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Tripathi A, Chauhan S, Khasa R. A Comprehensive Review of the Development and Therapeutic Use of Antivirals in Flavivirus Infection. Viruses 2025; 17:74. [PMID: 39861863 PMCID: PMC11769230 DOI: 10.3390/v17010074] [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: 11/09/2024] [Revised: 12/29/2024] [Accepted: 12/30/2024] [Indexed: 01/27/2025] Open
Abstract
Flaviviruses are a diverse group of viruses primarily transmitted through hematophagous insects like mosquitoes and ticks. Significant expansion in the geographic range, prevalence, and vectors of flavivirus over the last 50 years has led to a dramatic increase in infections that can manifest as hemorrhagic fever or encephalitis, leading to prolonged morbidity and mortality. Millions of infections every year pose a serious threat to worldwide public health, encouraging scientists to develop a better understanding of the pathophysiology and immune evasion mechanisms of these viruses for vaccine development and antiviral therapy. Extensive research has been conducted in developing effective antivirals for flavivirus. Various approaches have been extensively utilized in clinical trials for antiviral development, targeting virus entry, replication, polyprotein synthesis and processing, and egress pathways exploiting virus as well as host proteins. However, to date, no licensed antiviral drug exists to treat the diseases caused by these viruses. Understanding the mechanisms of host-pathogen interaction, host immunity, viral immune evasion, and disease pathogenesis is highly warranted to foster the development of antivirals. This review provides an extensively detailed summary of the most recent advances in the development of antiviral drugs to combat diseases.
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Affiliation(s)
- Aarti Tripathi
- Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA;
- Galveston National Laboratory, Galveston, TX 77555, USA
| | - Shailendra Chauhan
- Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA;
- Galveston National Laboratory, Galveston, TX 77555, USA
| | - Renu Khasa
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami/UHealth, Miami, FL 33136, USA
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Bagheri S, Fard GB, Talkhi N, Rashidi Zadeh D, Mobarra N, Mousavinezhad S, Khamse FM, Hosseini Bafghi M. Laboratory Biochemical and Hematological Parameters: Early Predictive Biomarkers for Diagnosing Hepatitis C Virus Infection. J Clin Lab Anal 2024; 38:e25127. [PMID: 39569979 DOI: 10.1002/jcla.25127] [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: 08/28/2024] [Revised: 10/20/2024] [Accepted: 11/09/2024] [Indexed: 11/22/2024] Open
Abstract
BACKGROUND Hepatitis C virus (HCV) infection is a worldwide concern, causing liver damage and necessitating early detection to prevent its spread. Studies indicate that evaluating changes in biochemical and hematological parameters, which serve as suitable predictors of inflammation, can be a reasonable method for diagnosing hepatitis C infection. METHODS This study analyzed 100 samples from high-risk patients positively identified via quantitative real-time PCR (qPCR). Anti-HCV titers, biochemical and inflammatory tests, and complete blood cell counts (CBCs) were performed for these individuals. Additionally, 100 HCV-negative individuals with normal laboratory results were selected as the control group. Receiver operating characteristic (ROC) curves were plotted to determine the cutoff values of the laboratory parameters. RESULTS According to the findings, the age, average white blood cell (WBC) count, platelet-to-lymphocyte ratio (PLR), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), lactate dehydrogenase (LDH), total bilirubin (TBIL), direct bilirubin (DBIL), alkaline phosphatase (ALP), serum glutamic-pyruvic transaminase (SGPT), and ferritin levels were significantly higher in HCV patients. On the other hand, red blood cell (RBC) counts, neutrophils, lymphocytes, hemoglobin-to-platelet ratio (HPR), and iron (Fe) levels were significantly lower in the case group compared to those in the control group (p < 0.05). Furthermore, the ROC curve analysis revealed that lymphocyte count, neutrophil count, and PLR were very strong predictors for hepatitis C infection (p < 0.0001, AUC = 1). CONCLUSION The study highlights significant biochemical and hematological differences between HCV patients and healthy subjects. These biomarkers are crucial for early diagnosis, potentially preventing liver damage and reducing HCV transmission.
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Affiliation(s)
- Saeede Bagheri
- Department of Laboratory Sciences, School of Paramedical and Rehabilitation Sciences, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ghazaleh Behrouzian Fard
- Department of Laboratory Sciences, School of Paramedical and Rehabilitation Sciences, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Nasrin Talkhi
- Department of Biostatistics, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davoud Rashidi Zadeh
- Department of Microbiology, Faculty of Basic Sciences, Mashhad Branch, Islamic Azad University, Mashhad, Iran
| | - Naser Mobarra
- Department of Laboratory Sciences, School of Paramedical and Rehabilitation Sciences, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyedmahdi Mousavinezhad
- Department of Laboratory Sciences, School of Paramedical Sciences, Sabzevar University of Medical Sciences, Sabzevar, Iran
| | - Fatemeh Mirzaeian Khamse
- Department of Laboratory Sciences, School of Paramedical and Rehabilitation Sciences, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahdi Hosseini Bafghi
- Department of Laboratory Sciences, School of Paramedical and Rehabilitation Sciences, Mashhad University of Medical Sciences, Mashhad, Iran
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Gonzales-Zamora JA, Quispe-Vicuña C, Reategui-Garcia ME, Araoz-Salinas JM, Ccami-Bernal F, Morocho-Alburqueque N, Espinoza-Herreros JP, Layme J, Aquino-Sandoval G, Campos VYM, Alave J. Identifying Gaps in the Treatment Guidelines for Hepatitis C in Peru to Meet International Standards: A Narrative Review. J Clin Med 2024; 13:3867. [PMID: 38999433 PMCID: PMC11242551 DOI: 10.3390/jcm13133867] [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: 05/04/2024] [Revised: 06/16/2024] [Accepted: 06/25/2024] [Indexed: 07/14/2024] Open
Abstract
Hepatitis C virus still represents a major cause of morbidity and mortality worldwide. In Peru, two national practice guidelines for the management of this infection were published more than 5 years ago; however, the latest breakthroughs in the treatment make it necessary to update these guidelines. We reviewed the most recent recommendations of the international guidelines and compared them with the current Peruvian guidelines. We found major differences, such as the use of Glecaprevir/Pibrentasvir as a first-line therapy, which is contemplated in the World Health Organization guideline, and recommended by American and European guidelines, but is not considered in the Peruvian guidelines. Another crucial difference lies in the management of patients with chronic kidney disease, who are treated nowadays with a variety of direct-acting antivirals, with no restrictions on the use of Sofosbuvir-based regimens in first-world countries, an approach that has not been adopted in Peru. We believe that standardization of the recommendations of the Peruvian guidelines is imperative, including the new therapeutic strategies that have emerged in recent years. We also suggest conducting a cost effectiveness analysis in the Peruvian context to allow for the implementation of new antivirals, and to achieve a better control of hepatitis C in the country.
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Affiliation(s)
- Jose A. Gonzales-Zamora
- Division of Infectious Diseases, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136, USA;
- Peruvian American Medical Society (PAMS), Albuquerque, NM 87111, USA; (J.M.A.-S.); (J.L.); (V.Y.M.C.)
| | | | - Martín E. Reategui-Garcia
- School of Medicine, Universidad Nacional de la Amazonía Peruana, Iquitos 16000, Peru; (M.E.R.-G.); (G.A.-S.)
| | - Julieta M. Araoz-Salinas
- Peruvian American Medical Society (PAMS), Albuquerque, NM 87111, USA; (J.M.A.-S.); (J.L.); (V.Y.M.C.)
| | - Fabricio Ccami-Bernal
- School of Medicine, Universidad Nacional de San Agustín de Arequipa, Arequipa 04001, Peru;
| | | | | | - Josue Layme
- Peruvian American Medical Society (PAMS), Albuquerque, NM 87111, USA; (J.M.A.-S.); (J.L.); (V.Y.M.C.)
