HBVcircle mice were reduced to below the lower limit of quantification. CONCLUSIONS We have discovered a small-molecule cccDNA inhibitor that reduces HBV cccDNA levels. cccDNA inhibitors potentially represent a new approach to completely cure patients chronically infected with HBV. IMPACT AND IMPLICATIONS Covalently closed circular DNA (cccDNA) persistence in HBV-infected hepatocytes is the root cause of chronic hepatitis B. We discovered a novel small-molecule cccDNA inhibitor that can specifically reduce cccDNA levels in HBV-infected hepatocytes. This type of molecule could offer a new approach to completely cure patients chronically infected with HBV.
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Affiliation(s)
- Li Wang
- Infectious Disease Discovery
| | | | | | | | | | | | | | | | | | - Hui Hu
- Infectious Disease Discovery
| | | | | | | | | | | | | | - Xin Zhang
- Preclinical Chemistry Manufacturing and Controls
| | | | | | - Lisa Sach-Peltason
- Data & Analytics, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Shanghai, Roche Innovation Center Basel
| | | | - Lu Gao
- Infectious Disease Discovery.
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18
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Jia H, Mai J, Wu M, Chen H, Li X, Li C, Liu J, Liu C, Hu Y, Zhu X, Jiang X, Hua B, Xia T, Liu G, Deng A, Liang B, Guo R, Lu H, Wang Z, Chen H, Zhang Z, Zhang H, Niu J, Ding Y. Safety, tolerability, pharmacokinetics, and antiviral activity of the novel core protein allosteric modulator ZM-H1505R (Canocapavir) in chronic hepatitis B patients: a randomized multiple-dose escalation trial. BMC Med 2023; 21:98. [PMID: 36927420 PMCID: PMC10022191 DOI: 10.1186/s12916-023-02814-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 03/06/2023] [Indexed: 03/18/2023] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) core protein-targeting antivirals (CpTAs) are promising therapeutic agents for treating chronic hepatitis B (CHB). In this study, the antiviral activity, pharmacokinetics (PK), and tolerability of ZM-H1505R (Canocapavir), a chemically unique HBV CpTA, were evaluated in patients with CHB. METHODS This study was a double-blind, randomized, placebo-controlled phase 1b trial in Chinese CHB patients. Noncirrhotic and treatment-naive CHB patients were divided into three cohorts (10 patients per cohort) and randomized within each cohort in a ratio of 4:1 to receive a single dose of 50, 100, or 200 mg of Canocapavir or placebo once a day for 28 consecutive days. RESULTS Canocapavir was well tolerated, with the majority of adverse reactions being grade I or II in severity. There were no serious adverse events, and no patients withdrew from the study. Corresponding to 50, 100, and 200 mg doses of Canocapavir, the mean plasma trough concentrations of the drug were 2.7-, 7.0-, and 14.6-fold of its protein-binding adjusted HBV DNA EC50 (135 ng/mL), respectively, with linear PK and a low-to-mild accumulation rate (1.26-1.99). After 28 days of treatment, the mean maximum HBV DNA declines from baseline were -1.54, -2.50, -2.75, and -0.47 log10 IU/mL for the 50, 100, and 200 mg of Canocapavir or placebo groups, respectively; and the mean maximum pregenomic RNA declines from baseline were -1.53, -2.35, -2.34, and -0.17 log10 copies/mL, respectively. CONCLUSIONS Canocapavir treatment is tolerated with efficacious antiviral activity in CHB patients, supporting its further development in treating HBV infection. TRIAL REGISTRATION ClinicalTrials.gov, number NCT05470829).
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Affiliation(s)
- Haiyan Jia
- Phase I Clinical Research Center, The First Hospital of Jilin University, No. 1 Xinmin Street, Changchun, Jilin Province, China
- Gynecology and Obstetrics Center, the First Hospital of Jilin University, Changchun, China
| | - Jiajia Mai
- Phase I Clinical Research Center, The First Hospital of Jilin University, No. 1 Xinmin Street, Changchun, Jilin Province, China
| | - Min Wu
- Phase I Clinical Research Center, The First Hospital of Jilin University, No. 1 Xinmin Street, Changchun, Jilin Province, China
| | - Hong Chen
- Phase I Clinical Research Center, The First Hospital of Jilin University, No. 1 Xinmin Street, Changchun, Jilin Province, China
| | - Xiaojiao Li
- Phase I Clinical Research Center, The First Hospital of Jilin University, No. 1 Xinmin Street, Changchun, Jilin Province, China
| | - Cuiyun Li
- Phase I Clinical Research Center, The First Hospital of Jilin University, No. 1 Xinmin Street, Changchun, Jilin Province, China
| | - Jingrui Liu
- Phase I Clinical Research Center, The First Hospital of Jilin University, No. 1 Xinmin Street, Changchun, Jilin Province, China
| | - Chengjiao Liu
- Phase I Clinical Research Center, The First Hospital of Jilin University, No. 1 Xinmin Street, Changchun, Jilin Province, China
| | - Yue Hu
- Phase I Clinical Research Center, The First Hospital of Jilin University, No. 1 Xinmin Street, Changchun, Jilin Province, China
| | - Xiaoxue Zhu
- Phase I Clinical Research Center, The First Hospital of Jilin University, No. 1 Xinmin Street, Changchun, Jilin Province, China
| | - Xiuhong Jiang
- Shanghai Zhimeng Biopharma, Inc, 1976 Gaoke Middle Road, Suite A-302, Pudong District, Shanghai, China
| | - Bo Hua
- Shanghai Zhimeng Biopharma, Inc, 1976 Gaoke Middle Road, Suite A-302, Pudong District, Shanghai, China
| | - Tian Xia
- Shanghai Zhimeng Biopharma, Inc, 1976 Gaoke Middle Road, Suite A-302, Pudong District, Shanghai, China
| | - Gang Liu
- Shanghai Zhimeng Biopharma, Inc, 1976 Gaoke Middle Road, Suite A-302, Pudong District, Shanghai, China
| | - Aiyun Deng
- Shanghai Zhimeng Biopharma, Inc, 1976 Gaoke Middle Road, Suite A-302, Pudong District, Shanghai, China
| | - Bo Liang
- Shanghai Zhimeng Biopharma, Inc, 1976 Gaoke Middle Road, Suite A-302, Pudong District, Shanghai, China
| | - Ruoling Guo
- Shanghai Zhimeng Biopharma, Inc, 1976 Gaoke Middle Road, Suite A-302, Pudong District, Shanghai, China
| | - Hui Lu
- Shanghai Zhimeng Biopharma, Inc, 1976 Gaoke Middle Road, Suite A-302, Pudong District, Shanghai, China
| | - Zhe Wang
- Shanghai Zhimeng Biopharma, Inc, 1976 Gaoke Middle Road, Suite A-302, Pudong District, Shanghai, China
| | - Huanming Chen
- Shanghai Zhimeng Biopharma, Inc, 1976 Gaoke Middle Road, Suite A-302, Pudong District, Shanghai, China
| | - Zhijun Zhang
- Shanghai Zhimeng Biopharma, Inc, 1976 Gaoke Middle Road, Suite A-302, Pudong District, Shanghai, China
| | - Hong Zhang
- Phase I Clinical Research Center, The First Hospital of Jilin University, No. 1 Xinmin Street, Changchun, Jilin Province, China.
| | - Junqi Niu
- Department of Hepatology, Center of Infectious Disease and Pathogen Biology, The First Hospital of Jilin University, Changchun, China.
| | - Yanhua Ding
- Phase I Clinical Research Center, The First Hospital of Jilin University, No. 1 Xinmin Street, Changchun, Jilin Province, China.
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19
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Liang Z, Tan Y, Huang Y, Liang T, Wei W, Wang M, Shi K. Design and Synthesis of (3-Phenylisoxazol-5-yl)methanimine Derivatives as Hepatitis B Virus Inhibitors. Chem Biodivers 2023; 20:e202201247. [PMID: 36811262 DOI: 10.1002/cbdv.202201247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Accepted: 02/09/2023] [Indexed: 02/24/2023]
Abstract
Series of (3-phenylisoxazol-5-yl)methanimine derivatives were synthesized, and evaluated for anti-hepatitis B virus (HBV) activity in vitro. Half of them more effectively inhibited HBsAg than 3TC, and more favor to inhibit secretion of HBeAg than to HBsAg. Part of the compounds with significant inhibition on HBeAg were also effectively inhibit replication of HBV DNA. Compound (E)-3-(4-fluorophenyl)-5-((2-phenylhydrazineylidene)methyl)isoxazole inhibited excellently HBeAg with IC50 in 0.65 μM (3TC(Lamivudine) in 189.90 μM), inhibited HBV DNA in 20.52 μM (3TC in 26.23 μM). Structures of compounds were determined by NMR and HRMS methods, and chlorination on phenyl ring of phenylisoxazol-5-yl was confirmed by X-ray diffraction analysis, and the structure-activity relationships (SARs) of the derivatives was discussed. This work provided a new class of potent non-nucleoside anti-HBV agents.
