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Chen K, Gao Z. Acacetin, a Natural Flavone with Potential in Improving Liver Disease Based on Its Anti-Inflammation, Anti-Cancer, Anti-Infection and Other Effects. Molecules 2024; 29:4872. [PMID: 39459239 PMCID: PMC11509893 DOI: 10.3390/molecules29204872] [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: 09/19/2024] [Revised: 10/07/2024] [Accepted: 10/12/2024] [Indexed: 10/28/2024] Open
Abstract
Liver disease is a global public problem, and the cost of its therapy is a large financial burden to governments. It is well known that drug therapy plays a critical role in the treatment of liver disease. However, present drugs are far from meeting clinical needs. Lots of efforts have been made to find novel agents to treat liver disease in the past several decades. Acacetin is a dihydroxy and monomethoxy flavone, named 5,7-dihydroxy-4'-methoxyflavone, which can be found in diverse plants. It has been reported that acacetin exhibits multiple pharmacological activities, including anti-cancer, anti-inflammation, anti-virus, anti-obesity, and anti-oxidation. These studies indicate the therapeutic potential of acacetin in liver disease. This review discussed the comprehensive information on the pathogenesis of liver disease (cirrhosis, viral hepatitis, drug-induced liver injury, and hepatocellular carcinoma), then introduced the biological source, structural features, and pharmacological properties of acacetin, and the possible application in preventing liver disease along with the pharmacokinetic and toxicity of acacetin, and future research directions. We systemically summarized the latest research progress on the potential therapeutic effect of acacetin on liver disease and existing problems. Based on the present published information, the natural flavone acacetin is an anticipated candidate agent for the treatment of liver disease.
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Affiliation(s)
- Kuihao Chen
- Department of Pharmacology, School of Medicine, Ningbo University, 818 Fenghua Rd., Ningbo 315211, China
| | - Zhe Gao
- Department of Pharmacy, Zhejiang Pharmaceutical University, 666 Siming Rd., Ningbo 315211, China
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He Y, Zhou J, Gao H, Liu C, Zhan P, Liu X. Broad-spectrum antiviral strategy: Host-targeting antivirals against emerging and re-emerging viruses. Eur J Med Chem 2024; 265:116069. [PMID: 38160620 DOI: 10.1016/j.ejmech.2023.116069] [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: 10/03/2023] [Revised: 12/06/2023] [Accepted: 12/16/2023] [Indexed: 01/03/2024]
Abstract
Viral infections are amongst the most prevalent diseases that pose a significant threat to human health. Targeting viral proteins or host factors represents two primary strategies for the development of antiviral drugs. In contrast to virus-targeting antivirals (VTAs), host-targeting antivirals (HTAs) offer advantages in terms of overcoming drug resistance and effectively combating a wide range of viruses, including newly emerging ones. Therefore, targeting host factors emerges as an extremely promising strategy with the potential to address critical challenges faced by VTAs. In recent years, extensive research has been conducted on the discovery and development of HTAs, leading to the approval of maraviroc, a chemokine receptor type 5 (CCR5) antagonist used for the treatment of HIV-1 infected individuals, with several other potential treatments in various stages of development for different viral infections. This review systematically summarizes advancements made in medicinal chemistry regarding various host targets and classifies them into four distinct catagories based on their involvement in the viral life cycle: virus attachment and entry, biosynthesis, nuclear import and export, and viral release.
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Affiliation(s)
- Yong He
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan, 250012, Shandong Province, PR China
| | - Jiahui Zhou
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan, 250012, Shandong Province, PR China
| | - Huizhan Gao
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan, 250012, Shandong Province, PR China
| | - Chuanfeng Liu
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan, 250012, Shandong Province, PR China
| | - Peng Zhan
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan, 250012, Shandong Province, PR China.
| | - Xinyong Liu
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan, 250012, Shandong Province, PR China.
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Vincenzi M, Mercurio FA, Leone M. EPHA2 Receptor as a Possible Therapeutic Target in Viral Infections. Curr Med Chem 2024; 31:5670-5701. [PMID: 37828671 DOI: 10.2174/0109298673256638231003111234] [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: 04/06/2023] [Revised: 08/02/2023] [Accepted: 08/24/2023] [Indexed: 10/14/2023]
Abstract
BACKGROUND The receptor tyrosine kinase EphA2 plays a role in many diseases, like cancer, cataracts, and osteoporosis. Interestingly, it has also been linked to viral infections. OBJECTIVE Herein, current literature has been reviewed to clarify EphA2 functions in viral infections and explore its potential role as a target in antiviral drug discovery strategies. METHODS Research and review articles along with preprints connecting EphA2 to different viruses have been searched through PubMed and the web. Structures of complexes between EphA2 domains and viral proteins have been retrieved from the PDB database. RESULTS EphA2 assumes a key role in Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein Barr virus (EBV) infections by directly binding, through its ligand binding domain, viral glycoproteins. For human cytomegalovirus (HCMV), the role of EphA2 in maintaining virus latency state, through cooperation with specific viral proteins, has also been speculated. In certain cells, with high EphA2 expression levels, following ligand stimulation, receptor activation might contribute to severe symptoms accompanying a few viral infections, including lung injuries often related to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). CONCLUSION Since EphA2 works as a host receptor for certain viruses, it might be worth more deeply investigating known compounds targeting its extracellular ligand binding domain as antiviral therapeutics. Due to EphA2's function in inflammation, its possible correlation with SARS-CoV-2 cannot be excluded, but more experimental studies are needed in this case to undoubtedly attribute the role of this receptor in viral infections.
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Affiliation(s)
- Marian Vincenzi
- Institute of Biostructures and Bioimaging, National Research Council of Italy (CNR-IBB), Naples, Italy
| | - Flavia Anna Mercurio
- Institute of Biostructures and Bioimaging, National Research Council of Italy (CNR-IBB), Naples, Italy
| | - Marilisa Leone
- Institute of Biostructures and Bioimaging, National Research Council of Italy (CNR-IBB), Naples, Italy
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Emanuelson C, Ankenbruck N, Kumbhare R, Thomas M, Connelly C, Baktash Y, Randall G, Deiters A. Transcriptional Inhibition of MicroRNA miR-122 by Small Molecules Reduces Hepatitis C Virus Replication in Liver Cells. J Med Chem 2022; 65:16338-16352. [PMID: 36449366 PMCID: PMC9942140 DOI: 10.1021/acs.jmedchem.2c01141] [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] [Indexed: 12/05/2022]
Abstract
MicroRNAs (miRNAs) are noncoding RNA molecules of 22-24 nucleotides that are estimated to regulate thousands of genes in humans, and their dysregulation has been implicated in many diseases. MicroRNA-122 (miR-122) is the most abundant miRNA in the liver and has been linked to the development of hepatocellular carcinoma and hepatitis C virus (HCV) infection. Its role in these diseases renders miR-122 a potential target for small-molecule therapeutics. Here, we report the discovery of a new sulfonamide class of small-molecule miR-122 inhibitors from a high-throughput screen using a luciferase-based reporter assay. Structure-activity relationship (SAR) studies and secondary assays led to the development of potent and selective miR-122 inhibitors. Preliminary mechanism-of-action studies suggest a role in the promoter-specific transcriptional inhibition of miR-122 expression through direct binding to the liver-enriched transcription factor hepatocyte nuclear factor 4α. Importantly, the developed inhibitors significantly reduce HCV replication in human liver cells.