- School of Medicine, Universidad Nacional Mayor de San Marcos, Lima 15001, Peru
| | - Gabriel Aquino-Sandoval
- School of Medicine, Universidad Nacional de la Amazonía Peruana, Iquitos 16000, Peru; (M.E.R.-G.); (G.A.-S.)
- Sociedad Científica de Estudiantes de Medicina de la Amazonía Peruana (SOCIEMAP), Universidad Nacional de la Amazonía Peruana, Iquitos 16000, Peru
| | - Victor Y. Melt Campos
- Peruvian American Medical Society (PAMS), Albuquerque, NM 87111, USA; (J.M.A.-S.); (J.L.); (V.Y.M.C.)
- Department of Community Health and Family Medicine, College of Medicine, University of Florida, Jacksonville, FL 32209, USA
| | - Jorge Alave
- School of Medicine, Universidad Peruana Union, Lima 15464, Peru
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Ahmad G, Sohail M, Bilal M, Rasool N, Qamar MU, Ciurea C, Marceanu LG, Misarca C. N-Heterocycles as Promising Antiviral Agents: A Comprehensive Overview. Molecules 2024; 29:2232. [PMID: 38792094 PMCID: PMC11123935 DOI: 10.3390/molecules29102232] [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: 03/07/2024] [Revised: 04/22/2024] [Accepted: 05/03/2024] [Indexed: 05/26/2024] Open
Abstract
Viruses are a real threat to every organism at any stage of life leading to extensive infections and casualties. N-heterocycles can affect the viral life cycle at many points, including viral entrance into host cells, viral genome replication, and the production of novel viral species. Certain N-heterocycles can also stimulate the host's immune system, producing antiviral cytokines and chemokines that can stop the reproduction of viruses. This review focused on recent five- or six-membered synthetic N-heterocyclic molecules showing antiviral activity through SAR analyses. The review will assist in identifying robust scaffolds that might be utilized to create effective antiviral drugs with either no or few side effects.
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Affiliation(s)
- Gulraiz Ahmad
- Department of Chemistry, Government College University, Faisalabad 38000, Pakistan; (G.A.); (M.S.)
| | - Maria Sohail
- Department of Chemistry, Government College University, Faisalabad 38000, Pakistan; (G.A.); (M.S.)
| | - Muhammad Bilal
- School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China;
| | - Nasir Rasool
- Department of Chemistry, Government College University, Faisalabad 38000, Pakistan; (G.A.); (M.S.)
| | - Muhammad Usman Qamar
- Institute of Microbiology, Faculty of Life Sciences, Government College University, Faisalabad 38000, Pakistan;
- Division of Infectious Diseases, Geneva University Hospitals, 1205 Geneva, Switzerland
- Department of Microbiology and Molecular Medicine, University of Geneva, 1205 Geneva, Switzerland
| | - Codrut Ciurea
- Faculty of Medicine, Transilvania University of Brasov, 500036 Brasov, Romania; (L.G.M.)
| | - Luigi Geo Marceanu
- Faculty of Medicine, Transilvania University of Brasov, 500036 Brasov, Romania; (L.G.M.)
| | - Catalin Misarca
- Faculty of Medicine, Transilvania University of Brasov, 500036 Brasov, Romania; (L.G.M.)
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Abdelaziz SMH. Morphometric, biochemical and histopathological effects of sofosbuvir (sovaldi) on testes of adult male albino rats. Ultrastruct Pathol 2024; 48:94-107. [PMID: 38160400 DOI: 10.1080/01913123.2023.2295453] [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: 09/19/2023] [Accepted: 12/12/2023] [Indexed: 01/03/2024]
Abstract
Sofosbuvir treatment regimens for chronic HCV infection have recently been linked to extra hepatic side effects. This study aimed to show how sofosbuvir affected the adult male albino rat testis. Forty adult male albino rats were used. The rats were equally split into two main groups (I and II), then each group subdivided into two subgroups (A and B). Each rat in group I (control) received 0.5 ml of distilled water every day for four weeks. Each rat in group II (sofosbuvir-treated) received 0.5 ml of distilled water containing 7.2 mg of sofosbuvir every day for four weeks. After four weeks (subgroups IA and IIA) and eight weeks (subgroups IB and IIB) of treatment, the rats were sacrificed. Histological, biochemical, and morphometric studies on the testes were conducted. The data were analyzed. Examination of testes of sovaldi treated group revealed histopathological changes. Biochemical and morphometric analysis showed reduced levels of reduced glutathione and seminiferous tubule epithelial height respectively. Following a 4-week drug withdrawal period, the testes only partially recovered. We concluded that sofosbuvir induced deteriorating changes in the adult male albino rats' testes. These changes were proved by histological and biochemical studies. These changes were incompletely reversible after cession of treatment. Researches investigating the effect of adding drugs that have antioxidant properties during sofosbuvir therapy are recommended.
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Affiliation(s)
- Safaa M H Abdelaziz
- Department of Anatomy and Physiology, College of Medicine, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
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Ngari JW, Leumi S, Han L, Liu C, Tong Y, Zhong J. Identification and characterization of Sofosbuvir-resistant mutations of hepatitis C virus genotype 3a replicon. J Med Virol 2023; 95:e29290. [PMID: 38102947 DOI: 10.1002/jmv.29290] [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: 09/27/2023] [Revised: 11/11/2023] [Accepted: 11/12/2023] [Indexed: 12/17/2023]
Abstract
Hepatitis C virus (HCV) infection is a major cause of chronic liver disease worldwide. Among its 8 genotypes (GT), GT3 has a relatively lower sustained virological response to highly effective direct-acting antiviral agents (DAA). Sofosbuvir (SOF), an anti-NS5B polymerase inhibitor, is a core component of many anti-HCV DAA cocktail regimens, and its resistant mutations are rare in clinics because these mutations usually severely impair the NS5B polymerase activity, including a mutation S282T in NS5B, the most frequently reported SOF-resistant mutation. In this study, we selected SOF-resistant variants of a previously developed GT3 subgenomic replicon (PR87A7). Two mutations were identified in the viral genome of SOF-resistant PR87A7 variants, Q606R in nontargeted NS3 and S282T in targeted N5SB. We demonstrated that Q606R could rescue the replication defect of S282T in PR87A7, and the resulting double mutant confers the SOF resistance. Finally, we showed that NS3-606R could not compensate for the replication defect of S282T in other GTs. In conclusion, we identified a novel GT3-specific combination of two mutations that confers SOF resistance. Our result calls for attention to potential mutations that may arise in nontargeted viral proteins during the SOF-based DAA treatment of chronic HCV.