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Affiliation(s)
- Zhengcheng Liang
- College of Chemistry and Chemical Engineering, Guangxi University, 530004, Nanning, China
| | - Yongqing Tan
- College of Chemistry and Chemical Engineering, Guangxi University, 530004, Nanning, China
| | - Yunhou Huang
- College of Chemistry and Chemical Engineering, Guangxi University, 530004, Nanning, China
| | - Taoyuan Liang
- College of Chemistry and Chemical Engineering, Guangxi University, 530004, Nanning, China
| | - Wanxing Wei
- College of Chemistry and Chemical Engineering, Guangxi University, 530004, Nanning, China
| | - Mian Wang
- College of Life Sciences, Guangxi University, 530004, Nanning, China
| | - Kaichuang Shi
- Guangxi Center for Animal Disease Control and Prevention, 530001, Nanning, China
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20
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Durantel D. Therapies against chronic hepatitis B infections: The times they are a-changin', but the changing is slow! Antiviral Res 2023; 210:105515. [PMID: 36603773 DOI: 10.1016/j.antiviral.2022.105515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 12/22/2022] [Indexed: 01/04/2023]
Abstract
PREAMBULAR NOTA BENE As a tribute to Dr Mike Bray, the following review of literature willbe mainly based on published data andconcepts, but will also contain my personal views, and in this respect could be more considered as a bioassay. Even though a cost-effective and excellent prophylactic vaccine exists since many years to protect against hepatitis B virus (HBV) infection, academic-researcher/drug-developers/stakeholders are still busy with the R&D of novel therapies that could eventually have an impact on its worldwide incidence. The Taiwanese experience have univocally demonstrated the effectiveness of constrained national HBV prophylactic vaccination programs to prevent the most dramatic HBV-induced end-stage liver disease, which is hepatocellular carcinoma; but yet the number of individuals chronically infected with the virus, for whom the existing prophylactic vaccine is no longer useful, remains high, with around 300 million individuals around the globe. In this review/bioassay, recent findings and novel concepts on prospective therapies against HBV infections will be discussed; yet it does not have the pretention to be exhaustive, as "pure immunotherapeutic concepts" will be mainly let aside (or referred to other reviews) due to a lack of expertise of this writer, but also due to the lack of, or incremental, positive results in clinical trials as-off today with these approaches.
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Affiliation(s)
- David Durantel
- Centre International de Recherche en Infectiologie (CIRI), INSERM U1111, UMR_5308 CNRS-Université de Lyon (UCBL1), ENS de Lyon, Lyon, 69007, France.
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21
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Wang S, Ren Y, Li Q, Wang Y, Jiang X, Xu S, Zhang X, Zhao S, Bradley DP, Woodson ME, Zhao F, Wu S, Li Y, Tian Y, Liu X, Tavis JE, Zhan P. Design, synthesis, and biological evaluation of novel sulfamoylbenzamide derivatives as HBV capsid assembly modulators. Bioorg Chem 2022; 129:106192. [PMID: 36265355 PMCID: PMC10591450 DOI: 10.1016/j.bioorg.2022.106192] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 09/25/2022] [Accepted: 10/01/2022] [Indexed: 11/02/2022]
Abstract
Capsid assembly modulators (CAMs) represent a novel class of antiviral agents targeting hepatitis B virus (HBV) capsid to disrupt the assembly process. NVR 3-778 is the first CAM to demonstrate antiviral activity in patients infected with HBV. However, the relatively low aqueous solubility and moderate activity in the human body halted further development of NVR 3-778. To improve the anti-HBV activity and the drug-like properties of NVR 3-778, we designed and synthesized a series of NVR 3-778 derivatives. Notably, phenylboronic acid-bearing compound 7b (EC50 = 0.83 ± 0.33 µM, CC50 = 19.4 ± 5.0 µM) displayed comparable anti-HBV activity to NVR 3-778 (EC50 = 0.73 ± 0.20 µM, CC50 = 23.4 ± 7.0 µM). Besides, 7b showed improved water solubility (328.8 µg/mL, pH 7) compared to NVR 3-778 (35.8 µg/mL, pH 7). Size exclusion chromatography (SEC) and quantification of encapsidated viral RNA were used to demonstrate that 7b behaves as a class II CAM similar to NVR 3-778. Moreover, molecular dynamics (MD) simulations were conducted to rationalize the structure-activity relationships (SARs) of these novel derivatives and to understand their key interactions with the binding pocket, which provide useful indications for guiding the further rational design of more effective anti-HBV drugs.
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Affiliation(s)
- Shuo Wang
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012 Jinan, Shandong, PR China
| | - Yujie Ren
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012 Jinan, Shandong, PR China
| | - Qilan Li
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, 1100, S. Grand Blvd, St. Louis, MO 63104, USA
| | - Ya Wang
- CAMS Key Laboratory of Antiviral Drug Research, Beijing Key Laboratory of Antimicrobial Agents, NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, 100050 Beijing, PR China
| | - Xiangyi Jiang
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012 Jinan, Shandong, PR China
| | - Shujing Xu
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012 Jinan, Shandong, PR China
| | - Xujie Zhang
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012 Jinan, Shandong, PR China
| | - Shujie Zhao
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012 Jinan, Shandong, PR China
| | - Daniel P Bradley
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, 1100, S. Grand Blvd, St. Louis, MO 63104, USA
| | - Molly E Woodson
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, 1100, S. Grand Blvd, St. Louis, MO 63104, USA
| | - Fabao Zhao
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012 Jinan, Shandong, PR China
| | - Shuo Wu
- CAMS Key Laboratory of Antiviral Drug Research, Beijing Key Laboratory of Antimicrobial Agents, NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, 100050 Beijing, PR China
| | - Yuhuan Li
- CAMS Key Laboratory of Antiviral Drug Research, Beijing Key Laboratory of Antimicrobial Agents, NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, 100050 Beijing, PR China
| | - Ye Tian
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012 Jinan, Shandong, PR China
| | - Xinyong Liu
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012 Jinan, Shandong, PR China.
| | - John E Tavis
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, 1100, S. Grand Blvd, St. Louis, MO 63104, USA.
| | - Peng Zhan
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012 Jinan, Shandong, PR China.
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22
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Liang Z, Huang Y, Li H, Zhang X, Shi K, Zang N, Wang M, Liang T, Wei W. Synthesis and evaluation of 3-phenylisoxazoline derivatives as non-nucleoside hepatitis B virus inhibitors. Tetrahedron 2022. [DOI: 10.1016/j.tet.2022.133177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022]
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23
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Unsal Tan O, Moncol J, Durantel D. Design, Synthesis and Evaluation of Novel 4‐(4‐Chlorobenzyl)‐6‐methylpyridazin‐3(2
H
)‐one Derivatives as Hepatitis B Virus Inhibitors. ChemistrySelect 2022. [DOI: 10.1002/slct.202203164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Affiliation(s)
- Oya Unsal Tan
- Department of Pharmaceutical Chemistry Faculty of Pharmacy Hacettepe University Ankara Turkey
| | - Jan Moncol
- Department of Inorganic Chemistry Faculty of Chemical and Food Technology Slovak University of Technology Bratislava Slovakia
| | - David Durantel
- INSERM U1052 Cancer Research Center of Lyon (CRCL) University of Lyon (UCBL1) CNRS UMR 5286, Centre Léon Bérard 69008 Lyon France
- INSERM U1111 International Center for Infectiology Research (CIRI) CNRS UMR_5308 University of Lyon (UCBL1) Lyon France
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24
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Ji X, Jiang X, Kobayashi C, Ren Y, Hu L, Gao Z, Kang D, Jia R, Zhang X, Zhao S, Watashi K, Liu X, Zhan P. Design, Synthesis, and Evaluation of a Set of Carboxylic Acid and Phosphate Prodrugs Derived from HBV Capsid Protein Allosteric Modulator NVR 3-778. Molecules 2022; 27:molecules27185987. [PMID: 36144715 PMCID: PMC9505734 DOI: 10.3390/molecules27185987] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 09/04/2022] [Accepted: 09/10/2022] [Indexed: 11/22/2022] Open
Abstract
Hepatitis B virus (HBV) capsid protein (Cp) is necessary for viral replication and the maintenance of viral persistence, having become an attractive target of anti-HBV drugs. To improve the water solubility of HBV capsid protein allosteric modulator (CpAM) NVR 3-778, a series of novel carboxylic acid and phosphate prodrugs were designed and synthesized using a prodrug strategy. In vitro HBV replication assay showed that these prodrugs maintained favorable antiviral potency (EC50 = 0.28−0.42 µM), which was comparable to that of NVR 3-778 (EC50 = 0.38 µM). More importantly, the cytotoxicity of prodrug N8 (CC50 > 256 µM) was significantly reduced compared to NVR 3-778 (CC50 = 13.65 ± 0.21 µM). In addition, the water solubility of prodrug N6 was hundreds of times better than that of NVR 3-778 in three phosphate buffers with various pH levels (2.0, 7.0, 7.4). In addition, N6 demonstrated excellent plasma and blood stability in vitro and good pharmacokinetic properties in rats. Finally, the hemisuccinate prodrug N6 significantly improved the candidate drug NVR 3-778’s water solubility and increased metabolic stability while maintaining its antiviral efficacy.
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Affiliation(s)
- Xiangkai Ji
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, Jinan 250012, China
| | - Xiangyi Jiang
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, Jinan 250012, China
| | - Chisa Kobayashi
- Department of Virology II, National Institute of Infectious Diseases, Tokyo 163-8001, Japan
- Department of Applied Biological Science, Tokyo University of Science, Noda 278-8510, Japan
| | - Yujie Ren
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, Jinan 250012, China
| | - Lide Hu
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, Jinan 250012, China
| | - Zhen Gao
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, Jinan 250012, China
| | - Dongwei Kang
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, Jinan 250012, China
| | - Ruifang Jia
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, Jinan 250012, China
| | - Xujie Zhang
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, Jinan 250012, China
| | - Shujie Zhao
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, Jinan 250012, China
| | - Koichi Watashi
- Department of Virology II, National Institute of Infectious Diseases, Tokyo 163-8001, Japan
- Department of Applied Biological Science, Tokyo University of Science, Noda 278-8510, Japan
- Research Center for Drug and Vaccine Development, National Institute of Infectious Diseases, Tokyo 163-8001, Japan
- Correspondence: (K.W.); (X.L.); (P.Z.)
| | - Xinyong Liu
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, Jinan 250012, China
- Correspondence: (K.W.); (X.L.); (P.Z.)
| | - Peng Zhan
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, Jinan 250012, China
- Correspondence: (K.W.); (X.L.); (P.Z.)