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Affiliation(s)
- Cole Emanuelson
- Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
| | - Nicholas Ankenbruck
- Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
| | - Rohan Kumbhare
- Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
| | - Meryl Thomas
- Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
| | - Colleen Connelly
- Department of Chemistry, North Carolina State University, Raleigh, North Carolina 27695, United States
| | - Yasmine Baktash
- Department of Microbiology, The University of Chicago, Chicago, Illinois 60637, United States
| | - Glenn Randall
- Department of Microbiology, The University of Chicago, Chicago, Illinois 60637, United States
| | - Alexander Deiters
- Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
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Hassan M, El-Ahwany E, Elzallat M, Rahim AA, Abu-Taleb H, Abdelrahman Y, Hassanein M. Role of MicroRNAs in the Development of Chronic Liver Disease in Hepatitis Virus-Infected Egyptian Population. Open Access Maced J Med Sci 2022. [DOI: 10.3889/oamjms.2022.10902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Background: The identification of miRNAs that play a role in the regulation of the viral life cycle and its related liver illness opens the door to the development of diagnostic biomarkers that can categorize patients at higher risk for developing end-stage liver disease. This study was designed to investigate the role of miRNAs in the development of viral hepatitis-induced chronic liver disease (CLD) in the Egyptian population, as well as their potential as possible diagnostic biomarkers for chronic hepatitis virus infection.
Methodology: The study involved 100 CLD patients; 55 cases of hepatitis C virus (HCV) and 45 cases of non-viral hepatitis, in addition to 40 healthy controls. The expression of five miRNAs (miR‐30, miR‐122, miR‐296, miR‐351, and miR‐431) was assessed using real-time PCR.
Results: Serum levels of miR‐30, miR‐122, miR‐296, miR‐351, and miR‐431 were significantly higher in all patients than the control group (p<0.01). Also, they were significantly greater in viral hepatitis cases compared to the non-viral hepatitis group (p<0.01). The sensitivities and specificities of miR-122a, miR‐30, miR‐296, miR‐351, and miR‐431 were (85.71%, 83.33%), (82.35%, 83.33%), (85.71%, 69.44%), (88.64%, 75.76%), and (87.80%, 65.79%), respectively.
Conclusions: miR‐30, miR‐122, miR‐296, miR‐351, and miR‐431 play key roles in the development of CLD as a consequence of viral infection. So, they have the potential to be targeted for the early detection of chronic hepatitis virus infection and allow for exploring a new frontier in the discovery of innovative therapeutics to combat chronic viral infection and its serious life-threatening complications including liver cancer.
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Role of Host Small GTPases in Apicomplexan Parasite Infection. Microorganisms 2022; 10:microorganisms10071370. [PMID: 35889089 PMCID: PMC9319929 DOI: 10.3390/microorganisms10071370] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 07/01/2022] [Accepted: 07/04/2022] [Indexed: 12/04/2022] Open
Abstract
The Apicomplexa are obligate intracellular parasites responsible for several important human diseases. These protozoan organisms have evolved several strategies to modify the host cell environment to create a favorable niche for their survival. The host cytoskeleton is widely manipulated during all phases of apicomplexan intracellular infection. Moreover, the localization and organization of host organelles are altered in order to scavenge nutrients from the host. Small GTPases are a class of proteins widely involved in intracellular pathways governing different processes, from cytoskeletal and organelle organization to gene transcription and intracellular trafficking. These proteins are already known to be involved in infection by several intracellular pathogens, including viruses, bacteria and protozoan parasites. In this review, we recapitulate the mechanisms by which apicomplexan parasites manipulate the host cell during infection, focusing on the role of host small GTPases. We also discuss the possibility of considering small GTPases as potential targets for the development of novel host-targeted therapies against apicomplexan infections.
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Verma HK, Prasad K, Kumar P, Lvks B. Viral hepatitis: A global burden needs future directions for the management. World J Gastroenterol 2022; 28:1718-1721. [PMID: 35581964 PMCID: PMC9048788 DOI: 10.3748/wjg.v28.i16.1718] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 10/09/2021] [Accepted: 03/25/2022] [Indexed: 02/06/2023] Open
Abstract
Viral hepatitis is an acute or chronic liver disease due to the infection from Hepatitis A, B, C, D and E viruses. It can cause severe liver damage such as cirrhosis, liver failure and liver cancer. To avoid such fatal complications, hepatitis patients must be diagnosed, pathologized and treated as soon as possible. Furthermore, these hepatitis viruses infect through different routes, resulting in distinct disease pathologies, severity and even the need for specific treatment strategies to combat the infection.
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Affiliation(s)
- Henu Kumar Verma
- Department of Immunopathology, Institute of Lungs Biology and Disease, Comprehensive Pneumology Center, Helmholtz Zentrum, Munich 80331, Bayren, Germany
| | - Kiran Prasad
- Department of Zoology, Guru Ghasidas Vishwavidyalaya, Bilaspur 495001, Chhattisgarh, India
| | - Pramod Kumar
- Department of Drug Delivery, Institute of Lung Biology and Disease, Helmholtz Research Center, Munich 80331, Bayren, Germany
| | - Bhaskar Lvks
- Department of Zoology, Guru Ghasidas Vishwavidyalaya, Bilaspur 495001, Chhattisgarh, India
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Structural organization of erythrocyte membrane microdomains and their relation with malaria susceptibility. Commun Biol 2021; 4:1375. [PMID: 34880413 PMCID: PMC8655059 DOI: 10.1038/s42003-021-02900-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 11/18/2021] [Indexed: 12/16/2022] Open
Abstract
Cholesterol-rich microdomains are membrane compartments characterized by specific lipid and protein composition. These dynamic assemblies are involved in several biological processes, including infection by intracellular pathogens. This work provides a comprehensive analysis of the composition of human erythrocyte membrane microdomains. Based on their floating properties, we also categorized the microdomain-associated proteins into clusters. Interestingly, erythrocyte microdomains include the vast majority of the proteins known to be involved in invasion by the malaria parasite Plasmodium falciparum. We show here that the Ecto-ADP-ribosyltransferase 4 (ART4) and Aquaporin 1 (AQP1), found within one specific cluster, containing the essential host determinant CD55, are recruited to the site of parasite entry and then internalized to the newly formed parasitophorous vacuole membrane. By generating null erythroid cell lines, we showed that one of these proteins, ART4, plays a role in P. falciparum invasion. We also found that genetic variants in both ART4 and AQP1 are associated with susceptibility to the disease in a malaria-endemic population.
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Chan SW, Shafi T, Ford RC. Kite-Shaped Molecules Block SARS-CoV-2 Cell Entry at a Post-Attachment Step. Viruses 2021; 13:v13112306. [PMID: 34835112 PMCID: PMC8619434 DOI: 10.3390/v13112306] [Citation(s) in RCA: 4] [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: 09/14/2021] [Revised: 11/02/2021] [Accepted: 11/15/2021] [Indexed: 12/13/2022] Open
Abstract
Anti-viral small molecules are currently lacking for treating coronavirus infection. The long development timescales for such drugs are a major problem, but could be shortened by repurposing existing drugs. We therefore screened a small library of FDA-approved compounds for potential severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) antivirals using a pseudovirus system that allows a sensitive read-out of infectivity. A group of structurally-related compounds, showing moderate inhibitory activity with IC50 values in the 2–5 μM range, were identified. Further studies demonstrated that these “kite-shaped” molecules were surprisingly specific for SARS-CoV-1 and SARS-CoV-2 and that they acted early in the entry steps of the viral infectious cycle, but did not affect virus attachment to the cells. Moreover, the compounds were able to prevent infection in both kidney- and lung-derived human cell lines. The structural homology of the hits allowed the production of a well-defined pharmacophore that was found to be highly accurate in predicting the anti-viral activity of the compounds in the screen. We discuss the prospects of repurposing these existing drugs for treating current and future coronavirus outbreaks.