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Affiliation(s)
- Jackline Wangu Ngari
- CAS Key Laboratory of Molecular Virology and Immunology, Unit of Viral Hepatitis, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai, China
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China
| | - Steve Leumi
- CAS Key Laboratory of Molecular Virology and Immunology, Unit of Viral Hepatitis, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai, China
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China
| | - Lin Han
- CAS Key Laboratory of Molecular Virology and Immunology, Unit of Viral Hepatitis, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai, China
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Chaolun Liu
- CAS Key Laboratory of Molecular Virology and Immunology, Unit of Viral Hepatitis, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai, China
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Yimin Tong
- CAS Key Laboratory of Molecular Virology and Immunology, Unit of Viral Hepatitis, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai, China
| | - Jin Zhong
- CAS Key Laboratory of Molecular Virology and Immunology, Unit of Viral Hepatitis, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai, China
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
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7
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Comunale BA, Larson RJ, Jackson-Ward E, Singh A, Koback FL, Engineer LD. The Functional Implications of Broad Spectrum Bioactive Compounds Targeting RNA-Dependent RNA Polymerase (RdRp) in the Context of the COVID-19 Pandemic. Viruses 2023; 15:2316. [PMID: 38140557 PMCID: PMC10747147 DOI: 10.3390/v15122316] [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: 10/31/2023] [Revised: 11/20/2023] [Accepted: 11/21/2023] [Indexed: 12/24/2023] Open
Abstract
BACKGROUND As long as COVID-19 endures, viral surface proteins will keep changing and new viral strains will emerge, rendering prior vaccines and treatments decreasingly effective. To provide durable targets for preventive and therapeutic agents, there is increasing interest in slowly mutating viral proteins, including non-surface proteins like RdRp. METHODS A scoping review of studies was conducted describing RdRp in the context of COVID-19 through MEDLINE/PubMed and EMBASE. An iterative approach was used with input from content experts and three independent reviewers, focused on studies related to either RdRp activity inhibition or RdRp mechanisms against SARS-CoV-2. RESULTS Of the 205 records screened, 43 studies were included in the review. Twenty-five evaluated RdRp activity inhibition, and eighteen described RdRp mechanisms of existing drugs or compounds against SARS-CoV-2. In silico experiments suggested that RdRp inhibitors developed for other RNA viruses may be effective in disrupting SARS-CoV-2 replication, indicating a possible reduction of disease progression from current and future variants. In vitro, in vivo, and human clinical trial studies were largely consistent with these findings. CONCLUSIONS Future risk mitigation and treatment strategies against forthcoming SARS-CoV-2 variants should consider targeting RdRp proteins instead of surface proteins.
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Affiliation(s)
- Brittany A. Comunale
- Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA
| | - Robin J. Larson
- Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA
- Department of Palliative Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA
| | - Erin Jackson-Ward
- Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA
- Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Aditi Singh
- Department of Biological Sciences, University of California San Diego, La Jolla, CA 92161, USA
| | | | - Lilly D. Engineer
- Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
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Izhari MA. Molecular Mechanisms of Resistance to Direct-Acting Antiviral (DAA) Drugs for the Treatment of Hepatitis C Virus Infections. Diagnostics (Basel) 2023; 13:3102. [PMID: 37835845 PMCID: PMC10572573 DOI: 10.3390/diagnostics13193102] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 09/23/2023] [Accepted: 09/28/2023] [Indexed: 10/15/2023] Open
Abstract
Hepatitis C virus (HCV) is a hepatotropic virus that affects millions of human lives worldwide. Direct-acting antiviral (DAA) regimens are the most effective HCV treatment option. However, amino acid substitution-dependent resistance to DAAs has been a major challenge. This study aimed to determine the increasing risk of DAA resistance due to substitutions in DAA target non-structural proteins (NS3/4A, NS5A, and NS5B). Using a Sequence Retrieval System (SRS) at the virus pathogen resource (ViPR/BV-BRC), n = 32763 target protein sequences were retrieved and analyzed for resistance-associated amino acid substitutions (RAASs) by the Sequence Feature Variant Type (SFVT) antiviral-resistance assessment modeling tool. Reference target protein sequences with 100% identity were retried from UniProt following NCBI BLAST. The types and locations of RAASs were identified and visualized by AlphaFold and PyMol. Linux-r-base/R-studio was used for the data presentation. Multi-drug-resistant variants of NS3/4A in genotype 1 (n = 9) and genotype 5 (n = 5) along with DAA-specific NS3/4A, NS5A, and NS5B variants were identified pan-genotypically. A total of 27 variants (RAASs) of all the targets were identified. Fourteen genotype 1-specific substitutions: V1196A, V1158I, D1194A/T/G, R1181K, T1080S, Q1106R, V1062A, S1148G, A1182V, Y2065N, M2000T, and L2003V were identified. The most frequent substitutions were V1062L and L2003M, followed by Q2002H. L2003V, Q2002H, M2000T, Y2065N, and NL2003M of NS5A and L2003M of NS5B conferred resistance to daclatasvir. S2702T NS5B was the sofosbuvir-resistant variant. D1194A NS3/4A was triple DAA (simeprevir, faldaprevir, and asunaprevir) resistant. The double-drug resistant variants R1181K (faldaprevir and asunaprevir), A1182V and Q1106K/R (faldaprevir and simeprevir), T1080S (faldaprevir and telaprevir), and single drug-resistant variants V1062L (telaprevir), D1194E/T (simeprevir), D1194G (asunaprevir), S1148A/G (simeprevir), and Q1106L (Boceprevir) of NS3/4A were determined. The molecular phenomenon of DAA resistance is paramount in the development of HCV drug candidates. RAASs in NS3, NS5A, and NS5B reduce the susceptibility to DAAs; therefore, continuous RAAS-dependent resistance profiling in HCV is recommended to minimize the probability of DAA therapeutic failure.
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Affiliation(s)
- Mohammad Asrar Izhari
- Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Al-Baha University, Al-Baha 65522, Saudi Arabia
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Diani E, Lagni A, Lotti V, Tonon E, Cecchetto R, Gibellini D. Vector-Transmitted Flaviviruses: An Antiviral Molecules Overview. Microorganisms 2023; 11:2427. [PMID: 37894085 PMCID: PMC10608811 DOI: 10.3390/microorganisms11102427] [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: 08/17/2023] [Revised: 09/18/2023] [Accepted: 09/25/2023] [Indexed: 10/29/2023] Open
Abstract
Flaviviruses cause numerous pathologies in humans across a broad clinical spectrum with potentially severe clinical manifestations, including hemorrhagic and neurological disorders. Among human flaviviruses, some viral proteins show high conservation and are good candidates as targets for drug design. From an epidemiological point of view, flaviviruses cause more than 400 million cases of infection worldwide each year. In particular, the Yellow Fever, dengue, West Nile, and Zika viruses have high morbidity and mortality-about an estimated 20,000 deaths per year. As they depend on human vectors, they have expanded their geographical range in recent years due to altered climatic and social conditions. Despite these epidemiological and clinical premises, there are limited antiviral treatments for these infections. In this review, we describe the major compounds that are currently under evaluation for the treatment of flavivirus infections and the challenges faced during clinical trials, outlining their mechanisms of action in order to present an overview of ongoing studies. According to our review, the absence of approved antivirals for flaviviruses led to in vitro and in vivo experiments aimed at identifying compounds that can interfere with one or more viral cycle steps. Still, the currently unavailability of approved antivirals poses a significant public health issue.
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Affiliation(s)
- Erica Diani
- Department of Diagnostic and Public Health, Microbiology Section, University of Verona, 37134 Verona, Italy; (A.L.); (V.L.); (R.C.)
| | - Anna Lagni
- Department of Diagnostic and Public Health, Microbiology Section, University of Verona, 37134 Verona, Italy; (A.L.); (V.L.); (R.C.)
| | - Virginia Lotti
- Department of Diagnostic and Public Health, Microbiology Section, University of Verona, 37134 Verona, Italy; (A.L.); (V.L.); (R.C.)
| | - Emil Tonon
- Unit of Microbiology, Azienda Ospedaliera Universitaria Integrata Verona, 37134 Verona, Italy;
| | - Riccardo Cecchetto
- Department of Diagnostic and Public Health, Microbiology Section, University of Verona, 37134 Verona, Italy; (A.L.); (V.L.); (R.C.)