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25
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Chen D, Tan X, Chen W, Liu Y, Li C, Wu J, Zheng J, Shen HC, Zhang M, Wu W, Wang L, Xiong J, Dai J, Sun K, Zhang JD, Xiang K, Li B, Ni X, Zhu Q, Gao L, Wang L, Feng S. Discovery of Novel cccDNA Reducers toward the Cure of Hepatitis B Virus Infection. J Med Chem 2022; 65:10938-10955. [PMID: 35973101 DOI: 10.1021/acs.jmedchem.1c02215] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Chronic hepatitis B virus (HBV) infection is a worldwide disease that causes thousands of deaths per year. Currently, there is no therapeutic that can completely cure already infected HBV patients due to the inability of humans to eliminate covalently closed circular DNA (cccDNA), which serves as the template to (re)initiate an infection even after prolonged viral suppression. Through phenotypic screening, we discovered xanthone series hits as novel HBV cccDNA reducers, and subsequent structure optimization led to the identification of a lead compound with improved antiviral activity and pharmacokinetic profiles. A representative compound 59 demonstrated good potency and oral bioavailability with no cellular toxicity. In an HBVcircle mouse model, compound 59 showed excellent efficacy in significantly reducing HBV antigens, DNA, and intrahepatic cccDNA levels.
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Affiliation(s)
- Dongdong Chen
- Department of Medicinal Chemistry, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
| | - Xuefei Tan
- Department of Medicinal Chemistry, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
| | - Wenming Chen
- Department of Medicinal Chemistry, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
| | - Yongfu Liu
- Department of Medicinal Chemistry, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
| | - Chao Li
- Department of Medicinal Chemistry, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
| | - Jun Wu
- Department of Medicinal Chemistry, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
| | - Jiamin Zheng
- Department of Medicinal Chemistry, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
| | - Hong C Shen
- Department of Medicinal Chemistry, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
| | - Meifang Zhang
- Lead Discovery, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
| | - Waikwong Wu
- Lead Discovery, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
| | - Lin Wang
- pCMC, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
| | - Jing Xiong
- pCMC, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
| | - Jieyu Dai
- Pharmaceutical Sciences, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
| | - Kai Sun
- Pharmaceutical Sciences, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
| | - Jitao David Zhang
- Pharmaceutical Science, Roche Innovation Center Basel, Roche Pharma Research & Early Development, Grenzacherstrasse 124, Basel CH-4070, Switzerland
| | - Kunlun Xiang
- Discovery Virology, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
| | - Baocun Li
- Discovery Virology, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
| | - XiaoJu Ni
- Discovery Virology, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
| | - Qihui Zhu
- Discovery Virology, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
| | - Lu Gao
- Discovery Virology, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
| | - Li Wang
- Discovery Virology, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
| | - Song Feng
- Department of Medicinal Chemistry, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China
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26
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Desmares M, Delphin M, Chardès B, Pons C, Riedinger J, Michelet M, Rivoire M, Verrier B, Salvetti A, Lucifora J, Durantel D. Insights on the antiviral mechanisms of action of the TLR1/2 agonist Pam3CSK4 in hepatitis B virus (HBV)-infected hepatocytes. Antiviral Res 2022; 206:105386. [PMID: 35963549 DOI: 10.1016/j.antiviral.2022.105386] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 07/20/2022] [Accepted: 07/23/2022] [Indexed: 12/31/2022]
Abstract
OBJECTIVES Pegylated-interferon-alpha (Peg-IFNα), an injectable innate immune protein, is still used to treat chronically HBV-infected patients, despite its poor tolerability. Peg-IFNα has the advantage over nucleos(t)ide analogues (NAs) to be administrated in finite regimen and to lead to a higher HBsAg loss rate. Yet it would be interesting to improve the efficacy (i.e. while decreasing doses), or replace, this old medicine by novel small molecules/stimulators able to engage innate immune receptors in both HBV replicating hepatocytes and relevant innate immune cells. We have previously identified the Toll-Like-Receptor (TLR)-2 agonist Pam3CSK4 as such a potential novel immune stimulator. The aim of this study was to gain insights on the antiviral mechanisms of action of this agonist in in vitro cultivated human hepatocytes. DESIGN We used in vitro models of HBV-infected cells, based on both primary human hepatocytes (PHH) and the non-transformed HepaRG cell line to investigate the MoA of Pam3SCK4 and identify relevant combinations with other approved or investigational drugs. RESULTS We exhaustively described the inhibitory anti-HBV phenotypes induced by Pam3CSK4, which include a strong decrease in HBV RNA production (inhibition of synthesis and acceleration of decay) and cccDNA levels. We confirmed the long-lasting anti-HBV activity of this agonist, better described the kinetics of antiviral events, and demonstrated the specificity of action through the TLR1/2- NF-κB canonical-pathway. Moreover, we found that FEN-1 could be involved in the regulation and inhibitory phenotype on cccDNA levels. Finally, we identified the combination of Pam3CSK4 with IFNα or an investigational kinase inhibitor (called 1C8) as valuable strategies to reduce cccDNA levels and obtain a long-lasting anti-HBV effect in vitro. CONCLUSIONS TLR2 agonists represent possible assets to improve the rate of HBV cure in patients. Further evaluations, including regulatory toxicity studies, are warranted to move toward clinical trials.
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Affiliation(s)
- Manon Desmares
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
| | - Marion Delphin
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
| | - Brieux Chardès
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
| | - Caroline Pons
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France; INSERM, U1111, Centre International de Recherche en Infectiologie (CIRI), University of Lyon (UCBL1), CNRS UMR_5308, ENS de Lyon, Lyon, France
| | - Juliette Riedinger
- INSERM, U1111, Centre International de Recherche en Infectiologie (CIRI), University of Lyon (UCBL1), CNRS UMR_5308, ENS de Lyon, Lyon, France
| | - Maud Michelet
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
| | | | - Bernard Verrier
- Laboratoire de Biologie Tissulaire et Ingénierie Thérapeutique, CNRS UMR_5305, University of Lyon (UCBL1), Lyon, France
| | - Anna Salvetti
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France; INSERM, U1111, Centre International de Recherche en Infectiologie (CIRI), University of Lyon (UCBL1), CNRS UMR_5308, ENS de Lyon, Lyon, France
| | - Julie Lucifora
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France; INSERM, U1111, Centre International de Recherche en Infectiologie (CIRI), University of Lyon (UCBL1), CNRS UMR_5308, ENS de Lyon, Lyon, France
| | - David Durantel
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France; INSERM, U1111, Centre International de Recherche en Infectiologie (CIRI), University of Lyon (UCBL1), CNRS UMR_5308, ENS de Lyon, Lyon, France.
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Li S, Li N, Yang S, Deng H, Li Y, Wang Y, Yang J, Lv J, Dong L, Yu G, Hou X, Wang G. The study of immune checkpoint inhibitors in chronic hepatitis B virus infection. Int Immunopharmacol 2022; 109:108842. [DOI: 10.1016/j.intimp.2022.108842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 04/19/2022] [Accepted: 05/04/2022] [Indexed: 11/09/2022]
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Bhat S, Kazim SN. HBV cccDNA-A Culprit and Stumbling Block for the Hepatitis B Virus Infection: Its Presence in Hepatocytes Perplexed the Possible Mission for a Functional Cure. ACS OMEGA 2022; 7:24066-24081. [PMID: 35874215 PMCID: PMC9301636 DOI: 10.1021/acsomega.2c02216] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/17/2023]
Abstract
Hepatitis B virus infection (HBV) is still a big health problem across the globe. It has been linked to the development of liver cirrhosis and hepatocellular carcinoma and can trigger different types of liver damage. Existing medicines are unable to disable covalently closed circular DNA (cccDNA), which may result in HBV persistence and recurrence. The current therapeutic goal is to achieve a functional cure, which means HBV-DNA no longer exists when treatment stops and the absence of HBsAg seroclearance. However, due to the presence of integrated HBV DNA and cccDNA functional treatment is now regarded to be difficult. In order to uncover pathways for potential therapeutic targets and identify medicines that could result in large rates of functional cure, a thorough understanding of the virus' biology is required. The proteins of the virus and episomal cccDNA are thought to be critical for the management and support of the HBV replication cycle as they interact directly with the host proteome to establish the best atmosphere for the virus while evading immune detection. The breakthroughs of host dependence factors, cccDNA transcription, epigenetic regulation, and immune-mediated breakdown have all produced significant progress in our understanding of cccDNA biology during the past decade. There are some strategies where cccDNA can be targeted either in a direct or indirect way and are presently at the point of discovery or preclinical or early clinical advancement. Editing of genomes, techniques targeting host dependence factors or epigenetic gene maintenance, nucleocapsid modulators, miRNA, siRNA, virion secretory inhibitors, and immune-mediated degradation are only a few examples. Though cccDNA approaches for direct targeting are still in the early stages of development, the assembly of capsid modulators and immune-reliant treatments have made it to the clinic. Clinical trials are currently being conducted to determine their efficiency and safety in patients, as well as their effect on viral cccDNA. The influence of recent breakthroughs in the development of new treatment techniques on cccDNA biology is also summarized in this review.