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Gill M, Sharafat J, Ikram F, Ul Qamar M, Rehman I, Saleem M, Noreen A, Khadim N, Horii A, Tahir B. Correlation Between Serum Ferritin and Hepcidin Levels in Chronic Hepatitis C Patients. Cureus 2021; 13:e17484. [PMID: 34603871 PMCID: PMC8476116 DOI: 10.7759/cureus.17484] [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] [Accepted: 08/27/2021] [Indexed: 11/05/2022] Open
Abstract
Background In addition to the known role of serum ferritin as an inflammatory mediator, its role in the induction of serum hepcidin is yet to be elucidated. This study aimed to identify a correlation between serum ferritin and hepcidin levels in chronic hepatitis C (CHC) patients and healthy individuals. Methodology A total of 44 male subjects, selected by convenient sampling technique, were included in this study. The study population was divided into group I including 22 healthy males and group II including age-matched 22 CHC patients. Serum hepcidin and serum ferritin levels of study participants in both groups were assessed. Serum parameters were compared between two groups using the Mann-Whitney U test. Spearman correlation test was applied between serum ferritin and serum hepcidin in each group. P-values of ≤0.05 were considered significant. Results The median values of serum ferritin in group I and group II were in the normal range, though serum ferritin of CHC patients was significantly higher than the healthy population (p = 0.03). The median values of serum hepcidin in both groups were below the normal range. In CHC patients, a negative nonsignificant correlation (rho = -0.34, p = 0.13) was observed between serum ferritin and serum hepcidin. A positive nonsignificant correlation (rho = 0.19, p = 0.4) was observed between serum ferritin and serum hepcidin in the healthy population. Conclusions Our study could not bring forth any conclusive remarks in favor of serum ferritin as an inflammatory mediator raising serum hepcidin levels among CHC patients. A negative nonsignificant correlation between studied parameters in CHC patients may indicate the involvement of some other factor such as hepatitis C virus in the reduction of serum hepcidin levels.
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Affiliation(s)
- Maria Gill
- Physiology, CMH Multan Institute of Medical Sciences, Multan, PAK
| | - Javaria Sharafat
- Physiology, CMH Multan Institute of Medical Sciences, Multan, PAK
| | - Faiza Ikram
- Physiology, CMH Multan Institute of Medical Sciences, Multan, PAK
| | - Misbah Ul Qamar
- Physiology, Akhtar Saeed Medical and Dental College, Lahore, PAK
| | - Irum Rehman
- Physiology, Margalla Institute of Health Sciences, Rawalpindi, PAK
| | - Mannal Saleem
- Physiology, CMH Multan Institute of Medical Sciences, Multan, PAK
| | - Ayesha Noreen
- Physiology, Nawaz Sharif Medical College, University of Gujrat, Gujrat, PAK
| | - Nadia Khadim
- Physiology, Nawaz Sharif Medical College, University of Gujrat, Gujrat, PAK
| | - Arusa Horii
- Physiology, Sargodha Medical College, Sargodha, PAK
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Brunotte L, Zheng S, Mecate-Zambrano A, Tang J, Ludwig S, Rescher U, Schloer S. Combination Therapy with Fluoxetine and the Nucleoside Analog GS-441524 Exerts Synergistic Antiviral Effects against Different SARS-CoV-2 Variants In Vitro. Pharmaceutics 2021; 13:pharmaceutics13091400. [PMID: 34575474 PMCID: PMC8466181 DOI: 10.3390/pharmaceutics13091400] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 08/30/2021] [Accepted: 09/01/2021] [Indexed: 12/15/2022] Open
Abstract
The ongoing SARS-CoV-2 pandemic requires efficient and safe antiviral treatment strategies. Drug repurposing represents a fast and low-cost approach to the development of new medical treatment options. The direct antiviral agent remdesivir has been reported to exert antiviral activity against SARS-CoV-2. Whereas remdesivir only has a very short half-life time and a bioactivation, which relies on pro-drug activating enzymes, its plasma metabolite GS-441524 can be activated through various kinases including the adenosine kinase (ADK) that is moderately expressed in all tissues. The pharmacokinetics of GS-441524 argue for a suitable antiviral drug that can be given to patients with COVID-19. Here, we analyzed the antiviral property of a combined treatment with the remdesivir metabolite GS-441524 and the antidepressant fluoxetine in a polarized Calu-3 cell culture model against SARS-CoV-2. The combined treatment with GS-441524 and fluoxetine were well-tolerated and displayed synergistic antiviral effects against three circulating SARS-CoV-2 variants in vitro in the commonly used reference models for drug interaction. Thus, combinatory treatment with the virus-targeting GS-441524 and the host-directed drug fluoxetine might offer a suitable therapeutic treatment option for SARS-CoV-2 infections.
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Affiliation(s)
- Linda Brunotte
- Institute of Virology, Center for Molecular Biology of Inflammation, and “Cells in Motion” Interfaculty Centre, University of Muenster, Von-Esmarch-Str. 56, D-48149 Muenster, Germany; (L.B.); (A.M.-Z.); (S.L.)
| | - Shuyu Zheng
- Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Haartmaninkatu 8, 00029 Helsinki, Finland; (S.Z.); (J.T.)
| | - Angeles Mecate-Zambrano
- Institute of Virology, Center for Molecular Biology of Inflammation, and “Cells in Motion” Interfaculty Centre, University of Muenster, Von-Esmarch-Str. 56, D-48149 Muenster, Germany; (L.B.); (A.M.-Z.); (S.L.)
| | - Jing Tang
- Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Haartmaninkatu 8, 00029 Helsinki, Finland; (S.Z.); (J.T.)
| | - Stephan Ludwig
- Institute of Virology, Center for Molecular Biology of Inflammation, and “Cells in Motion” Interfaculty Centre, University of Muenster, Von-Esmarch-Str. 56, D-48149 Muenster, Germany; (L.B.); (A.M.-Z.); (S.L.)
| | - Ursula Rescher
- Institut-Associated Research Group Regulatory Mechanisms of Inflammation, Institute of Medical Biochemistry, Center for Molecular Biology of Inflammation, and “Cells in Motion” Interfaculty Centre, University of Muenster, Von-Esmarch-Str. 56, D-48149 Muenster, Germany;
| | - Sebastian Schloer
- Institut-Associated Research Group Regulatory Mechanisms of Inflammation, Institute of Medical Biochemistry, Center for Molecular Biology of Inflammation, and “Cells in Motion” Interfaculty Centre, University of Muenster, Von-Esmarch-Str. 56, D-48149 Muenster, Germany;
- Correspondence: ; Tel.: +49-2518352113; Fax: +49-2518356748
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Li X, Peng T. Strategy, Progress, and Challenges of Drug Repurposing for Efficient Antiviral Discovery. Front Pharmacol 2021; 12:660710. [PMID: 34017257 PMCID: PMC8129523 DOI: 10.3389/fphar.2021.660710] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 04/16/2021] [Indexed: 12/17/2022] Open
Abstract
Emerging or re-emerging viruses are still major threats to public health. Prophylactic vaccines represent the most effective way to prevent virus infection; however, antivirals are more promising for those viruses against which vaccines are not effective enough or contemporarily unavailable. Because of the slow pace of novel antiviral discovery, the high disuse rates, and the substantial cost, repurposing of the well-characterized therapeutics, either approved or under investigation, is becoming an attractive strategy to identify the new directions to treat virus infections. In this review, we described recent progress in identifying broad-spectrum antivirals through drug repurposing. We defined the two major categories of the repurposed antivirals, direct-acting repurposed antivirals (DARA) and host-targeting repurposed antivirals (HTRA). Under each category, we summarized repurposed antivirals with potential broad-spectrum activity against a variety of viruses and discussed the possible mechanisms of action. Finally, we proposed the potential investigative directions of drug repurposing.