- Unit of Microbiology, Azienda Ospedaliera Universitaria Integrata Verona, 37134 Verona, Italy;
| | - Davide Gibellini
- Department of Diagnostic and Public Health, Microbiology Section, University of Verona, 37134 Verona, Italy; (A.L.); (V.L.); (R.C.)
- Unit of Microbiology, Azienda Ospedaliera Universitaria Integrata Verona, 37134 Verona, Italy;
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Kumar S, Basu M, Ghosh P, Pal U, Ghosh MK. COVID-19 therapeutics: Clinical application of repurposed drugs and futuristic strategies for target-based drug discovery. Genes Dis 2023; 10:1402-1428. [PMID: 37334160 PMCID: PMC10079314 DOI: 10.1016/j.gendis.2022.12.019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 12/07/2022] [Accepted: 12/16/2022] [Indexed: 06/17/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes the complicated disease COVID-19. Clinicians are continuously facing huge problems in the treatment of patients, as COVID-19-specific drugs are not available, hence the principle of drug repurposing serves as a one-and-only hope. Globally, the repurposing of many drugs is underway; few of them are already approved by the regulatory bodies for their clinical use and most of them are in different phases of clinical trials. Here in this review, our main aim is to discuss in detail the up-to-date information on the target-based pharmacological classification of repurposed drugs, the potential mechanism of actions, and the current clinical trial status of various drugs which are under repurposing since early 2020. At last, we briefly proposed the probable pharmacological and therapeutic drug targets that may be preferred as a futuristic drug discovery approach in the development of effective medicines.
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Affiliation(s)
- Sunny Kumar
- Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), TRUE Campus, CN-6, Sector–V, Salt Lake, Kolkata-700091 & 4, Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India
| | - Malini Basu
- Department of Microbiology, Dhruba Chand Halder College, Dakshin Barasat, West Bengal 743372, India
| | - Pratyasha Ghosh
- Department of Economics, Bethune College, University of Calcutta, Kolkata 700006, India
| | - Uttam Pal
- Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), TRUE Campus, CN-6, Sector–V, Salt Lake, Kolkata-700091 & 4, Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India
| | - Mrinal K. Ghosh
- Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), TRUE Campus, CN-6, Sector–V, Salt Lake, Kolkata-700091 & 4, Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India
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Yao X, Gao S, Wang J, Li Z, Huang J, Wang Y, Wang Z, Chen J, Fan X, Wang W, Jin X, Pan X, Yu Y, Lagrutta A, Yan N. Structural basis for the severe adverse interaction of sofosbuvir and amiodarone on L-type Ca v channels. Cell 2022; 185:4801-4810.e13. [PMID: 36417914 PMCID: PMC9891081 DOI: 10.1016/j.cell.2022.10.024] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Revised: 08/24/2022] [Accepted: 10/26/2022] [Indexed: 11/23/2022]
Abstract
Drug-drug interaction of the antiviral sofosbuvir and the antiarrhythmics amiodarone has been reported to cause fatal heartbeat slowing. Sofosbuvir and its analog, MNI-1, were reported to potentiate the inhibition of cardiomyocyte calcium handling by amiodarone, which functions as a multi-channel antagonist, and implicate its inhibitory effect on L-type Cav channels, but the molecular mechanism has remained unclear. Here we present systematic cryo-EM structural analysis of Cav1.1 and Cav1.3 treated with amiodarone or sofosbuvir alone, or sofosbuvir/MNI-1 combined with amiodarone. Whereas amiodarone alone occupies the dihydropyridine binding site, sofosbuvir is not found in the channel when applied on its own. In the presence of amiodarone, sofosbuvir/MNI-1 is anchored in the central cavity of the pore domain through specific interaction with amiodarone and directly obstructs the ion permeation path. Our study reveals the molecular basis for the physical, pharmacodynamic interaction of two drugs on the scaffold of Cav channels.
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Affiliation(s)
- Xia Yao
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA,These authors contribute equally
| | - Shuai Gao
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA,These authors contribute equally.,Present address: School of Pharmaceutical Sciences, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China,To whom correspondence should be addressed: N. Yan (); S. Gao ()
| | - Jixin Wang
- Department of Genetic and Cellular Toxicology, ADME & Discovery Toxicology, Preclinical Development, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA,These authors contribute equally
| | - Zhangqiang Li
- State Key Laboratory of Membrane Biology, Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China,These authors contribute equally
| | - Jian Huang
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
| | - Yan Wang
- Department of Biological Sciences, St. John’s University, Queens, NY 11439, USA
| | - Zhifei Wang
- Department of Biological Sciences, St. John’s University, Queens, NY 11439, USA
| | - Jiaofeng Chen
- State Key Laboratory of Membrane Biology, Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Xiao Fan
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
| | - Weipeng Wang
- State Key Laboratory of Membrane Biology, Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Xueqin Jin
- State Key Laboratory of Membrane Biology, Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Xiaojing Pan
- State Key Laboratory of Membrane Biology, Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Yong Yu
- Department of Biological Sciences, St. John’s University, Queens, NY 11439, USA
| | - Armando Lagrutta
- Department of Genetic and Cellular Toxicology, ADME & Discovery Toxicology, Preclinical Development, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA
| | - Nieng Yan
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA,Lead contact.,To whom correspondence should be addressed: N. Yan (); S. Gao ()
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12
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Finding a chink in the armor: Update, limitations, and challenges toward successful antivirals against flaviviruses. PLoS Negl Trop Dis 2022; 16:e0010291. [PMID: 35482672 PMCID: PMC9049358 DOI: 10.1371/journal.pntd.0010291] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Flaviviruses have caused large epidemics and ongoing outbreaks for centuries. They are now distributed in every continent infecting up to millions of people annually and may emerge to cause future epidemics. Some of the viruses from this group cause severe illnesses ranging from hemorrhagic to neurological manifestations. Despite decades of research, there are currently no approved antiviral drugs against flaviviruses, urging for new strategies and antiviral targets. In recent years, integrated omics data-based drug repurposing paired with novel drug validation methodologies and appropriate animal models has substantially aided in the discovery of new antiviral medicines. Here, we aim to review the latest progress in the development of both new and repurposed (i) direct-acting antivirals; (ii) host-targeting antivirals; and (iii) multitarget antivirals against flaviviruses, which have been evaluated both in vitro and in vivo, with an emphasis on their targets and mechanisms. The search yielded 37 compounds that have been evaluated for their efficacy against flaviviruses in animal models; 20 of them are repurposed drugs, and the majority of them exhibit broad-spectrum antiviral activity. The review also highlighted the major limitations and challenges faced in the current in vitro and in vivo evaluations that hamper the development of successful antiviral drugs for flaviviruses. We provided an analysis of what can be learned from some of the approved antiviral drugs as well as drugs that failed clinical trials. Potent in vitro and in vivo antiviral efficacy alone does not warrant successful antiviral drugs; current gaps in studies need to be addressed to improve efficacy and safety in clinical trials.