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Affiliation(s)
- Sajad
Ahmad Bhat
- Jamia Millia Islamia Central University, Centre for Interdisciplinary Research in Basic Sciences, New Delhi 110025, India
| | - Syed Naqui Kazim
- Jamia Millia Islamia Central University, Centre for Interdisciplinary Research in Basic Sciences, New Delhi 110025, India
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29
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Zhou H, Wang X, Steer CJ, Song G, Niu J. Efficient silencing of hepatitis B virus S gene through CRISPR-mediated base editing. Hepatol Commun 2022; 6:1652-1663. [PMID: 35338607 PMCID: PMC9234685 DOI: 10.1002/hep4.1933] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 02/06/2022] [Accepted: 02/13/2022] [Indexed: 12/11/2022] Open
Abstract
Hepatitis B virus (HBV) infection is a major risk factor of liver cirrhosis and hepatocellular carcinoma. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) has been used to precisely edit the HBV genome and eliminate HBV through non-homologous end-joining repair of double-stranded break (DSB). However, the CRISPR/Cas9-mediated DSB triggers instability of host genome and exhibits low efficiency to edit genome, limiting its application. CRISPR cytidine base editors (CBEs) could silence genes by generating a premature stop codon. Here we developed a CRISPR base editor approach to precisely edit single nucleotide within the HBV genome to impair HBV gene expression. Specifically, a single-guide RNA (sgRNA) was designed to edit the 30th codon of HBV S gene, which encodes HBV surface antigen (HBsAg), from CAG (glutamine) to stop codon TAG. We next used human hepatoma PLC/PRF/5 cells carrying the HBV genome to establish a cell line that expresses a CBE (PLC/PRF/5-CBE). Lentivirus was used to introduce sgRNA into PLC/PRF/5-CBE cells. Phenotypically, 71% of PLC/PRF/5-CBE cells developed a premature stop codon within the S gene. Levels of HBs messenger RNA were significantly decreased. A 92% reduction of HBsAg secretion was observed in PLC/PRF/5-CBE cells. The intracellular HBsAg was also reduced by 84% after treatment of gRNA_S. Furthermore, no off-target effect was detected in predicted off-target loci within the HBV genome. Sequencing confirmed that 95%, 93%, 93%, 9%, and 72% S gene sequences of HBV genotypes B, C, F, G, and H had the binding site of sgRNA. Conclusion: Our findings indicate that CRISPR-mediated base editing is an efficient approach to silence the HBV S gene, suggesting its therapeutic potential to eliminate HBV.
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Affiliation(s)
- Hao Zhou
- Department of HepatologyThe First Hospital of Jilin UniversityChangchunChina
- Department of MedicineUniversity of Minnesota Medical SchoolMinneapolisMinnesotaUSA
| | - Xiaomei Wang
- Department of HepatologyThe First Hospital of Jilin UniversityChangchunChina
- Department of MedicineUniversity of Minnesota Medical SchoolMinneapolisMinnesotaUSA
| | - Clifford J. Steer
- Department of MedicineUniversity of Minnesota Medical SchoolMinneapolisMinnesotaUSA
| | - Guisheng Song
- Department of MedicineUniversity of Minnesota Medical SchoolMinneapolisMinnesotaUSA
| | - Junqi Niu
- Department of HepatologyThe First Hospital of Jilin UniversityChangchunChina
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30
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Proliferation of CD11b+ myeloid cells induced by TLR4 signaling promotes hepatitis B virus clearance. Cytokine 2022; 153:155867. [PMID: 35390759 DOI: 10.1016/j.cyto.2022.155867] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Revised: 02/10/2022] [Accepted: 03/14/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUNDS AND AIMS Effective immune response plays a key role in the clearance of hepatitis B virus (HBV). However, the specific role of innate immune response in the clearance of virus is still unclear. Here we investigated the effect of TLR4 signaling on the proliferation and differentiation of CD11b+ myeloid cells, which contributes to virus clearance. METHODS C57BL/6 mice were pretreated with TLR4 ligand lipopolysaccharide by intraperitoneal injection. Hydrodynamic injection (HI) was performed to establish HBV-replicated mice. The viremia was monitored. The immune cells were isolated from liver and spleen of the mice. The proliferation and differentiation of CD11b+ myeloid cells were analyzed by flow cytometry. The changes of CD11b+ myeloid cells and its role in virus clearance during HBV infection after LPS stimulation were analyzed. RESULTS LPS stimulation induced the proliferation of CD11b+ myeloid cells which differentiated into neutrophils and inflammatory mononuclear macrophages. The expression of F4/80 protein on the surface of mononuclear macrophages in the liver of LPS-stimulated mice was significantly lower than that of control. It indicated that intrahepatic Kupffer cells were significantly decreased in the LPS-stimulated mice, which promoted the clearance of virus. CONCLUSION LPS stimulation induces the proliferation of CD11b+ myeloid cells that differentiate into inflammatory neutrophils and monocytes, which inhibits HBV replication. And the decrease of intrahepatic Kupffer cells also contributes to the clearance of HBV during HBV infection.
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31
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Li J, Yu M, Zong R, Fan C, Ren F, Wu W, Li C. Deacetylation of Notch1 by SIRT1 contributes to HBsAg- and HBeAg-mediated M2 macrophage polarization. Am J Physiol Gastrointest Liver Physiol 2022; 322:G459-G471. [PMID: 35234049 DOI: 10.1152/ajpgi.00338.2021] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Hepatic macrophages are involved in both pathogen clearance and immunopathogenesis. Emerging evidence demonstrates that macrophage polarization plays a critical role in hepatitis B virus (HBV)-induced immune impairment and liver pathology. However, it remains largely unknown as to how HBV infection facilitates M2 macrophage polarization. Here, a mouse HBV infection model was established by hydrodynamic injection with a vector containing 1.3-fold overlength HBV genome via the tail vein. Coculture experiments with HBV-producing HepG2.2.15 cells and macrophages were established in vitro. We found that HBV-inhibited M1 while enhancing M2 markers, which was accompanied by decreased proinflammatory tumor necrosis factor-α (TNF-α) and augmented anti-inflammatory IL-10 expression. Furthermore, both hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) secretion contributed to HBV-triggered macrophage polarization from M1 toward M2 phenotype. Mechanistically, HBsAg and HBeAg could upregulate the sirtuins 1 (SIRT1) deacetylase expression, which in turn promote deacetylation of the Notch1 intracellular domain (NICD), leading to increased Akt phosphorylation and decreased NF-κB nuclear translocation in macrophages. Our findings suggest that NICD deacetylation by SIRT1 contributes to HBsAg- and HBeAg-mediated M2 macrophage polarization, raising the possibility of targeting SIRT1/Notch1 pathway in macrophages to treat HBV immune evasion and chronic HBV infection.NEW & NOTEWORTHY This study identified a previously unrecognized molecular mechanism of HBV-mediated suppression of innate immune responses. We demonstrate that deacetylation of NICD by SIRT1 contributes to HBsAg- and HBeAg-mediated M2 macrophage polarization, which may aid in the development of new macrophage-based immunotherapy for chronic HBV infection and related diseases.
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Affiliation(s)
- Jiahui Li
- Department of Anatomy and Histology Embryology, Jinzhou Medical University, Jinzhou, People's Republic of China.,Department of Physiology, School of Basic Medical Sciences, Wuhan University, Wuhan, People's Republic of China.,Department of Anatomy, Youjiang Medical University for Nationalities, Baise, People's Republic of China
| | - Mengxue Yu
- Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, People's Republic of China.,Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Wuhan University, Wuhan, People's Republic of China
| | - Ruobin Zong
- Department of Physiology, School of Basic Medical Sciences, Wuhan University, Wuhan, People's Republic of China
| | - Chengpeng Fan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Wuhan University, Wuhan, People's Republic of China
| | - Fu Ren
- Department of Anatomy, Shenyang Medical College, Shenyang, People's Republic of China
| | - Wei Wu
- Institute of Humanities and Social Sciences, Shenyang University, Shenyang, People's Republic of China
| | - Changyong Li
- Department of Physiology, School of Basic Medical Sciences, Wuhan University, Wuhan, People's Republic of China
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32
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Su X, Zheng L, Zhang H, Shen T, Liu Y, Hu X. Secular Trends of Acute Viral Hepatitis Incidence and Mortality in China, 1990 to 2019 and Its Prediction to 2030: The Global Burden of Disease Study 2019. Front Med (Lausanne) 2022; 9:842088. [PMID: 35360747 PMCID: PMC8962367 DOI: 10.3389/fmed.2022.842088] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 02/21/2022] [Indexed: 11/13/2022] Open
Abstract
Background Understanding the patterns and trends in the context of both incidence and mortality and anticipating future trends is important for viral hepatitis prevention, treatment, and guiding resource allocation in China. The objective of this study is to provide a comprehensive temporal analysis of acute viral hepatitis and its type using the most updated data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD 2019) to estimate the incidence and mortality of hepatitis from 1990 to 2019 and make predictions to 2030. Methods The age-standardized incidence (ASIR) and mortality rate (ASMR) of viral hepatitis in China were obtained from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD 2019). Trends of ASIR and ASMR for viral hepatitis were plotted using locally weighted regression (LOESS). We used joinpoint regression analysis to detect temporal changes and estimate the annual percent of change (APC) of each trend segment and the corresponding 95% confidence interval (CI). A Bayesian age-period-cohort analysis was employed to describe ASIR and ASMR trends between 1990 and 2019 and projections to 2030. Results In 1990, there were 67 million incident cases of acute viral hepatitis, which then decreased to 47 million incidence cases in 2019. Hepatitis A and hepatitis B account for the majority of acute viral hepatitis, and the most pronounced declines in hepatitis B (−48.7%) and hepatitis C (−39.0%) were observed between 1990 and 2019. The ASIR of overall acute viral hepatitis shows a persistent decline, with an average annual percent of change (AAPC) of −1.9% (95% CI: −1.9, −1.8) between 1990 and 2019. The trend of ASMR demonstrated a rapid decline between 1990 and 2005, followed by a slow decline until 2030. Conclusion Our study reveals favorable declining trends of incidence and mortality for acute viral hepatitis in China from 1990 and 2019, and these favorable trends are predicted to continue up to 2030. Despite the favorable trends observed, the absolute number of viral hepatitis, especially hepatitis A and B, is still substantial in China. A scaled-up vaccine campaign is still needed to tackle the large number of vaccine preventable hepatitis infections.