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Affiliation(s)
- Xinlei Li
- State Key Laboratory of Respiratory Disease, Sino-French Hoffmann Institute, College of Basic Medicine, Guangzhou Medical University, Guangzhou, China
| | - Tao Peng
- State Key Laboratory of Respiratory Disease, Sino-French Hoffmann Institute, College of Basic Medicine, Guangzhou Medical University, Guangzhou, China
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Malikova AZ, Shcherbakova AS, Konduktorov KA, Zemskaya AS, Dalina AA, Popenko VI, Leonova OG, Morozov AV, Kurochkin NN, Smirnova OA, Kochetkov SN, Kozlov MV. Pre-Senescence Induction in Hepatoma Cells Favors Hepatitis C Virus Replication and Can Be Used in Exploring Antiviral Potential of Histone Deacetylase Inhibitors. Int J Mol Sci 2021; 22:4559. [PMID: 33925399 PMCID: PMC8123837 DOI: 10.3390/ijms22094559] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 04/16/2021] [Accepted: 04/22/2021] [Indexed: 12/22/2022] Open
Abstract
Recent evidence suggests that fibrotic liver injury in patients with chronic hepatitis C correlates with cellular senescence in damaged liver tissue. However, it is still unclear how senescence can affect replication of the hepatitis C virus (HCV). In this work, we report that an inhibitor of cyclin-dependent kinases 4/6, palbociclib, not only induced in hepatoma cells a pre-senescent cellular phenotype, including G1 arrest in the cell cycle, but also accelerated viral replicon multiplication. Importantly, suppression of HCV replication by direct acting antivirals (DAAs) was barely affected by pre-senescence induction, and vice versa, the antiviral activities of host-targeting agents (HTAs), such as inhibitors of human histone deacetylases (HDACi), produced a wide range of reactions-from a dramatic reduction to a noticeable increase. It is very likely that under conditions of the G1 arrest in the cell cycle, HDACi exhibit their actual antiviral potency, since their inherent anticancer activity that complicates the interpretation of test results is minimized.
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Paone S, D'Alessandro S, Parapini S, Celani F, Tirelli V, Pourshaban M, Olivieri A. Characterization of the erythrocyte GTPase Rac1 in relation to Plasmodium falciparum invasion. Sci Rep 2020; 10:22054. [PMID: 33328606 PMCID: PMC7744522 DOI: 10.1038/s41598-020-79052-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 11/30/2020] [Indexed: 12/01/2022] Open
Abstract
Malaria is still a devastating disease with 228 million cases globally and 405,000 lethal outcomes in 2018, mainly in children under five years of age. The threat of emerging malaria strains resistant to currently available drugs has made the search for novel drug targets compelling. The process by which Plasmodium falciparum parasites invade the host cell has been widely studied, but only a few erythrocyte proteins involved in this process have been identified so far. The erythrocyte protein Rac1 is a GTPase that plays an important role in host cell invasion by many intracellular pathogens. Here we show that Rac1 is recruited in proximity to the site of parasite entry during P. falciparum invasion process and that subsequently localizes to the parasitophorous vacuole membrane. We also suggest that this GTPase may be involved in erythrocyte invasion by P. falciparum, by testing the effect of specific Rac1 inhibitory compounds. Finally, we suggest a secondary role of the erythrocyte GTPase also in parasite intracellular development. We here characterize a new erythrocyte protein potentially involved in P. falciparum invasion of the host cell and propose the human GTPase Rac1 as a novel and promising antimalarial drug target.
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Affiliation(s)
- Silvio Paone
- Dipartimento di Malattie Infettive, Istituto Superiore di Sanità, Rome, Italy.,Dipartimento di Sanità Pubblica e Malattie Infettive, Sapienza University of Rome, Rome, Italy
| | - Sarah D'Alessandro
- Dipartimento di Scienze Biomediche, Chirurgiche e Odontoiatriche, University of Milan, Milan, Italy
| | - Silvia Parapini
- Dipartimento di Scienze Biomediche Per La Salute, University of Milan, Milan, Italy
| | - Francesco Celani
- Dipartimento di Malattie Infettive, Istituto Superiore di Sanità, Rome, Italy
| | - Valentina Tirelli
- Dipartimento di Malattie Infettive, Istituto Superiore di Sanità, Rome, Italy
| | | | - Anna Olivieri
- Dipartimento di Malattie Infettive, Istituto Superiore di Sanità, Rome, Italy.
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15
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Safarnezhad Tameshkel F, Karbalaie Niya MH, Zamani F, Motamed N, Ajdarkosh H, Vafaeimanesh J, Khoonsari M, Sohrabi MR, Aten S, Azarkeivan A, Eslami MS, Perumal D, Maadi M, Ghanbari B, Keyvani H. Resistance-associated substitutions (RASs) to HCV direct-acting antivirals (DAAs) at baseline of treatment in thalassemia patients: a referral center study. Arch Virol 2020; 165:2193-2203. [PMID: 32638116 DOI: 10.1007/s00705-020-04728-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 06/07/2020] [Indexed: 02/06/2023]
Abstract
Patients with thalassemia major are at high risk of hepatitis C through blood transfusion from donors infected by hepatitis C virus (HCV). The use of direct-acting antiviral (DAA) therapy against such HCV infections has increased in different populations. However, resistant viral variants can affect treatment outcomes, and therefore improved surveillance strategies are needed. Accordingly, we aimed to evaluate resistance-associated substitutions (RASs) to HCV DAAs at the baseline of treatment in thalassemia patients in a referral center. Out of 89 thalassemia patients who suffered from HCV infection and were referred to our center between 2016 and 2017, 43 underwent further analysis of the HCV nonstructural proteins NS5A and NS5B using polymerase chain reaction (PCR) sequencing methods. Unique primers were designed using bioinformatics software for separate detection of HCV subtypes 1a, 3a, and 1b. Detection of RASs was performed based on previously published literature. Statistical analysis was carried out using SPSS version 19. The participants, 60.4% (26/43) of whom were male, had a mean age ± standard deviation (SD) of 33.0 ± 5.0 years. HCV subtype 1a was found in 27 cases, 3a in 13, and 1b in three. In HCV subtype 1a there were 163 mutations in NS5A and 212 mutations in NS5B. The frequency of RASs was 20.9% (8 RASs in 9 patients), including M28V and H58P in subtype 1a, L28M, R30Q, C316N, and C316S in subtype 1b, and S24F in subtype 3a. Statistically, the subtype 1b and a higher mutation rate in NS5A were associated with RASs (p-value < 0.05). The emergence of natural RASs to HCV DAAs serves as a warning of the risk of drug resistance in response to the broad usage of antivirals. However, relapses in these DAA-treated HCV-infected thalassemia patients are rarely reported. Our findings indicate that the prevalence of RASs prevalence at baseline was 20.9% in these patients, and this calls for extrapolation to a larger population study, as highlighted in other studies, with larger sample sizes, high-throughput methods, and follow-up in order to fully evaluate treatment outcomes in RASs-detected individuals. Optimized therapeutic strategies, particularly in complex, difficult-to-cure patients, can effectively prevent DAA treatment failure as a result of selection for RASs.