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13
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Majid A, Khan S, Siraj S, Haleem S, ul Haq N, Ullah R, Ali EA, Mustafa A, Hussain H, Sohaib M. Emergence of resistance against direct acting antivirals in chronic HCV patients: A real-world study. Saudi J Biol Sci 2022; 29:2613-2619. [PMID: 35531150 PMCID: PMC9072881 DOI: 10.1016/j.sjbs.2021.12.044] [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: 10/26/2021] [Revised: 12/02/2021] [Accepted: 12/19/2021] [Indexed: 01/09/2023] Open
Abstract
Interferon/Ribavirin therapy has been replaced by Direct Acting Antivirals (DAAs) due to emergence of Resistance Associated Variants (RAVs) and decrease Sustain Virologic Response (SVR). Current study investigated treatment response of Sofosbuvir and Ribavirin in chronic HCV patients. Total 256 HCV patients with genotype 1a, 2 and 3a received sofosbuvir/ribavirin according to international standards. HCV RNA presence in serum was used as marker for end treatment response (ETR) and sustain virologic response after 24 weeks of treatment (SVR24) in each case. Response to treatment with SOF + RBV was found statistically significant among different HCV genotypes (GT) as out of 47 HCV GT1 patients 42(89.36%) resulted into good ETR but 4(9.52%) of these relapsed and 5(10.63%) led into virologic failure. 5(100%) HCV GT2 patients resulted into SVR24 whereas, out of 204 HCV GT3 patients 194(95.69%) achieved good ETR however, 8(4.12%) of these relapsed and 10(4.90%) resulted in to virologic failure. Efficacy of therapy was found non-significant in treatment naïve and treatment experienced patients as in this study out of 145 treatment naïve patients 139(95.86%) achieved good ETR where 4(2.87%) relapsed while 6(4.13%) led into virologic break through on the other hand among 111 treatment experienced patients 102(91.89%) resulted into good ETR but 8(7.84%) relapsed whereas 9(8.10%) lead into virologic failure. Current study also propose that various liver and spleen complications/liver cirrhosis are related to response of HCV patients to SOF + RBV therapy whereas, variables like old age, gender is not compromising treatment response to DAAs therapy. Various mild side effects encountered by patients during treatment were fatigue, insomnia, headache, nausea, burning body, diarrhea, cough. Overall, this study reported 89.45% efficacy of SOF + RBV regime in chronic HCV Pakistani patients. Current study suggests hunting for possible reasons of resistance so that SOF + RBV therapy may not share the same fortune as previous therapies in near future.
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Affiliation(s)
- Abdul Majid
- Department of Zoology, Kohat University of Science and Technology, Kohat, Pakistan
| | | | - Sami Siraj
- Institute of Basic Medical Sciences, Khyber Medical University, Pakistan
| | - Sumbal Haleem
- Department of Zoology, Kohat University of Science and Technology, Kohat, Pakistan
| | - Najib ul Haq
- Peshawar Medical College, Riphah International University, Pakistan
| | - Riaz Ullah
- Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Essam A. Ali
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Adeela Mustafa
- Community Medicine Department, Khyber Medical College Peshawar, Pakistan
| | - Hidayat Hussain
- Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3, D-06120 Halle (Salle), Germany
| | - Muhammad Sohaib
- Department of Soil Science, College of Food and Agricultural Sciences, King Saud University, 12 Riyadh 11451, Saudi Arabia
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14
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Shoun AA, Abozahra R, Baraka K, Mehrez M, Abdelhamid SM. Identifying Different Mutation Sites Leading to Resistance to the Direct-Acting Antiviral (DAA) Sofosbuvir in Hepatitis C Virus Patients from Egypt. Microorganisms 2022; 10:microorganisms10040679. [PMID: 35456731 PMCID: PMC9024585 DOI: 10.3390/microorganisms10040679] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 03/13/2022] [Accepted: 03/17/2022] [Indexed: 02/04/2023] Open
Abstract
The hepatitis C virus (HCV) is a major global health challenge and a leading cause of morbidity and mortality. Many direct-acting antivirals (DAAs) target essential macromolecules involved in the virus’ life cycle. Although such DAAs achieve great success in reducing the viral load in genotype 1 infections, other genotypes demonstrate different levels of response. This study focused on mutation sites associated with patients with genotype 4a infections that failed to respond to treatment with sofosbuvir. The genotyping of HCV samples from patients with virological failure, and responder patients, was conducted using Geno2Pheno webserver-based full NS5B sequences. We constructed 3D structural models for all the samples and used structural analysis to investigate the effect of amino acid substitution on the observed resistance to SOF-based treatment, and the docking of sofosbuvir into the active sites of the 10 models was performed. Finally, 10 molecular dynamic (MD) simulation experiments were conducted to compare the stability of the 3D models of the resistant samples against the stability of the 3D models of the responder samples. The results highlighted the presence of HCV subtype 4a in all ten samples; in addition, an amino acid (aa) substitution in the palm region may hinder HCV polymerase activity. In this study, we provide evidence that a mutation in the NS5B gene that induces resistance to sofosbuvir in patients with the S282T/C/R mutant virus is present in the Egyptian population. Overall, the docking and MD results support our findings and highlight the significant impact of the identified mutations on the resistance of HCV NS5B RNA-dependent RNA polymerase to direct-acting antivirals (DAAs).
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Affiliation(s)
- Aly Atef Shoun
- Microbiology and Immunology Department, Faculty of Pharmacy, Sinai University, El Arish 45518, Egypt
- Correspondence:
| | - Rania Abozahra
- Microbiology and Immunology Department, Faculty of Pharmacy, Damanhour University, Damanhour 22511, Egypt; (R.A.); (K.B.); (S.M.A.)
| | - Kholoud Baraka
- Microbiology and Immunology Department, Faculty of Pharmacy, Damanhour University, Damanhour 22511, Egypt; (R.A.); (K.B.); (S.M.A.)
| | - Mai Mehrez
- National Hepatology and Tropical Medicine Research Institute (NHTMRI), Cairo 11511, Egypt;
| | - Sarah M. Abdelhamid
- Microbiology and Immunology Department, Faculty of Pharmacy, Damanhour University, Damanhour 22511, Egypt; (R.A.); (K.B.); (S.M.A.)
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15
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Malik GF, Zakaria N, Majeed MI, Ismail FW. Viral Hepatitis - The Road Traveled and the Journey Remaining. Hepat Med 2022; 14:13-26. [PMID: 35300491 PMCID: PMC8922334 DOI: 10.2147/hmer.s352568] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Accepted: 02/24/2022] [Indexed: 12/16/2022] Open
Abstract
Hepatitis is defined as inflammation of the liver and is commonly due to infection with The hepatotropic viruses - hepatitis A, B, C, D and E. Hepatitis carries one of the highest disease burdens globally and has caused significant morbidity and mortality among different patient populations. Clinical presentation varies from asymptomatic or acute flu-like illness to acute liver failure or chronic liver disease, characterized by jaundice, hepatomegaly and ascites among many other signs. Eventually, this can lead to fibrosis (cirrhosis) of the liver parenchyma and carries a risk of development into hepatocellular carcinoma. Hepatitis B and C are most notorious for causing liver cirrhosis; in 2019, an estimated 296 million people worldwide had chronic hepatitis B infection and 58 million are currently estimated to have chronic hepatitis C, with 1.5 million new infections of both hepatitis B and C, occurring annually. With the help of latest serological biomarkers and viral nucleic acid amplification tests, it has become rather simple to efficiently screen, diagnose and monitor patients with hepatitis, and to commence with appropriate antiviral treatment. More importantly, the development of vaccinations against some of these viruses has greatly helped to curb the infection rates. Whilst there has been exceptional progress over the years in the management of viral hepatitis, many hurdles still remain which must be addressed in order to proceed towards a hepatitis-free world. This review will shed light on the origin and discovery of the hepatitis viruses, the global epidemiology and clinical symptoms, diagnostic modalities, currently available treatment options, the importance of prevention, and the journey needed to move forward towards the eradication of its global disease burden.