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33
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Hui RWH, Mak LY, Seto WK, Yuen MF. RNA interference as a novel treatment strategy for chronic hepatitis B infection. Clin Mol Hepatol 2022; 28:408-424. [PMID: 35172540 PMCID: PMC9293617 DOI: 10.3350/cmh.2022.0012] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 02/16/2022] [Indexed: 11/26/2022] Open
Abstract
Chronic hepatitis B (CHB) is a major cause of liver-related morbidity and mortality. Functional cure of CHB, defined as sustainable hepatitis B surface antigen (HBsAg) seroclearance, is associated with improved clinical outcomes. However, functional cure is rarely attainable by current treatment modalities. RNA interference (RNAi) by small-interfering RNA (siRNA) and anti-sense oligonucleotide (ASO) has been studied as a novel treatment strategy for CHB. RNAi targets post-transcriptional messenger RNAs and pregenomic RNAs to reduce hepatitis B virus (HBV) antigen production and viral replication. By reducing viral antigens, host immune reconstitution against HBV may also be attained. Phase I/II trials on siRNAs have demonstrated them to be safe and well-tolerated. siRNA is effective when given in monthly doses with different total number of doses according to different trial design, and can lead to sustainable dose-dependent mean HBsAg reduction by 2–2.5 log. Incidences of HBsAg seroclearance after siRNA therapy have also been reported. ASOs have also been studied in early phase trials, and a phase Ib study using frequent dosing regimen within 4 weeks could achieve similar HBsAg reduction of 2 log from baseline. Given the established efficacy and safety of nucleos(t) ide analogues (NAs), future RNAi regimens will likely include NA backbone. While the current evidence on RNAi appears promising, it remains undetermined whether the potent HBsAg reduction by RNAi can result in a high rate of HBsAg seroclearance with durability. Data on RNAi from phase IIb/III trials are keenly anticipated.
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Affiliation(s)
- Rex Wan-Hin Hui
- Department of Medicine, The University of Hong Kong, Hong Kong
| | - Lung-Yi Mak
- Department of Medicine, The University of Hong Kong, Hong Kong.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Wai-Kay Seto
- Department of Medicine, The University of Hong Kong, Hong Kong.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Man-Fung Yuen
- Department of Medicine, The University of Hong Kong, Hong Kong.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
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Zhao Q, Song SY, Zhang YQ, Ren X, Zhang P, Li X, Fu XM, Wang CY. The underlying mechanisms of anti-hepatitis B effects of formula Le-Cao-Shi and its single herbs by network pharmacology and gut microbiota analysis. Biomed Pharmacother 2022; 148:112692. [PMID: 35151160 DOI: 10.1016/j.biopha.2022.112692] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 01/27/2022] [Accepted: 02/02/2022] [Indexed: 12/14/2022] Open
Abstract
Formula Le-Cao-Shi (LCS), a traditional Chinese medicine (TCM), has been used as folk remedy for treating hepatitis B for a long time. In our previous study, the anti-hepatitis B effects of LCS have been verified. In the present study, the anti-hepatitis B activities of LCS and its three single herbs were investigated in vitro by HepG2.2.15 cellular model, and the mechanisms against hepatitis B were deciphered via network pharmacology and gut microbiota analysis. By network pharmacology method, twelve key compounds that played a vital role in LCS were filtered from 213 ingredients. The targets RORA, CDK2, RELA, AKT1, IKBKG, PRKCβ and CASP3 were directly related to hepatitis B pathway, which indicated that LCS could exert anti-hepatitis B effect by co-regulating cell cycle and inflammatory pathways. The interactions between candidate compounds and target proteins that were directly involved in hepatitis B pathway were validated by molecular docking simulation and RT-PCR. By gut microbiota analysis, it was revealed that LCS could alter the disordered microbial composition in the infected ducks towards normal, especially the restoration of three key strains, namely Streptococcus alactolyticus, Enterococcus cecorum and Bacteroides fragilis. The above findings could provide a scientific basis for further development and utilization of LCS against hepatitis B.
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Affiliation(s)
- Qing Zhao
- Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, PR China; Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, PR China
| | - Shu-Yue Song
- Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, PR China; Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, PR China
| | - Yu-Qi Zhang
- Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, PR China; Center for Innovation Marine Drug Screening & Evaluation of Pilot National Laboratory for Marine Science and Technology, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266071, PR China
| | - Xia Ren
- Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, PR China; Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, PR China
| | - Peng Zhang
- Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, PR China; Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, PR China
| | - Xin Li
- Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, PR China; Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, PR China
| | - Xiu-Mei Fu
- Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, PR China; Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, PR China; College of Economics, Ocean University of China, Qingdao 266100, PR China
| | - Chang-Yun Wang
- Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, PR China; Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, PR China.
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Wei J, Shi Y, Zou C, Zhang H, Peng H, Wang S, Xia L, Yang Y, Zhang X, Liu J, Zhou H, Luo M, Huang A, Wang D. Cellular Id1 inhibits hepatitis B virus transcription by interacting with the novel covalently closed circular DNA-binding protein E2F4. Int J Biol Sci 2022; 18:65-81. [PMID: 34975318 PMCID: PMC8692152 DOI: 10.7150/ijbs.62106] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 10/05/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC), which required developing novel therapies targeting the inhibition of HBV transcription and replication due to current limited treatment options. We explored novel target for the development of novel therapies targeting the inhibition of HBV replication and transcription. The expression of Id1 and E2F4 in HCC cells and tissues was detected by qRT-PCR and western blot. We investigated the Id1 and E2F4-mediated transcription of HBV infection by using HepG2.2.15, HepAD38, HepG2-NTCP cell lines and AAV/HBV-infected mice. Interactions between the two host proteins and viral covalently closed circular DNA (cccDNA) were assessed using subcellular localization, protein-protein interaction, chromatin immunoprecipitation, and luciferase assays. Ectopic Id1 significantly reduced HBV transcription and replication in both HBV-expressing cells and AAV/HBV-infected mice. Id1 and E2F4 could form a heterodimer to prevent E2F4 from promoting HBV transcription and replication. E2F4 could directly bind to cccDNA and activate the HBV core promoter in cell lines. Furthermore, in vitro binding experiments confirmed that the sequence 1758'-TTAAAGGTC-1766', which is highly conserved among HBV genotypes, is the target site of the E2F4 homodimer. The findings suggest that E2F4 function as novel cccDNA-binding protein to directly activate HBV transcription by binding to Cp promoter region. Our results highlight the ability that E2F4 represent a pan-potential therapeutic target against HBV transcription and provide more clues to better understand the life cycle of HBV.
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Affiliation(s)
- Jie Wei
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China.,Department of Clinical Laboratory, Zhuhai People's Hospital (Zhuhai hospital affiliated with Jinan University), Zhuhai, Guangdong, 519000, China
| | - Yueyuan Shi
- College of Laboratory Medicine, Chongqing Medical University, Yuzhong, Chongqing, 400016, China.,Department of Clinical Laboratory, The People's Hospital of Yubei District of Chongqing City, Chongqing, 401120, China
| | - Chunhong Zou
- College of Laboratory Medicine, Chongqing Medical University, Yuzhong, Chongqing, 400016, China
| | - Hongpeng Zhang
- Department of Laboratory Medicine, Chongqing Health Center for Women and Children, Chongqing, China, 401147, China
| | - Hui Peng
- Division of Gastroenterology, Cedars-Sinai Medical Center, Los Angeles, California. Davis Bldg., Room 3094, 8700 Beverly Blvd., Los Angeles, CA 90048
| | - Shilei Wang
- College of Laboratory Medicine, Chongqing Medical University, Yuzhong, Chongqing, 400016, China
| | - Lulu Xia
- College of Laboratory Medicine, Chongqing Medical University, Yuzhong, Chongqing, 400016, China
| | - Yuan Yang
- College of Laboratory Medicine, Chongqing Medical University, Yuzhong, Chongqing, 400016, China
| | - Xiang Zhang
- College of Laboratory Medicine, Chongqing Medical University, Yuzhong, Chongqing, 400016, China
| | - Junye Liu
- College of Laboratory Medicine, Chongqing Medical University, Yuzhong, Chongqing, 400016, China
| | - Hua Zhou
- Department of Clinical Laboratory, The Second Affiliated Hospital of Chongqing Medical University, Yuzhong, Chongqing, 400010, China
| | - Miao Luo
- Department of Clinical Laboratory, The People's Hospital of Yubei District of Chongqing City, Chongqing, 401120, China
| | - Ailong Huang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
| | - Deqiang Wang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China.,College of Laboratory Medicine, Chongqing Medical University, Yuzhong, Chongqing, 400016, China
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Asrani P, Tiwari K, Eapen MS, McAlinden KD, Haug G, Johansen MD, Hansbro PM, Flanagan KL, Hassan MI, Sohal SS. Clinical features and mechanistic insights into drug repurposing for combating COVID-19. Int J Biochem Cell Biol 2022; 142:106114. [PMID: 34748991 PMCID: PMC8570392 DOI: 10.1016/j.biocel.2021.106114] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 10/24/2021] [Accepted: 11/01/2021] [Indexed: 02/07/2023]
Abstract
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged from Wuhan in China before it spread to the entire globe. It causes coronavirus disease of 2019 (COVID-19) where mostly individuals present mild symptoms, some remain asymptomatic and some show severe lung inflammation and pneumonia in the host through the induction of a marked inflammatory 'cytokine storm'. New and efficacious vaccines have been developed and put into clinical practice in record time, however, there is a still a need for effective treatments for those who are not vaccinated or remain susceptible to emerging SARS-CoV-2 variant strains. Despite this, effective therapeutic interventions against COVID-19 remain elusive. Here, we have reviewed potential drugs for COVID-19 classified on the basis of their mode of action. The mechanisms of action of each are discussed in detail to highlight the therapeutic targets that may help in reducing the global pandemic. The review was done up to July 2021 and the data was assessed through the official websites of WHO and CDC for collecting the information on the clinical trials. Moreover, the recent research papers were also assessed for the relevant data. The search was mainly based on keywords like Coronavirus, SARS-CoV-2, drugs (specific name of the drugs), COVID-19, clinical efficiency, safety profile, side-effects etc.This review outlines potential areas for future research into COVID-19 treatment strategies.