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Affiliation(s)
| | - Mohammad Hadi Karbalaie Niya
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran.,Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Farhad Zamani
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Nima Motamed
- Department of Social Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Hossein Ajdarkosh
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Jamshid Vafaeimanesh
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran.,Gastroenterology and Hepatology Disease Research Center, Qom University of Medical Sciences, Qom, Iran
| | - Mahmoodreza Khoonsari
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Masood Reza Sohrabi
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Sima Aten
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Azita Azarkeivan
- Pediatric Hematology Oncology, Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Thalassemia Clinic, Tehran, Iran
| | - Masoumeh Sadat Eslami
- Pediatric Hematology Oncology, Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Thalassemia Clinic, Tehran, Iran
| | - Dhayaneethie Perumal
- Faculty of Science, Engineering and Computing, Kingston University, Kingston, UK
| | - Mansooreh Maadi
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Behrooz Ghanbari
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Hossein Keyvani
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran. .,Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran.
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16
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Eller C, Heydmann L, Colpitts CC, El Saghire H, Piccioni F, Jühling F, Majzoub K, Pons C, Bach C, Lucifora J, Lupberger J, Nassal M, Cowley GS, Fujiwara N, Hsieh SY, Hoshida Y, Felli E, Pessaux P, Sureau C, Schuster C, Root DE, Verrier ER, Baumert TF. A genome-wide gain-of-function screen identifies CDKN2C as a HBV host factor. Nat Commun 2020; 11:2707. [PMID: 32483149 PMCID: PMC7264273 DOI: 10.1038/s41467-020-16517-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 05/03/2020] [Indexed: 12/21/2022] Open
Abstract
Chronic HBV infection is a major cause of liver disease and cancer worldwide. Approaches for cure are lacking, and the knowledge of virus-host interactions is still limited. Here, we perform a genome-wide gain-of-function screen using a poorly permissive hepatoma cell line to uncover host factors enhancing HBV infection. Validation studies in primary human hepatocytes identified CDKN2C as an important host factor for HBV replication. CDKN2C is overexpressed in highly permissive cells and HBV-infected patients. Mechanistic studies show a role for CDKN2C in inducing cell cycle G1 arrest through inhibition of CDK4/6 associated with the upregulation of HBV transcription enhancers. A correlation between CDKN2C expression and disease progression in HBV-infected patients suggests a role in HBV-induced liver disease. Taken together, we identify a previously undiscovered clinically relevant HBV host factor, allowing the development of improved infectious model systems for drug discovery and the study of the HBV life cycle.
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Affiliation(s)
- Carla Eller
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, F-67000, Strasbourg, France
| | - Laura Heydmann
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, F-67000, Strasbourg, France
| | - Che C Colpitts
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, F-67000, Strasbourg, France
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada
| | - Houssein El Saghire
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, F-67000, Strasbourg, France
| | - Federica Piccioni
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
| | - Frank Jühling
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, F-67000, Strasbourg, France
| | - Karim Majzoub
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, F-67000, Strasbourg, France
| | - Caroline Pons
- Inserm, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
| | - Charlotte Bach
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, F-67000, Strasbourg, France
| | - Julie Lucifora
- Inserm, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
| | - Joachim Lupberger
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, F-67000, Strasbourg, France
| | - Michael Nassal
- Department of Internal Medicine II/Molecular Biology, University Hospital Freiburg, Freiburg, Germany
| | - Glenn S Cowley
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
| | - Naoto Fujiwara
- Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Sen-Yung Hsieh
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taipei, Taiwan
| | - Yujin Hoshida
- Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Emanuele Felli
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, F-67000, Strasbourg, France
- Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil, 67000, Strasbourg, France
| | - Patrick Pessaux
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, F-67000, Strasbourg, France
- Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil, 67000, Strasbourg, France
| | - Camille Sureau
- Laboratoire de Virologie Moléculaire, INTS, Paris, France
| | - Catherine Schuster
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, F-67000, Strasbourg, France
| | - David E Root
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
| | - Eloi R Verrier
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, F-67000, Strasbourg, France.
| | - Thomas F Baumert
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, F-67000, Strasbourg, France.
- Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil, 67000, Strasbourg, France.
- Institut Universitaire de France (IUF), Paris, France.
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17
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Mailly L, Baumert TF. Hepatitis C virus infection and tight junction proteins: The ties that bind. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2020; 1862:183296. [PMID: 32268133 DOI: 10.1016/j.bbamem.2020.183296] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 03/25/2020] [Accepted: 03/28/2020] [Indexed: 02/07/2023]
Abstract
The hepatitis C virus (HCV) is a major cause of liver diseases ranging from liver inflammation to advanced liver diseases like cirrhosis and hepatocellular carcinoma (HCC). HCV infection is restricted to the liver, and more specifically to hepatocytes, which represent around 80% of liver cells. The mechanism of HCV entry in human hepatocytes has been extensively investigated since the discovery of the virus 30 years ago. The entry mechanism is a multi-step process relying on several host factors including heparan sulfate proteoglycan (HSPG), low density lipoprotein receptor (LDLR), tetraspanin CD81, Scavenger Receptor class B type I (SR-BI), Epidermal Growth Factor Receptor (EGFR) and Niemann-Pick C1-like 1 (NPC1L1). Moreover, in order to establish a persistent infection, HCV entry is dependent on the presence of tight junction (TJ) proteins Claudin-1 (CLDN1) and Occludin (OCLN). In the liver, tight junction proteins play a role in architecture and homeostasis including sealing the apical pole of adjacent cells to form bile canaliculi and separating the basolateral domain drained by sinusoidal blood flow. In this review, we will highlight the role of liver tight junction proteins in HCV infection, and we will discuss the potential targeted therapeutic approaches to improve virus eradication.
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Affiliation(s)
- Laurent Mailly
- Université de Strasbourg, INSERM, UMR-S1110, Institut de Recherche sur les Maladies Virales et Hépatiques, F-67000 Strasbourg, France.
| | - Thomas F Baumert
- Université de Strasbourg, INSERM, UMR-S1110, Institut de Recherche sur les Maladies Virales et Hépatiques, F-67000 Strasbourg, France; Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, F-67000 Strasbourg, France; Institut Universitaire de France, F-75231 Paris, France.