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Affiliation(s)
- Ghulam Fareed Malik
- Section of Gastroenterology, Department of Medicine, The Aga Khan University, Karachi, Pakistan
| | - Noval Zakaria
- Section of Gastroenterology, Department of Medicine, The Aga Khan University, Karachi, Pakistan
| | | | - Faisal Wasim Ismail
- Section of Gastroenterology, Department of Medicine, The Aga Khan University, Karachi, Pakistan
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16
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Yan L, Cao R, Zhang H, Li Y, Li W, Li X, Fan S, Li S, Zhong W. Design, synthesis and evaluation of 2'-acetylene-7-deaza-adenosine phosphoamidate derivatives as anti-EV71 and anti-EV-D68 agents. Eur J Med Chem 2021; 226:113852. [PMID: 34560428 DOI: 10.1016/j.ejmech.2021.113852] [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: 08/01/2021] [Revised: 09/10/2021] [Accepted: 09/11/2021] [Indexed: 11/29/2022]
Abstract
A series of phosphoamidate derivatives of nucleoside 2'-acetylene-7-deaza-adenosine (NITD008) were synthesized and evaluated for their in vitro antiviral activities against the enteroviruses EV71 and EV-D68. The phosphoamidate (15f) containing a hexyl ester of l-alanine exhibited the most promising activity against EV71 (IC50 = 0.13 ± 0.08 μM) and was 4-times more potent than NITD008. Meanwhile, the derivative containing a cyclohexyl ester of l-alanine (15l) exhibited the most potent activity with high selectivity index against both EV71 (IC50 = 0.19 ± 0.27 μM, SI = 117.00) and EV-D68 (IC50 = 0.17 ± 0.16 μM, SI = 130.76), which were both higher than that of NITD008. The results indicated that the phosphoamidate 15l was the most promising candidate for further development as antiviral agents for the treatment of both EV71 and EV-D68 infection.
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Affiliation(s)
- Linjie Yan
- National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, PR China
| | - Ruiyuan Cao
- National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, PR China
| | - Hongjie Zhang
- National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, PR China
| | - Yuexiang Li
- National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, PR China
| | - Wei Li
- National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, PR China
| | - Xiaoyuan Li
- National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, PR China
| | - Shiyong Fan
- National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, PR China
| | - Song Li
- National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, PR China.
| | - Wu Zhong
- National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, PR China.
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17
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Changes in serum interferon-γ-inducible protein-10 levels and liver stiffness among chronic hepatitis C Egyptian patients in response to directly acting antiviral agents. Eur J Gastroenterol Hepatol 2021; 33:e335-e340. [PMID: 33470694 DOI: 10.1097/meg.0000000000002059] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND Interferon-γ inducible protein-10 (IP-10) is chemokine biomarker of liver inflammation, elevated in patients with chronic hepatitis C infection. AIMS Investigating if changes in serum IP-10 levels in response to directly acting antiviral agents (DAAs) treatment for chronic HCV patients are paralleled by changes in liver stiffness measurements (LSM), and assessing role of using serum IP-10 as a noninvasive accurate method to predict changes in hepatic necro-inflammation and fibrosis. MATERIAL AND METHODS A prospective observational study included 92 Egyptian chronic HCV patients, who received treatment with sofosbuvir with daclatasvir regimen. Patients were classified into two groups; group I (53 patients) with non to mild significant liver fibrosis (F0-F1), and group II (39 patients) with significant to advanced liver fibrosis (F2-F4). Fibroscan and serum IP-10 were assessed pretreatment and 3 months after end of treatment. RESULTS All patients achieved SVR. Both IP-10 and LSM showed significant decline after treatment in both groups. No significant correlation was found between changes in LSM and IP-10. IP-10 detected liver cirrhosis at cut off level of 17.8 pg/ml, with 75% sensitivity and 73.86% specificity, with area under the curve = 0.66, however, IP-10 had no statistical significance in detecting advanced fibrosis. CONCLUSION IP-10 might be of significance as a noninvasive predictor of liver cirrhosis. IP-10 significant decline post-DAAs treatment in chronic HCV genotype IV infected patients reflects significant improvement in fibrosis stage and hepatic necro-inflammation in response to treatment. No significant correlation was detected in the changes of both IP-10 and LSM.
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18
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Current Trends and Limitations in Dengue Antiviral Research. Trop Med Infect Dis 2021; 6:tropicalmed6040180. [PMID: 34698303 PMCID: PMC8544673 DOI: 10.3390/tropicalmed6040180] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 09/22/2021] [Accepted: 09/24/2021] [Indexed: 12/13/2022] Open
Abstract
Dengue is the most prevalent arthropod-borne viral disease worldwide and affects approximately 2.5 billion people living in over 100 countries. Increasing geographic expansion of Aedes aegypti mosquitoes (which transmit the virus) has made dengue a global health concern. There are currently no approved antivirals available to treat dengue, and the only approved vaccine used in some countries is limited to seropositive patients. Treatment of dengue, therefore, remains largely supportive to date; hence, research efforts are being intensified for the development of antivirals. The nonstructural proteins, 3 and 5 (NS3 and NS5), have been the major targets for dengue antiviral development due to their indispensable enzymatic and biological functions in the viral replication process. NS5 is the largest and most conserved nonstructural protein encoded by flaviviruses. Its multifunctionality makes it an attractive target for antiviral development, but research efforts have, this far, not resulted in the successful development of an antiviral targeting NS5. Increase in structural insights into the dengue NS5 protein will accelerate drug discovery efforts focused on NS5 as an antiviral target. In this review, we will give an overview of the current state of therapeutic development, with a focus on NS5 as a therapeutic target against dengue.
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19
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Mohamed AF, Abo-Ouf AM, Arafa MAA. Histological and biochemical studies on effect of Sofosbuvir (Sovaldi) on adult male albino rat kidney. Ultrastruct Pathol 2021; 45:286-296. [PMID: 34392788 DOI: 10.1080/01913123.2021.1966148] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Sofosbuvir (sovaldi) is the backbone of many anti-HCV drugs. We aimed to demonstrate the effect of sofosbuvir on the adult male albino rat kidney. Sixty adult male albino rats were used. The animals were divided equally into 2 main groups (I and II), and each group was divided equally into 3 subgroups (A, B, and C). In group I (control group), each rat was gavaged 0.5 ml distilled water daily for 4 weeks. In group II (sofosbuvir treated group), each albino rat was gavaged 0.5 ml distilled water containing 7.2 mg sofosbuvir daily for 4 weeks. The rats were sacrificed at the end of the 4th week (subgroups IA and IIA), 6th week (subgroups IB and IIB), and 8th week (subgroups IC and IIC) from the start of the treatment. The kidneys were used for histological study while blood samples were used for biochemical study. The obtained data were statistically analyzed. Sofosbuvir (sovaldi) induced pathological changes that gave the criteria of acute Kidney injury in the adult male albino rats. The pathological changes were confirmed by elevation of serum level of urea and creatinine. After 2 and 4 weeks of drug withdrawal, the kidney incompletely recovered. We concluded that sofosbuvir induced criteria of acute tubular injury in the kidney of the adult male albino rats. This renal injury was proved by histological and biochemical studies. These insults were incompletely reversible after the end the treatment.