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Affiliation(s)
- Purva Asrani
- Department of Microbiology, University of Delhi, South Campus, New Delhi, India
| | - Keshav Tiwari
- ICAR - National Institute for Plant Biotechnology, New Delhi, India
| | - Mathew Suji Eapen
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, Australia
| | - Kielan Darcy McAlinden
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, Australia
| | - Greg Haug
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, Australia; Department of Respiratory Medicine, Launceston General Hospital, Launceston 7250, Australia
| | - Matt D Johansen
- Centre for Inflammation, Centenary Institute, Sydney, NSW 2050, Australia; University of Technology Sydney, Faculty of Science, School of Life Sciences, Ultimo, NSW 2007, Australia
| | - Philip M Hansbro
- Centre for Inflammation, Centenary Institute, Sydney, NSW 2050, Australia; University of Technology Sydney, Faculty of Science, School of Life Sciences, Ultimo, NSW 2007, Australia
| | - Katie L Flanagan
- Clinical School, College of Health and Medicine, University of Tasmania, Launceston, Tasmania 7250, Australia; School of Health and Biomedical Science, RMIT University, Melbourne, Victoria, Australia; Department of Immunology and Pathology, Monash University, Melbourne, Victoria, Australia; Tasmania Vaccine Trial Centre, Clifford Craig Foundation, Launceston General Hospital, Launceston, Tasmania 7250, Australia
| | - Md Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Sukhwinder Singh Sohal
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, Australia.
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Ma Y, Zhao S, Ren Y, Cherukupalli S, Li Q, Woodson ME, Bradley DP, Tavis JE, Liu X, Zhan P. Design, synthesis and evaluation of heteroaryldihydropyrimidine analogues bearing spiro ring as hepatitis B virus capsid protein inhibitors. Eur J Med Chem 2021; 225:113780. [PMID: 34438123 PMCID: PMC10591454 DOI: 10.1016/j.ejmech.2021.113780] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 08/03/2021] [Accepted: 08/13/2021] [Indexed: 01/22/2023]
Abstract
GLS4, a potent antiviral drug candidate, has been widely studied and entered into phase II clinical trials. Nevertheless, the therapeutic application of GLS4 is limited due to poor water solubility, short half-life, and low bioavailability. In order to improve the hydrophilicity and pharmacokinetic (PK) properties of GLS4, herein, we retained the dominant fragments, and used a scaffold hopping strategy to replace the easily metabolized morpholine ring of GLS4 with diverse sizes of spiro rings consisting of hydrogen bond donor and acceptor substituents. Potent in vitroanti-HBV activity and low cytotoxicity were observed for compound 4r (EC50 = 0.20 ± 0.00 μM, CC50 > 87.03 μM), which was more potent than the positive control lamivudine (EC50 = 0.37 ± 0.04 μM, CC50 > 100.00 μM) in this assay and was about a quarter as effective as GLS4 (EC50 = 0.045 ± 0.01 μM, CC50 > 99.20 μM). Preliminary structure-activity relationship (SAR) analysis and molecular docking studies were carried out to explore potential interactions and binding mode between compounds and target protein. In terms of the physicochemical properties, 4r was predicted to be consistent with the rule-of-five, which means 4r may have favourable absorption and permeation. Finally, ADMET and PK characteristics of 4r and GLS4 were predicted to be comparable in most aspects, implying that the two compounds may have similar profiles in vivo.
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Affiliation(s)
- Yue Ma
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China
| | - Shujie Zhao
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China
| | - Yujie Ren
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China
| | - Srinivasulu Cherukupalli
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China
| | - Qilan Li
- Department of Molecular Microbiology and Immunology, Doisy Research Center, Saint Louis University School of Medicine, 1100 S. Grand Blvd, St. Louis, MO, 63104, USA
| | - Molly E Woodson
- Department of Molecular Microbiology and Immunology, Doisy Research Center, Saint Louis University School of Medicine, 1100 S. Grand Blvd, St. Louis, MO, 63104, USA
| | - Daniel P Bradley
- Department of Molecular Microbiology and Immunology, Doisy Research Center, Saint Louis University School of Medicine, 1100 S. Grand Blvd, St. Louis, MO, 63104, USA
| | - John E Tavis
- Department of Molecular Microbiology and Immunology, Doisy Research Center, Saint Louis University School of Medicine, 1100 S. Grand Blvd, St. Louis, MO, 63104, USA.
| | - Xinyong Liu
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China.
| | - Peng Zhan
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China.
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38
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Armandi A, Rosso C, Ribaldone DG, Caviglia GP. Moving towards core antigen for the management of patients with overt and occult HBV infection. Panminerva Med 2021; 63:499-507. [PMID: 33073556 DOI: 10.23736/s0031-0808.20.04163-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Chronic Hepatitis B virus (HBV) infection encompasses a wide virologic and clinical spectrum with heterogeneous outcomes. The natural history of chronic HBV infection ranges from an inactive carrier state (hepatitis B e antigen-negative chronic infection) to progressive chronic hepatitis that may evolve in end-stage liver disease and hepatocellular carcinoma. The issue becomes even more complicated when we consider the unique biology of the virus; the HBV covalently-closed-circular DNA, that acts as virus transcription template, is the key factor responsible of the persistence of the infection even after hepatitis B surface antigen loss. In the last decade, novel serological and immunological biomarkers associated to the core protein of HBV have been approached in different clinical conditions. Remarkable results have been obtained both in the setting of overt and occult HBV infection. Here, we reviewed the meaning and the potential clinical applications of the measurement of core antigen and antibodies.
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Affiliation(s)
- Angelo Armandi
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Chiara Rosso
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Davide G Ribaldone
- Department of Medical Sciences, University of Turin, Turin, Italy
- Division of Gastroenterology, Molinette Hospital, Città della Salute e della Scienza, Turin, Italy
| | - Gian P Caviglia
- Department of Medical Sciences, University of Turin, Turin, Italy -
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39
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Delphin M, Desmares M, Schuehle S, Heikenwalder M, Durantel D, Faure-Dupuy S. How to get away with liver innate immunity? A viruses' tale. Liver Int 2021; 41:2547-2559. [PMID: 34520597 DOI: 10.1111/liv.15054] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 08/20/2021] [Accepted: 09/08/2021] [Indexed: 12/24/2022]
Abstract
In their never-ending quest towards persistence within their host, hepatitis viruses have developed numerous ways to counteract the liver innate immunity. This review highlights the different and common mechanisms employed by these viruses to (i) establish in the liver (passive entry or active evasion from immune recognition) and (ii) actively inhibit the innate immune response (ie modulation of pattern recognition receptor expression and/or signalling pathways, modulation of interferon response and modulation of immune cells count or phenotype).
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Affiliation(s)
- Marion Delphin
- International Center for Infectiology Research (CIRI), INSERM U1111, CNRS UMR5308, Université de Lyon (UCBL1), Lyon, France
| | - Manon Desmares
- International Center for Infectiology Research (CIRI), INSERM U1111, CNRS UMR5308, Université de Lyon (UCBL1), Lyon, France
| | - Svenja Schuehle
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany
| | - David Durantel
- International Center for Infectiology Research (CIRI), INSERM U1111, CNRS UMR5308, Université de Lyon (UCBL1), Lyon, France.,DEVweCAN Laboratory of Excellence, Lyon, France
| | - Suzanne Faure-Dupuy
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany
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40
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Yamasaki M, Matsuda N, Matoba K, Kondo S, Kanegae Y, Saito I, Nomoto A. Acetophenone 4-nitrophenylhydrazone inhibits Hepatitis B virus replication by modulating capsid assembly. Virus Res 2021; 306:198565. [PMID: 34555437 DOI: 10.1016/j.virusres.2021.198565] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 09/08/2021] [Accepted: 09/09/2021] [Indexed: 02/07/2023]
Abstract
Hepatitis B virus (HBV) is the causative agent of chronic liver disease and is correlated with the development of subsequent hepatic cirrhosis and hepatocellular carcinoma. Current antiviral therapy using nucleos(t)ide analogs is effective in suppressing viral replication and interrupting disease progression, but HBV is rarely cured completely. Thus, there remains an unmet need for the development of novel anti-HBV drugs. Here, we report the identification of N-(4-Nitrophenyl)-1-phenylethanone hydrazone (ANPH) as a novel structural class of selective inhibitors targeting the replication of the HBV genome using adenovirus vector-mediated HBV genome transduction. ANPH inhibited viral genome replication in HepG2.2.15 cells by inducing the formation of empty capsids devoid of pregenomic RNA without affecting its transcription and translation. Biochemical assays using a truncated core protein consisting of the assembly domain showed that ANPH accelerates the formation of morphologically intact capsids. Taken together, we propose that ANPH might provide a new structural scaffold to design a new anti-HBV drug in medicinal chemistry as well as chemical probes for HBV core protein functions in the future.