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18
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Lee H, Jarhad DB, Yu J, Lee C, Jeong LS. Asymmetric Synthesis of 2'- C-Methyl-4'-selenonucleosides as Anti-Hepatitis C Virus Agents. J Org Chem 2019; 84:14414-14426. [PMID: 31608633 DOI: 10.1021/acs.joc.9b01462] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
In search of a new template for anti-hepatitis C virus (HCV) agents, we designed and synthesized the 2'-C-methyl-4'-selenopyrimidine and -purine nucleosides and their phosphoramidate prodrugs to replace a furanose oxygen of anti-HCV nucleos(t)ides with a selenium atom on the basis that selenium is a chemical isostere of oxygen. These nucleosides are expected to show different physicochemical properties such as better lipophilicity which might enhance the penetration across cell membranes and the conformational constraint induced by a bulky selenium atom in the sugar ring. The 2'-C-methyl-4'-selenopyrimidine and -purine nucleosides 8 and 9 were synthesized from 2-C-methyl-d-ribono-γ-lactone (14) via construction of 2-C-methyl-d-selenosugar 18 through C-4 epimerization and SN2 cyclization with Se2- as key steps. The key 4'-selenosugar was converted to the 2'-C-methyl-4'-selenopyrimidine and -purine nucleosides using Pummerer-type rearrangement and Vorbrüggen glycosylation, respectively. In addition, the ProTide strategy has been applied to synthesize the adenine and uracil phosphoramidate derivatives 10a and 10b to overcome the limitations associated with parent nucleosides such as inefficient conversion to their corresponding 5'-monophosphate form and poor cellular uptake. The regio- and stereochemistry of 4'-selenonucleosides were confirmed by 2D NOESY NMR spectroscopy and X-ray crystallography. None of the final pyrimidine and purine nucleosides and their prodrugs exhibited significant anti-HCV activity up to 100 μM.
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Affiliation(s)
- Hyejin Lee
- Research Institute of Pharmaceutical Sciences, College of Pharmacy , Seoul National University , Seoul 08820 , Korea
| | - Dnyandev B Jarhad
- Research Institute of Pharmaceutical Sciences, College of Pharmacy , Seoul National University , Seoul 08820 , Korea
| | - Jinha Yu
- Research Institute of Pharmaceutical Sciences, College of Pharmacy , Seoul National University , Seoul 08820 , Korea
| | - Choongho Lee
- College of Pharmacy , Dongguk University , Goyang , Gyeonggi-do 10326 , Korea
| | - Lak Shin Jeong
- Research Institute of Pharmaceutical Sciences, College of Pharmacy , Seoul National University , Seoul 08820 , Korea
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19
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Hu JH, Chang ML, Liu NJ, Yeh CT, Huang TJ. Effect of HCV treatment response on insulin resistance: A systematic review and meta-analysis. Exp Ther Med 2019; 18:3568-3578. [PMID: 31602234 PMCID: PMC6777273 DOI: 10.3892/etm.2019.7995] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 08/08/2019] [Indexed: 02/06/2023] Open
Abstract
Sustained virological response (SVR) in hepatitis C virus (HCV) patients treated with pegylated interferon α-2a and ribavirin is associated with reduced insulin resistance (IR), measured as a reduction of homeostasis model assessment (HOMA) scores after 24 weeks of therapy, and reduced fasting serum insulin and serum glucose levels. The present meta-analysis aimed to evaluate the effect of HCV treatment response on IR in HCV patients who achieved SVR and those who did not (non-SVR) after receiving interferon (IFN)-based therapy. The PubMed, Cochrane and Embase databases were searched using combinations of the following search terms: ‘HCV’, ‘hepatitis C’, ‘interferon’, ‘antiviral’, ‘treatment response’ and ‘insulin resistance’. The incidence of IR, HOMA-IR and HOMA-β, as well as fasting glucose and fasting insulin levels, were summarized in terms of basal values and values after the end of treatment for each study. A total of 8 studies were included in the final analysis. There was no significant difference in the reduction in IR between the SVR and non-SVR groups (odds ratio, 0.995; 95% CI=0.613–1.616; P=0.984). However, the SVR group had a significantly higher mean reduction in HOMA-IR (difference in means=−0.485; 95%CI=−0.713 to −0.256; P<0.001) and HOMA-β (difference in means=−15.448; 95%CI=−23.326 to −7.570; P<0.001) compared to the non-SVR group. In conclusion, HCV patients who achieved SVR after IFN-based therapy exhibited improvement in HOMA-IR and HOMA-β. The present results suggest that clinical management of IR and serum glucose levels may be an important way to impact the therapeutic response in HCV patients.
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Affiliation(s)
- Jing-Hong Hu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Yunlin 63862, Taiwan, R.O.C
| | - Ming-Ling Chang
- Department of Gastroenterology and Hepatology, Liver Research Center, Chang Gung Memorial Hospital, Linkou 33305, Taiwan, R.O.C.,Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 33378, Taiwan, R.O.C.,Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou 33305, Taiwan, R.O.C
| | - Nai-Jen Liu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou 33305, Taiwan, R.O.C
| | - Chu-Ting Yeh
- Department of Gastroenterology and Hepatology, Liver Research Center, Chang Gung Memorial Hospital, Linkou 33305, Taiwan, R.O.C.,Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 33378, Taiwan, R.O.C.,Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou 33305, Taiwan, R.O.C
| | - Tung-Jung Huang
- Division of Thoracic Medicine, Department of Internal Medicine and Department of Medicine, Chang Gung Memorial Hospital, Yunlin 63862, Taiwan, R.O.C
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20
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Caroleo B, Caroleo MC, Cimellaro A, Colangelo L, Perticone M, Di Mizio G, De Sarro G, Gallelli L. Glecaprevir/Pibrentasvir Induced Cholestatic Jaundice in a HCV Patient with Renal Failure. A Case Presentation. Curr Drug Saf 2019; 14:67-71. [PMID: 30444202 DOI: 10.2174/1574886313666181116100452] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 10/25/2018] [Accepted: 11/12/2018] [Indexed: 12/26/2022]
Abstract
BACKGROUND Direct-acting Antivirals (DAA) are currently used in the treatment of chronic HCV infection. In patients with renal failure Glecaprevir/Pibrentasvir (genotype 1-6) is recommended for its safety and efficacy. CASE PRESENTATION Although these pharmacological characteristics, an adverse drug reaction (ADR) has been reported during Glecaprevir/Pibrentasvir treatment, such as the development of cholestatic jaundice in an elderly patient with chronic HCV (genotype 2) infection. At examination, patient was jaundiced associated with intense pruritus. RESULTS Ultrasound and laboratory biochemical tests excluded a liver failure (e.g. liver cancer, and liver lithiasis) or pancreatic cancer while Naranjo probability scale (score 6) suggested an association between cholestatic jaundice and Glecaprevir/Pibrentasvir administration. About 1 month after drug discontinuation, an improvement has been documented in both jaundice and pruritus, with a normalization in bilirubin levels (total bilirubin: 0.96 mg/dL), HCV-RNA was undetected also. It is worth mentioning that although we reported the development of cholestatic jaundice upon treatment with Glecaprevir/Pibrentasvir we recorded a clinical efficacy (HCV-RNA <15 IU/L) after 4 weeks from the beginning of the treatment, with a complete remission of clinical symptoms until 7 months after drug discontinuation. CONCLUSION These data support the clinical efficacy of Glecaprevir/Pibrentasvir association in elderly patients, despite the sub-optimal period of treatment.