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Affiliation(s)
- Amany F Mohamed
- Department Of Anatomy And Embryology, Faculty Of Medicine For Girls, Al-Azhar University, Cairo, Egypt
| | - Amany M Abo-Ouf
- Department Of Anatomy And Embryology, Faculty Of Medicine For Girls, Al-Azhar University, Cairo, Egypt
| | - Mona A A Arafa
- Department Of Anatomy And Embryology, Faculty Of Medicine For Girls, Al-Azhar University, Cairo, Egypt
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20
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Dangi M, Khichi A, Jakhar R, Chhillar AK. Growing Preferences towards Analog-based Drug Discovery. Curr Pharm Biotechnol 2021; 22:1030-1045. [PMID: 32900347 DOI: 10.2174/1389201021666200908121409] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 06/29/2020] [Accepted: 08/21/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND The major concern of today's time is the developing resistance in most of the clinically derived pathogenic micro-organisms for available drugs through several mechanisms. Therefore, there is a dire need to develop novel molecules with drug-like properties that can be effective against the otherwise resistant micro-organisms. METHODS New drugs can be developed using several methods like structure-based drug design, ligandbased drug design, or by developing analogs of the available drugs to further improve their effects. However, the smartness is to opt for the techniques that have comparatively less expenditure, lower failure rates, and faster discovery rates. RESULTS Analog-Based Drug Design (ABDD) is one such technique that researchers worldwide are opting to develop new drug-like molecules with comparatively lower market values. They start by first designing the analogs sharing structural and pharmacological similarities to the existing drugs. This method embarks on scaffold structures of available drugs already approved by the clinical trials, but are left ineffective because of resistance developed by the pathogens. CONCLUSION In this review, we have discussed some recent examples of anti-fungal and anti-bacterial (antimicrobial) drugs that were designed based on the ABDD technique. Also, we have tried to focus on the in silico tools and techniques that can contribute to the designing and computational screening of the analogs, so that these can be further considered for in vitro screening to validate their better biological activities against the pathogens with comparatively reduced rates of failure.
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Affiliation(s)
- Mehak Dangi
- Centre for Bioinformatics, M.D. University, Rohtak-124001, Haryana, India
| | - Alka Khichi
- Centre for Bioinformatics, M.D. University, Rohtak-124001, Haryana, India
| | - Ritu Jakhar
- Centre for Bioinformatics, M.D. University, Rohtak-124001, Haryana, India
| | - Anil K Chhillar
- Centre for Bioinformatics, M.D. University, Rohtak-124001, Haryana, India
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21
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Españo E, Kim D, Kim J, Park SK, Kim JK. COVID-19 Antiviral and Treatment Candidates: Current Status. Immune Netw 2021; 21:e7. [PMID: 33728100 PMCID: PMC7937511 DOI: 10.4110/in.2021.21.e7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 01/27/2021] [Accepted: 01/31/2021] [Indexed: 02/06/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 has severely impacted global health and economy. There is currently no effective approved treatment for COVID-19; although vaccines have been granted emergency use authorization in several countries, they are currently only administered to high-risk individuals, thereby leaving a gap in virus control measures. The scientific and clinical communities and drug manufacturers have collaborated to speed up the discovery of potential therapies for COVID-19 by taking advantage of currently approved drugs as well as investigatory agents in clinical trials. In this review, we stratified some of these candidates based on their potential targets in the progression of COVID-19 and discuss some of the results of ongoing clinical evaluations.
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Affiliation(s)
- Erica Españo
- Department of Pharmacy, Korea University College of Pharmacy, Sejong 30019, Korea
| | - Dajung Kim
- Department of Pharmacy, Korea University College of Pharmacy, Sejong 30019, Korea
| | - Jiyeon Kim
- Department of Pharmacy, Korea University College of Pharmacy, Sejong 30019, Korea
| | - Song-Kyu Park
- Department of Pharmacy, Korea University College of Pharmacy, Sejong 30019, Korea
| | - Jeong-Ki Kim
- Department of Pharmacy, Korea University College of Pharmacy, Sejong 30019, Korea
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22
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Rahimi P, Sharafi H, Bahramali G, SajadianFard F, Asadi NS, Alavian SM, Iranpur Mobarakeh V, Moravej SZ. Prevalence of Naturally-Occurring NS5A and NS5B Resistance-Associated Substitutions in Iranian Patients With Chronic Hepatitis C Infection. Front Microbiol 2021; 11:617375. [PMID: 33584581 PMCID: PMC7876467 DOI: 10.3389/fmicb.2020.617375] [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: 10/14/2020] [Accepted: 12/30/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Hepatitis C virus (HCV), non-structural 5A (NS5A), and non-structural 5B (NS5B) resistance-associated substitutions (RASs) are the main causes of failure to direct-acting antiviral agents (DAAs). NS5A and NS5B RASs can occur in patients with HCV infection naturally and before exposure to DAAs. OBJECTIVES This study aimed to evaluate naturally-occurring NS5A and NS5B RASs in Iranian patients with HCV genotype 1a (HCV-1a) and -3a infections. METHODS In this cross-sectional study, viral RNA was extracted from serum specimens. NS5A and NS5B regions were amplified using RT-PCR followed by DNA sequencing. The results of nucleotide sequences were aligned against reference sequences of HCV-1a and -3a and the amino acid substitutions were analyzed using geno2pheno [hcv] web application. RESULTS Among 135 patients with hepatitis C, NS5A amino acid substitutions/RASs were identified in 26.4% and 15.9% of patients with HCV-1a and -3a infections, respectively. The identified amino acid substitutions/RASs in the NS5A region of patients with HCV-1a infection were M28T/V/I 11.1%, Q30R/H 4.2%, L31M 1.4%, and H58Y/P/C/D/Q/S/T 16.7%. Y93H substitution was not found in HCV-1a sequences. In patients with HCV-3a infection, NS5A amino acid substitutions/RASs were A30T/K 9.5%, L31F 1.6%, P58S/T/C 3.2%, Y93H 3.2%, and Y93N 3.2%. No resistance substitutions were identified in NS5B sequences from patients with HCV-1a and -3a infections. CONCLUSION In this study, baseline amino acid substitutions/RASs were only identified in the NS5A region in Iranian patients with HCV-1a and -3a infections, and the prevalence of these amino acid substitutions/RASs were in accordance with similar studies. There were no RASs in the HCV-1a and -3a NS5B region.
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Affiliation(s)
- Pooneh Rahimi
- Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, Iran
| | | | - Golnaz Bahramali
- Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, Iran
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23
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Nimgaonkar I, Archer NF, Becher I, Shahrad M, LeDesma RA, Mateus A, Caballero-Gómez J, Berneshawi AR, Ding Q, Douam F, Gaska JM, Savitski MM, Kim H, Ploss A. Isocotoin suppresses hepatitis E virus replication through inhibition of heat shock protein 90. Antiviral Res 2021; 185:104997. [PMID: 33326835 PMCID: PMC8649941 DOI: 10.1016/j.antiviral.2020.104997] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 11/21/2020] [Accepted: 12/10/2020] [Indexed: 02/07/2023]
Abstract
Hepatitis E virus (HEV) causes 14 million infections and 60,000 deaths per year globally, with immunocompromised persons and pregnant women experiencing severe symptoms. Although ribavirin can be used to treat chronic hepatitis E, toxicity in pregnant patients and the emergence of resistant strains are major concerns. Therefore there is an imminent need for effective HEV antiviral agents. The aims of this study were to develop a drug screening platform and to discover novel approaches to targeting steps within the viral life cycle. We developed a screening platform for molecules inhibiting HEV replication and selected a candidate, isocotoin. Isocotoin inhibits HEV replication through interference with heat shock protein 90 (HSP90), a host factor not previously known to be involved in HEV replication. Additional work is required to understand the compound's translational potential, however this suggests that HSP90-modulating molecules, which are in clinical development as anti-cancer agents, may be promising therapies against HEV.