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Affiliation(s)
- Manabu Yamasaki
- Institute of Microbial Chemistry (BIKAKEN), Shinagawa-ku, Tokyo, Japan.
| | - Norie Matsuda
- Institute of Microbial Chemistry (BIKAKEN), Shinagawa-ku, Tokyo, Japan
| | - Kazuaki Matoba
- Institute of Microbial Chemistry (BIKAKEN), Shinagawa-ku, Tokyo, Japan
| | - Saki Kondo
- Laboratory of Molecular Genetics, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan
| | - Yumi Kanegae
- Laboratory of Molecular Genetics, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan; Core Research Facilities of Basic Science (Molecular Genetics), Research Center for Medical Science, Jikei University School of Medicine
| | - Izumu Saito
- Laboratory of Molecular Genetics, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan
| | - Akio Nomoto
- Institute of Microbial Chemistry (BIKAKEN), Shinagawa-ku, Tokyo, Japan
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Duvoux C, Belli LS, Fung J, Angelico M, Buti M, Coilly A, Cortesi P, Durand F, Féray C, Fondevila C, Lebray P, Martini S, Nevens F, Polak WG, Rizzetto M, Volpes R, Zoulim F, Samuel D, Berenguer M. 2020 position statement and recommendations of the European Liver and Intestine Transplantation Association (ELITA): management of hepatitis B virus-related infection before and after liver transplantation. Aliment Pharmacol Ther 2021; 54:583-605. [PMID: 34287994 DOI: 10.1111/apt.16374] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 11/25/2020] [Accepted: 04/01/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Prophylaxis of HBV recurrence is critical after liver transplantation in HBV patients. Despite new prophylactic schemes, most European LT centres persist on a conservative approach combining hepatitis B immunoglobulin (HBIG) and nucleos(t)ides analogues (NA). AIM This setting prompted the European Liver Intestine Transplantation Association (ELITA) to look for a consensus on the prevention of HBV recurrence. METHODS Based on a 4-round Delphi process, ELITA investigated 16 research questions and established 50 recommendations. RESULTS Prophylaxis should be driven according to 3 simplified risk groups: Low and high virological risk patients, with undetectable and detectable HBV DNA pre-LT, respectively, and special populations (HDV, HCC, poorly adherent patients). In low-risk patients, short-term (4 weeks) combination of third-generation NA+ HBIG, or third generation NA monotherapy can be considered as prophylactic options. In high-risk patients, HBIG can be discontinued once HBV DNA undetectable. Combined therapy for 1 year is advised. HBV-HCC patients should be treated according to their virological risk. In HDV/HBV patients, indefinite dual prophylaxis remains the gold standard. Full withdrawal of HBV prophylaxis following or not HBV vaccination should only be attempted in the setting of clinical trials. Organs from HBsAg+ve donors may be considered after assessment of risks, benefits, and patient consent. They should not be used if HDV is present. In poorly adherent patients, dual long-term prophylaxis is recommended. Budget impact analysis should be taken into account to drive prophylactic regimen. CONCLUSIONS These ELITA recommendations should stimulate a more rational and homogeneous approach to HBV prophylaxis across LT programs.
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42
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Ligat G, Verrier ER, Nassal M, Baumert TF. Hepatitis B virus-host interactions and novel targets for viral cure. Curr Opin Virol 2021; 49:41-51. [PMID: 34029994 PMCID: PMC7613419 DOI: 10.1016/j.coviro.2021.04.009] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 04/22/2021] [Accepted: 04/23/2021] [Indexed: 02/06/2023]
Abstract
Chronic infection with HBV is a major cause of advanced liver disease and hepatocellular carcinoma. Nucleos(t)ide analogues effectively control HBV replication but viral cure is rare. Hence treatment has often to be administered for an indefinite duration, increasing the risk for selection of drug resistant virus variants. PEG-interferon-α-based therapies can sometimes cure infection but suffer from a low response rate and severe side-effects. CHB is characterized by the persistence of a nuclear covalently closed circular DNA (cccDNA), which is not targeted by approved drugs. Targeting host factors which contribute to the viral life cycle provides new opportunities for the development of innovative therapeutic strategies aiming at HBV cure. An improved understanding of the host immune system has resulted in new potentially curative candidate approaches. Here, we review the recent advances in understanding HBV-host interactions and highlight how this knowledge contributes to exploiting host-targeting strategies for a viral cure.
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Affiliation(s)
- Gaëtan Ligat
- Université de Strasbourg, F-67000 Strasbourg, France; Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMRS 1110, F-67000 Strasbourg, France.
| | - Eloi R Verrier
- Université de Strasbourg, F-67000 Strasbourg, France; Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMRS 1110, F-67000 Strasbourg, France.
| | - Michael Nassal
- University Hospital Freiburg, Dept. of Internal Medicine 2/Molecular Biology, D79106 Freiburg, Germany.
| | - Thomas F Baumert
- Université de Strasbourg, F-67000 Strasbourg, France; Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMRS 1110, F-67000 Strasbourg, France; Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil, 67000 Strasbourg, France.
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43
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Brezgin S, Kostyusheva A, Bayurova E, Volchkova E, Gegechkori V, Gordeychuk I, Glebe D, Kostyushev D, Chulanov V. Immunity and Viral Infections: Modulating Antiviral Response via CRISPR-Cas Systems. Viruses 2021; 13:1373. [PMID: 34372578 PMCID: PMC8310348 DOI: 10.3390/v13071373] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 07/07/2021] [Accepted: 07/09/2021] [Indexed: 12/13/2022] Open
Abstract
Viral infections cause a variety of acute and chronic human diseases, sometimes resulting in small local outbreaks, or in some cases spreading across the globe and leading to global pandemics. Understanding and exploiting virus-host interactions is instrumental for identifying host factors involved in viral replication, developing effective antiviral agents, and mitigating the severity of virus-borne infectious diseases. The diversity of CRISPR systems and CRISPR-based tools enables the specific modulation of innate immune responses and has contributed impressively to the fields of virology and immunology in a very short time. In this review, we describe the most recent advances in the use of CRISPR systems for basic and translational studies of virus-host interactions.
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Affiliation(s)
- Sergey Brezgin
- National Medical Research Center of Tuberculosis and Infectious Diseases, Ministry of Health, 127994 Moscow, Russia; (S.B.); (A.K.); (V.C.)
- Institute of Immunology, Federal Medical Biological Agency, 115522 Moscow, Russia
- Scientific Center for Genetics and Life Sciences, Division of Biotechnology, Sirius University of Science and Technology, 354340 Sochi, Russia
| | - Anastasiya Kostyusheva
- National Medical Research Center of Tuberculosis and Infectious Diseases, Ministry of Health, 127994 Moscow, Russia; (S.B.); (A.K.); (V.C.)
| | - Ekaterina Bayurova
- Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products of Russian Academy of Sciences, 108819 Moscow, Russia; (E.B.); (I.G.)
| | - Elena Volchkova
- Department of Infectious Diseases, Sechenov University, 119991 Moscow, Russia;
| | - Vladimir Gegechkori
- Department of Pharmaceutical and Toxicological Chemistry, Sechenov University, 119991 Moscow, Russia;
| | - Ilya Gordeychuk
- Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products of Russian Academy of Sciences, 108819 Moscow, Russia; (E.B.); (I.G.)
- Department of Organization and Technology of Immunobiological Drugs, Sechenov University, 119991 Moscow, Russia
| | - Dieter Glebe
- National Reference Center for Hepatitis B Viruses and Hepatitis D Viruses, Institute of Medical Virology, Justus Liebig University of Giessen, 35392 Giessen, Germany;
| | - Dmitry Kostyushev
- National Medical Research Center of Tuberculosis and Infectious Diseases, Ministry of Health, 127994 Moscow, Russia; (S.B.); (A.K.); (V.C.)
- Scientific Center for Genetics and Life Sciences, Division of Biotechnology, Sirius University of Science and Technology, 354340 Sochi, Russia
| | - Vladimir Chulanov
- National Medical Research Center of Tuberculosis and Infectious Diseases, Ministry of Health, 127994 Moscow, Russia; (S.B.); (A.K.); (V.C.)
- Scientific Center for Genetics and Life Sciences, Division of Biotechnology, Sirius University of Science and Technology, 354340 Sochi, Russia
- Department of Infectious Diseases, Sechenov University, 119991 Moscow, Russia;
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Qu B, Brown RJP. Strategies to Inhibit Hepatitis B Virus at the Transcript Level. Viruses 2021; 13:v13071327. [PMID: 34372533 PMCID: PMC8310268 DOI: 10.3390/v13071327] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 07/02/2021] [Accepted: 07/06/2021] [Indexed: 12/11/2022] Open
Abstract
Approximately 240 million people are chronically infected with hepatitis B virus (HBV), despite four decades of effective HBV vaccination. During chronic infection, HBV forms two distinct templates responsible for viral transcription: (1) episomal covalently closed circular (ccc)DNA and (2) host genome-integrated viral templates. Multiple ubiquitous and liver-specific transcription factors are recruited onto these templates and modulate viral gene transcription. This review details the latest developments in antivirals that inhibit HBV gene transcription or destabilize viral transcripts. Notably, nuclear receptor agonists exhibit potent inhibition of viral gene transcription from cccDNA. Small molecule inhibitors repress HBV X protein-mediated transcription from cccDNA, while small interfering RNAs and single-stranded oligonucleotides result in transcript degradation from both cccDNA and integrated templates. These antivirals mediate their effects by reducing viral transcripts abundance, some leading to a loss of surface antigen expression, and they can potentially be added to the arsenal of drugs with demonstrable anti-HBV activity. Thus, these candidates deserve special attention for future repurposing or further development as anti-HBV therapeutics.