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Affiliation(s)
- Benedetto Caroleo
- Department of Medical and Surgical Science, Elderly Operative Unit, Mater Domini Hospital, University of Catanzaro, Catanzaro, Italy
| | - Maria Cristina Caroleo
- Department of Pharmacy Health and Nutritional Sciences, University of Calabria, Rende (CS), Calabria, Italy
| | - Antonio Cimellaro
- Department of Medical and Surgical Science, Elderly Operative Unit, Mater Domini Hospital, University of Catanzaro, Catanzaro, Italy
| | - Lidia Colangelo
- Department of Medical and Surgical Science, Elderly Operative Unit, Mater Domini Hospital, University of Catanzaro, Catanzaro, Italy
| | - Maria Perticone
- Department of Medical and Surgical Science, Elderly Operative Unit, Mater Domini Hospital, University of Catanzaro, Catanzaro, Italy
| | - Giulio Di Mizio
- Department of Law and Economic Science, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Giovambattista De Sarro
- Department of Health Sciences, Clinical Pharmacology and Pharmacovigilance Unit, Mater Domini Hospital, University of Catanzaro, Catanzaro, Italy
| | - Luca Gallelli
- Department of Health Sciences, Clinical Pharmacology and Pharmacovigilance Unit, Mater Domini Hospital, University of Catanzaro, Catanzaro, Italy
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21
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Fukasawa M. [Anti-hepatitis C Virus Strategy Targeting the Entry Steps]. YAKUGAKU ZASSHI 2019; 139:89-95. [PMID: 30606936 DOI: 10.1248/yakushi.18-00164-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Hepatitis C virus (HCV) infection is a major leading cause of chronic severe liver diseases such as cirrhosis and hepatocellular carcinoma. The recent direct-acting antivirals (DAAs) for the treatment of HCV infection offer very high cure rates, but DAAs are vulnerable to drug resistance because HCV is an RNA virus, which generally has very high mutation rates. DAA resistance-associated variants of HCV could reduce the effectiveness of DAAs in the future. Thus, the continuous development of new anti-HCV drugs against different target molecules is needed. We have been studying the host factors involved in HCV entry into cells. From those studies, we obtained novel candidates for host-targeting anti-HCV entry inhibitors, such as monoclonal antibodies against HCV receptors, which can be used together with DAAs. In this symposium review, we present and discuss our recent work on anti-HCV strategies targeting HCV entry steps.
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Affiliation(s)
- Masayoshi Fukasawa
- Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases
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22
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Heterogeneity and coexistence of oncogenic mechanisms involved in HCV-associated B-cell lymphomas. Crit Rev Oncol Hematol 2019; 138:156-171. [PMID: 31092372 DOI: 10.1016/j.critrevonc.2019.04.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 04/02/2019] [Accepted: 04/03/2019] [Indexed: 12/15/2022] Open
Abstract
The association of HCV-infection with B-lymphomas is supported by the regression of most indolent/low-grade lymphomas following anti-viral therapy. Studies on direct and indirect oncogenic mechanisms have elucidated the pathogenesis of HCV-associated B-lymphoma subtypes. These include B-lymphocyte proliferation and sustained clonal expansion by HCV-envelope protein stimulation of B-cell receptors, and prolonged HCV-infected B-cell growth by overexpression of an anti-apoptotic BCL-2 oncogene caused by the increased frequency of t(14;18) chromosomal translocations in follicular lymphomas. HCV has been implicated in lymphomagenesis by a "hit-and-run" mechanism, inducing enhanced mutation rate in immunoglobulins and anti-oncogenes favoring immune escape, due to permanent genetic damage by double-strand DNA-breaks. More direct oncogenic mechanisms have been identified in cytokines and chemokines in relation to NS3 and Core expression, particularly in diffuse large B-cell lymphoma. By reviewing genetic alterations and disrupted signaling pathways, we intend to highlight how mutually non-contrasting mechanisms cooperate with environmental factors toward progression of HCV-lymphoma.
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23
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Stanciu C, Trifan A, Muzica C, Sfarti C. Efficacy and safety of alisporivir for the treatment of hepatitis C infection. Expert Opin Pharmacother 2019; 20:379-384. [PMID: 30576256 DOI: 10.1080/14656566.2018.1560424] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Accepted: 12/14/2018] [Indexed: 02/07/2023]
Abstract
Alisporivir (ALV) (previously known as Debio 025) is a potent, pangenotypic host-targeting antiviral oral agent acting on cyclophilin A, which is necessary for HCV replication. Areas covered: This article reviews the therapeutic efficacy and safety of ALV for the treatment of HCV infection. Expert opinion: Direct-acting antivirals (DAAs) have revolutionized the HCV antiviral treatment paradigm with success rates well above 95% for all HCV genotypes. However, challenges still remain in certain patient populations such as those who have developed resistance and have experienced multi-DAA failure. To cure HCV infection, a treatment regimen must combine antiviral potency and a high barrier to resistance. ALV fulfills this need as shown by the studies evaluating its clinical efficacy. Nevertheless, ALV missed the chance to be included in the HCV treatment armamentarium after the FDA halted clinical studies following reports of serious side effects (three cases of pancreatitis, one lethal). However, it is possible that ALV could still be considered for HCV-infected non-cirrhotic patients that are infected with a multiresistant virus or with HCV genotype 3, although it must be said that the drug industry would be reluctant to invest in new antivirals if the current clinical need is effectively met.
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Affiliation(s)
- Carol Stanciu
- a Department of Gastroenterology , Grigore T. Popa University of Medicine and Pharmacy , Iasi , Romania
- b Department of Gastroenterology , St. Spiridon, Emergency Clinical Hospital , Iasi , Romania
| | - Anca Trifan
- a Department of Gastroenterology , Grigore T. Popa University of Medicine and Pharmacy , Iasi , Romania
- b Department of Gastroenterology , St. Spiridon, Emergency Clinical Hospital , Iasi , Romania
| | - Cristina Muzica
- b Department of Gastroenterology , St. Spiridon, Emergency Clinical Hospital , Iasi , Romania
| | - Catalin Sfarti
- a Department of Gastroenterology , Grigore T. Popa University of Medicine and Pharmacy , Iasi , Romania
- b Department of Gastroenterology , St. Spiridon, Emergency Clinical Hospital , Iasi , Romania
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Alazard-Dany N, Denolly S, Boson B, Cosset FL. Overview of HCV Life Cycle with a Special Focus on Current and Possible Future Antiviral Targets. Viruses 2019; 11:v11010030. [PMID: 30621318 PMCID: PMC6356578 DOI: 10.3390/v11010030] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 12/31/2018] [Accepted: 01/02/2019] [Indexed: 12/12/2022] Open
Abstract
Hepatitis C infection is the leading cause of liver diseases worldwide and a major health concern that affects an estimated 3% of the global population. Novel therapies available since 2014 and 2017 are very efficient and the WHO considers HCV eradication possible by the year 2030. These treatments are based on the so-called direct acting antivirals (DAAs) that have been developed through research efforts by academia and industry since the 1990s. After a brief overview of the HCV life cycle, we describe here the functions of the different targets of current DAAs, the mode of action of these DAAs and potential future inhibitors.