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Affiliation(s)
- Bingqian Qu
- Division of Veterinary Medicine, Paul Ehrlich Institute, 63225 Langen, Germany
- European Virus Bioinformatics Center, 07743 Jena, Germany
- Correspondence: (B.Q.); (R.J.P.B.)
| | - Richard J. P. Brown
- Division of Veterinary Medicine, Paul Ehrlich Institute, 63225 Langen, Germany
- Correspondence: (B.Q.); (R.J.P.B.)
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45
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Shah NJ, Aloysius MM, Sharma NR, Pallav K. Advances in treatment and prevention of hepatitis B. World J Gastrointest Pharmacol Ther 2021. [DOI: 10.4292/wjg.v12.i4.56] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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46
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Shah NJ, Aloysius MM, Sharma NR, Pallav K. Advances in treatment and prevention of hepatitis B. World J Gastrointest Pharmacol Ther 2021; 12:56-78. [PMID: 34316384 PMCID: PMC8290928 DOI: 10.4292/wjgpt.v12.i4.56] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 03/22/2021] [Accepted: 05/22/2021] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B (CHB) continues to contribute to worldwide morbidity and mortality significantly. Scientists, clinicians, pharmaceutical companies, and health organizations have dedicated substantial Intellectual and monetary resources to finding a cure, increasing immunization rates, and reducing the global burden of CHB. National and international health-related organizations including the center for disease control, the national institute of health, the American Association for the study of liver disease (AASLD), The European association for the study of the Liver (EASL), The Asia Pacific association for the study of the Liver (APASL) and the world health organization release periodic recommendations for disease prevention and treatment. Our review of the most recent guidelines by EASL, AASLD, APASL, and Taiwan Association for the Study of the Liver revealed that an overwhelming majority of cited studies were published before 2018. We reviewed Hepatitis B-related literature published 2018 onwards to identify recent developments and current barriers that will likely direct future efforts towards eradicating hepatitis B. The breakthrough in our understanding of the hepatitis B virus life cycle and resulting drug development is encouraging with significant room for further progress. Data from high-risk populations, most vulnerable to the devastating effects of hepatitis B infection and reactivation remain sparse. Utilization of systems approach, optimization of experimental models, identification and validation of next-generation biomarkers, and precise modulation of the human immune response will be critical for future innovation. Within the foreseeable future, new treatments will likely complement conventional therapies rather than replace them. Most Importantly, pragmatic management of CHB related population health challenges must be prioritized to produce real-world results.
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Affiliation(s)
- Niraj James Shah
- Department of Internal Medicine, Digestive Disease, University of Mississippi Medical Center, Jackson, MS 39216, United States
| | - Mark M Aloysius
- Department of Internal Medicine, The Wright Center for Graduate Medical Education, Scranton, PA 18505, United States
| | - Neil Rohit Sharma
- Department of Internal Medicine, Interventional Oncology and Surgical Endoscopy, Parkview Regional Medical Center, Parkview Cancer Institute, Fort Wayne, IN 46845, United States
| | - Kumar Pallav
- Department of Internal Medicine, Interventional Oncology and Surgical Endoscopy, Parkview Regional Medical Center, Parkview Cancer Institute, Fort Wayne, IN 46845, United States
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47
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Current management & future directions in post-liver transplant recurrence of viral hepatitis. JOURNAL OF LIVER TRANSPLANTATION 2021. [DOI: 10.1016/j.liver.2021.100027] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
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Clark MP, Huynh T, Rao S, Mackiewicz L, Mason H, Romal S, Stutz MD, Ahn SH, Earnest L, Sozzi V, Littlejohn M, Tran BM, Wiedemann N, Vincan E, Torresi J, Netter HJ, Mahmoudi T, Revill P, Pellegrini M, Ebert G. Clinical stage drugs targeting inhibitor of apoptosis proteins purge episomal Hepatitis B viral genome in preclinical models. Cell Death Dis 2021; 12:641. [PMID: 34162831 PMCID: PMC8222287 DOI: 10.1038/s41419-021-03924-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 05/31/2021] [Accepted: 05/31/2021] [Indexed: 12/19/2022]
Abstract
A major unmet clinical need is a therapeutic capable of removing hepatitis B virus (HBV) genome from the liver of infected individuals to reduce their risk of developing liver cancer. A strategy to deliver such a therapy could utilize the ability to target and promote apoptosis of infected hepatocytes. Presently there is no clinically relevant strategy that has been shown to effectively remove persistent episomal covalently closed circular HBV DNA (cccDNA) from the nucleus of hepatocytes. We used linearized single genome length HBV DNA of various genotypes to establish a cccDNA-like reservoir in immunocompetent mice and showed that clinical-stage orally administered drugs that antagonize the function of cellular inhibitor of apoptosis proteins can eliminate HBV replication and episomal HBV genome in the liver. Primary human liver organoid models were used to confirm the clinical relevance of these results. This study underscores a clinically tenable strategy for the potential elimination of chronic HBV reservoirs in patients.
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Affiliation(s)
- Michelle P Clark
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
| | - Thao Huynh
- Victorian Infectious Diseases Reference Laboratory, The Royal Melbourne Hospital at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Shringar Rao
- Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Liana Mackiewicz
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
| | - Hugh Mason
- Victorian Infectious Diseases Reference Laboratory, The Royal Melbourne Hospital at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Shahla Romal
- Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Michael D Stutz
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR, USA
| | - Sang H Ahn
- Department of Internal Medicine, Yonsei University, Seoul, South Korea
| | - Linda Earnest
- Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Vitina Sozzi
- Victorian Infectious Diseases Reference Laboratory, The Royal Melbourne Hospital at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Margaret Littlejohn
- Victorian Infectious Diseases Reference Laboratory, The Royal Melbourne Hospital at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
- Department of Infectious Diseases, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Bang M Tran
- Department of Infectious Diseases, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | | | - Elizabeth Vincan
- Victorian Infectious Diseases Reference Laboratory, The Royal Melbourne Hospital at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
- Department of Infectious Diseases, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
- Curtin Medical School, Curtin University, Perth, WA, Australia
| | - Joseph Torresi
- Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Hans J Netter
- Victorian Infectious Diseases Reference Laboratory, The Royal Melbourne Hospital at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | | | - Peter Revill
- Victorian Infectious Diseases Reference Laboratory, The Royal Melbourne Hospital at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
- Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Marc Pellegrini
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
- Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia.
| | - Gregor Ebert
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
- Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia.
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany.
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Identification of novel hepatitis B virus therapeutic vaccine candidates derived from polymerase protein. Aging (Albany NY) 2021; 13:14372-14384. [PMID: 34016795 PMCID: PMC8202855 DOI: 10.18632/aging.203053] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Accepted: 04/28/2021] [Indexed: 01/05/2023]
Abstract
Hepatitis B virus (HBV) infection is a worldwide health problem with high morbidity and mortality rates. The therapeutic vaccine is a promising method of treatment, and HBV polymerase plays a vital role in viral replication. Therefore, a therapeutic vaccine that binds to HBV DNA polymerase may control HBV infection. We predicted and selected epitopes of polymerase using online databases and analysis software. We then performed molecular docking and peptide binding assays to evaluate the binding energies and affinities between polymerase epitopes and the HLA-A0201 molecule. Finally, we induced T cells from the peripheral blood mononuclear cells (PBMCs) of healthy donors using each epitope and quantified the functions of epitope-specific T cells by IFN-γELISPOT assay, T2 cell cytotoxicity assay, HepG2.2.15 cell cytotoxicity assay and HBV gene expression assays. Four epitopes (RVTGGVFLV, GLLGFAAPF, LLDDEAGPL and YMDDVVLGA) had low binding energy and two epitopes (RVTGGVFLV and GLLGFAAPF) had a high binding affinity. The T cells stimulated by two epitopes (GLLGFAAPF and HLYSHPIIL) had a greater ability to induce immune response and suppress HBV. The HBV DNA polymerase epitopes identified in this study are promising targets for designing an epitope-based therapeutic vaccine against HBV.
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Abstract
Preclinical testing of novel therapeutics for chronic hepatitis B (CHB) requires suitable animal models. Equids host homologs of hepatitis C virus (HCV). Because coinfections of hepatitis B virus (HBV) and HCV occur in humans, we screened 2,917 specimens from equids from five continents for HBV. We discovered a distinct HBV species (Equid HBV, EqHBV) in 3.2% of donkeys and zebras by PCR and antibodies against EqHBV in 5.4% of donkeys and zebras. Molecular, histopathological, and biochemical analyses revealed that infection patterns of EqHBV resembled those of HBV in humans, including hepatotropism, moderate liver damage, evolutionary stasis, and potential horizontal virus transmission. Naturally infected donkeys showed chronic infections resembling CHB with high viral loads of up to 2.6 × 109 mean copies per milliliter serum for >6 mo and weak antibody responses. Antibodies against Equid HCV were codetected in 26.5% of donkeys seropositive for EqHBV, corroborating susceptibility to both hepatitis viruses. Deltavirus pseudotypes carrying EqHBV surface proteins were unable to infect human cells via the HBV receptor NTCP (Na+/taurocholate cotransporting polypeptide), suggesting alternative viral entry mechanisms. Both HBV and EqHBV deltavirus pseudotypes infected primary horse hepatocytes in vitro, supporting a broad host range for EqHBV among equids and suggesting that horses might be suitable for EqHBV and HBV infections in vivo. Evolutionary analyses suggested that EqHBV originated in Africa several thousand years ago, commensurate with the domestication of donkeys. In sum, EqHBV naturally infects diverse equids and mimics HBV infection patterns. Equids provide a unique opportunity for preclinical testing of novel therapeutics for CHB and to investigate HBV/HCV interplay upon coinfection.
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