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Affiliation(s)
- Nathalie Alazard-Dany
- CIRI-Centre International de Recherche en Infectiologie, Univ Lyon, Université Claude Bernard Lyon 1, Inserm, U1111, CNRS, UMR5308, ENS Lyon, F-69007 Lyon, France.
| | - Solène Denolly
- CIRI-Centre International de Recherche en Infectiologie, Univ Lyon, Université Claude Bernard Lyon 1, Inserm, U1111, CNRS, UMR5308, ENS Lyon, F-69007 Lyon, France.
| | - Bertrand Boson
- CIRI-Centre International de Recherche en Infectiologie, Univ Lyon, Université Claude Bernard Lyon 1, Inserm, U1111, CNRS, UMR5308, ENS Lyon, F-69007 Lyon, France.
| | - François-Loïc Cosset
- CIRI-Centre International de Recherche en Infectiologie, Univ Lyon, Université Claude Bernard Lyon 1, Inserm, U1111, CNRS, UMR5308, ENS Lyon, F-69007 Lyon, France.
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25
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Baumert TF, Berg T, Lim JK, Nelson DR. Status of Direct-Acting Antiviral Therapy for Hepatitis C Virus Infection and Remaining Challenges. Gastroenterology 2019; 156:431-445. [PMID: 30342035 PMCID: PMC6446912 DOI: 10.1053/j.gastro.2018.10.024] [Citation(s) in RCA: 141] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 10/05/2018] [Accepted: 10/08/2018] [Indexed: 12/12/2022]
Abstract
Chronic infection with hepatitis C virus is a major cause of liver disease and hepatocellular carcinoma worldwide. After the discovery of hepatitis C virus 3 decades ago, the identification of the structure of the viral proteins, combined with high-throughput replicon models, enabled the discovery and development of direct-acting antivirals. These agents have revolutionized patient care, with cure rates of more than 90%. We review the status of direct-acting antiviral therapies for hepatitis C virus infection and discuss remaining challenges. We highlight licensed compounds, discuss the potential to shorten therapy even further, and review different options for treatment failure and resistance. We also provide an overview of clinical experience with generic agents and evidence for their efficacy. Finally, we discuss the need for new drugs and outline promising targets for future therapies.
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Affiliation(s)
- Thomas F Baumert
- INSERM, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France; Université de Strasbourg, Strasbourg, France; Pôle Hépato-digestif, Institut Hospitalo-Universitaire, Nouvel Hôpital Civil, Strasbourg, France.
| | - Thomas Berg
- Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, Leipzig, Germany
| | - Joseph K Lim
- Section of Digestive Diseases and Yale Liver Center, Yale University School of Medicine, New Haven, Connecticut
| | - David R Nelson
- Department of Medicine, University of Florida, Gainesville, Florida.
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26
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Mailly L, Wrensch F, Heydmann L, Fauvelle C, Brignon N, Zeisel MB, Pessaux P, Keck ZY, Schuster C, Fuerst TR, Foung SKH, Baumert TF. In vivo combination of human anti-envelope glycoprotein E2 and -Claudin-1 monoclonal antibodies for prevention of hepatitis C virus infection. Antiviral Res 2018; 162:136-141. [PMID: 30599173 DOI: 10.1016/j.antiviral.2018.12.018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Revised: 11/14/2018] [Accepted: 12/28/2018] [Indexed: 12/20/2022]
Abstract
Despite the development of direct-acting antivirals (DAAs), hepatitis C virus (HCV) infection remains a major cause for liver disease and cancer worldwide. Entry inhibitors block virus host cell entry and, therefore, prevent establishment of chronic infection and liver disease. Due to their unique mechanism of action, entry inhibitors provide an attractive antiviral strategy in organ transplantation. In this study, we developed an innovative approach in preventing HCV infection using a synergistic combination of a broadly neutralizing human monoclonal antibody (HMAb) targeting the HCV E2 protein and a host-targeting anti-claudin 1 (CLDN1) humanized monoclonal antibody. An in vivo proof-of-concept study in human liver-chimeric FRG-NOD mice proved the efficacy of the combination therapy at preventing infection by an HCV genotype 1b infectious serum. While administration of individual antibodies at lower doses only showed a delay in HCV infection, the combination therapy was highly protective. Furthermore, the combination proved to be effective in preventing infection of primary human hepatocytes by neutralization-resistant HCV escape variants selected during liver transplantation, suggesting that a combination therapy is suited for the neutralization of difficult-to-treat variants. In conclusion, our findings suggest that the combination of two HMAbs targeting different steps of virus entry improves treatment efficacy while simultaneously reducing treatment duration and costs. Our approach not only provides a clinical perspective to employ HMAb combination therapies to prevent graft re-infection and its associated liver disease but may also help to alleviate the urgent demand for organ transplants by allowing the transplantation of organs from HCV-positive donors.
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Affiliation(s)
- Laurent Mailly
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000, Strasbourg, France; Université de Strasbourg, 67000, Strasbourg, France
| | - Florian Wrensch
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000, Strasbourg, France; Université de Strasbourg, 67000, Strasbourg, France
| | - Laura Heydmann
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000, Strasbourg, France; Université de Strasbourg, 67000, Strasbourg, France
| | - Catherine Fauvelle
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000, Strasbourg, France; Université de Strasbourg, 67000, Strasbourg, France
| | - Nicolas Brignon
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000, Strasbourg, France; Université de Strasbourg, 67000, Strasbourg, France
| | - Mirjam B Zeisel
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000, Strasbourg, France; Université de Strasbourg, 67000, Strasbourg, France; Inserm U1052, CNRS UMR 5286, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL), Lyon, France
| | - Patrick Pessaux
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000, Strasbourg, France; Université de Strasbourg, 67000, Strasbourg, France; Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - Zhen-Yong Keck
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
| | - Catherine Schuster
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000, Strasbourg, France; Université de Strasbourg, 67000, Strasbourg, France
| | - Thomas R Fuerst
- University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, MD, USA; Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD, USA
| | - Steven K H Foung
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
| | - Thomas F Baumert
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000, Strasbourg, France; Université de Strasbourg, 67000, Strasbourg, France; Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; Institut Universitaire de France, Paris, France.
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27
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Dengue drug discovery: Progress, challenges and outlook. Antiviral Res 2018; 163:156-178. [PMID: 30597183 DOI: 10.1016/j.antiviral.2018.12.016] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 12/22/2018] [Accepted: 12/25/2018] [Indexed: 12/14/2022]
Abstract
In the context of the only available vaccine (DENGVAXIA) that was marketed in several countries, but poses higher risks to unexposed individuals, the development of antivirals for dengue virus (DENV), whilst challenging, would bring significant benefits to public health. Here recent progress in the field of DENV drug discovery made in academic laboratories and industry is reviewed. Characteristics of an ideal DENV antiviral molecule, given the specific immunopathology provoked by this acute viral infection, are described. New chemical classes identified from biochemical, biophysical and phenotypic screens that target viral (especially NS4B) and host proteins, offer promising opportunities for further development. In particular, new methodologies ("omics") can accelerate the discovery of much awaited flavivirus specific inhibitors. Challenges and opportunities in lead identification activities as well as the path to clinical development of dengue drugs are discussed. To galvanize DENV drug discovery, collaborative public-public partnerships and open-access resources will greatly benefit both the DENV research community and DENV patients.
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28
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Onda M, Hakamata W. Antiviral Activity and Mechanism of Action of Endoplasmic Reticulum Glucosidase Inhibitors: A Mini Review. TRENDS GLYCOSCI GLYC 2018. [DOI: 10.4052/tigg.1753.1j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Affiliation(s)
- Momoko Onda
- Department of Chemistry and Life Science, College of Bioresource Sciences, Nihon University
| | - Wataru Hakamata
- Department of Chemistry and Life Science, College of Bioresource Sciences, Nihon University
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