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Affiliation(s)
- Ila Nimgaonkar
- Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, Princeton, NJ, USA
| | - Nicholas F Archer
- Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, Princeton, NJ, USA
| | - Isabelle Becher
- Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Mohammad Shahrad
- Department of Computer Science, Princeton University, Princeton, NJ, USA
| | - Robert A LeDesma
- Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, Princeton, NJ, USA
| | - André Mateus
- Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Javier Caballero-Gómez
- Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, Princeton, NJ, USA
| | - Andrew R Berneshawi
- Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, Princeton, NJ, USA
| | - Qiang Ding
- Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, Princeton, NJ, USA
| | - Florian Douam
- Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, Princeton, NJ, USA
| | - Jenna M Gaska
- Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, Princeton, NJ, USA
| | - Mikhail M Savitski
- Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Hahn Kim
- Princeton University Small Molecule Screening Center, Frick Laboratory, Princeton University, Princeton, NJ, USA; Department of Chemistry, Frick Laboratory, Princeton University, Princeton, NJ, USA
| | - Alexander Ploss
- Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, Princeton, NJ, USA.
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24
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Effective quantification of ravidasvir (an NS5A inhibitor) and sofosbuvir in rat plasma by validated LC-MS/MS method and its application to pharmacokinetic study. ARAB J CHEM 2020. [DOI: 10.1016/j.arabjc.2020.09.048] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
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25
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Li J, Abosmaha E, Coffin CS, Labonté P, Bukong TN. Reticulon-3 modulates the incorporation of replication competent hepatitis C virus molecules for release inside infectious exosomes. PLoS One 2020; 15:e0239153. [PMID: 32941510 PMCID: PMC7498005 DOI: 10.1371/journal.pone.0239153] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 08/31/2020] [Indexed: 12/11/2022] Open
Abstract
Background Cell released microvesicles specifically, exosomes, play an important role in mediating immunologic escape, treatment resistance, and disease persistence of Hepatitis C virus (HCV) infection. Reports on the molecular compositions of exosomes released by cells under diverse conditions, especially during viral infections, suggest that their cargo contents are not randomly loaded. However, the precise molecular mechanisms directing the selective cargo sorting and loading inside infectious viral exosomes remains elusive. Aim To decipher the role of Reticulon 3 (RTN3) in the selective molecular cargo sorting and loading inside infectious viral exosomes during HCV infection. Methods We used Huh7 cells–JFH1 HCV infection and HCV Full-Length (FL) replicon systems. Additionally, we analyzed human liver and serum exosome samples from healthy and treatment naïve HCV infected individuals. Our experiments made use of molecular biology and immunology techniques. Results HCV infection (JFH1-Huh7 or HCV-FL replicon cells) was associated with increased RTN3L&S isoforms expression in cells and cell released exosomes. Accordingly, increased expression of RTN3L&S was observed in liver and serum exosome samples of HCV infected individuals compared to healthy controls. RNA-ChIP analysis revealed that RTN3L&S interacted with dsHCV RNA. Lentiviral CRISPR/Cas9 mediated knockdown (KD) of RTN3 and plasmid overexpression (OE) of wild type, C- and N-terminal deletion mutants of RTN3L&S in HCV- infected Huh7 cells differentially impacted the cellular release of infectious viral exosomes. RTN3L&S KD significantly decreased, while RTN3S OE significantly increased the number of Huh7 cell-released infectious exosomes. The C-terminal domain of RTN3 interacted with and modulated the loading of dsHCV RNA inside infectious exosomes. Antiviral treatment of HCV infected Huh7 cells reduced virus-induced RTN3L&S expression and attenuated the release of infectious exosomes. Conclusion RTN3 constitutes a novel regulator and a potential therapeutic target that mediates the specific loading of infectious viral exosomes.
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Affiliation(s)
- Jingjing Li
- INRS-Institut Armand-Frappier, Institut National de la Recherche Scientifique, Laval, Québec, Canada
| | - Ebtisam Abosmaha
- INRS-Institut Armand-Frappier, Institut National de la Recherche Scientifique, Laval, Québec, Canada
| | - Carla S. Coffin
- Department of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Patrick Labonté
- INRS-Institut Armand-Frappier, Institut National de la Recherche Scientifique, Laval, Québec, Canada
| | - Terence Ndonyi Bukong
- INRS-Institut Armand-Frappier, Institut National de la Recherche Scientifique, Laval, Québec, Canada
- * E-mail:
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26
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Ibrahim MAA, Sharaf Eldin HEM, Elswaidy NRM. Role of aqueous extract of saffron in ameliorating effect of sofosbuvir on the cerebellar cortex in rat. Anat Rec (Hoboken) 2020; 304:714-724. [PMID: 32721089 DOI: 10.1002/ar.24501] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 06/10/2020] [Accepted: 06/30/2020] [Indexed: 01/27/2023]
Abstract
Sofosbuvir is a promising antiviral drug against chronic hepatitis C virus. Although it is characterized by its high efficacy, its adverse effects on nervous tissue are still unclear. Saffron is known for its neuroprotective property. This is a biochemical, histological and immunohistochemical study of the effect of sofosbuvir on the cerebellar cortex of rat and the possible ameliorating role of saffron's aqueous extract. Twenty-four adult male Wistar albino rats were equally divided into four groups; control, saffron extract-treated, sofosbuvir-treated (41.1 mg/kg/day for 6 weeks) and group concomitantly treated with saffron extract and sofosbuvir. Sofosbuvir-treated group recorded a significant increase in cerebellar malondialdehyde level coupling with a significant decrease in tissue glutathione and superoxide dismutase. Light microscopy revealed reduced number of Purkinje cells. The granular layer depicted many granular cells and Bergmann astrocytes with nuclear and cytoplasmic alterations. Electron microscopy revealed disorganized molecular layer with disarranged myelinated axons and disrupted mitochondria. Few shrunken Purkinje cells showed electron-dense cytoplasm and rarefied nuclei, indistinct nuclear envelope and dilated perinuclear space, areas of vacuolated cytoplasm, fragmented rough endoplasmic reticulum and few dark mitochondria. Some axons with tiny mitochondria were detected. A significant upregulation in immunohistochemical expression of GFAP-positive astrocytes was recorded. Concomitant administration of saffron extract significantly improved all studied parameters. Saffron extract is beneficial in ameliorating sofosbuvir-induced cerebellar morphological changes mainly through its antioxidant and neuroprotective properties.
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Affiliation(s)
| | | | - Noha R M Elswaidy
- Histology and Cell Biology Department, Tanta University, Tanta, Egypt
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27
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Ahmad M, Dwivedy A, Mariadasse R, Tiwari S, Kar D, Jeyakanthan J, Biswal BK. Prediction of Small Molecule Inhibitors Targeting the Severe Acute Respiratory Syndrome Coronavirus-2 RNA-dependent RNA Polymerase. ACS OMEGA 2020; 5:18356-18366. [PMID: 32743211 PMCID: PMC7391942 DOI: 10.1021/acsomega.0c02096] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 06/30/2020] [Indexed: 05/08/2023]
Abstract
The current COVID-19 outbreak warrants the design and development of novel anti-COVID therapeutics. Using a combination of bioinformatics and computational tools, we modelled the 3D structure of the RdRp (RNA-dependent RNA polymerase) of SARS-CoV2 (severe acute respiratory syndrome coronavirus-2) and predicted its probable GTP binding pocket in the active site. GTP is crucial for the formation of the initiation complex during RNA replication. This site was computationally targeted using a number of small molecule inhibitors of the hepatitis C RNA polymerase reported previously. Further optimizations suggested a lead molecule that may prove fruitful in the development of potent inhibitors against the RdRp of SARS-CoV2.
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Affiliation(s)
- Mohammed Ahmad
- National
Institute of Immunology, New Delhi 110067, India
| | | | - Richard Mariadasse
- Department
of Bioinformatics, Alagappa University, karaikudi 630004, Tamil Nadu, India
| | - Satish Tiwari
- National
Institute of Immunology, New Delhi 110067, India
| | - Deepsikha Kar
- National
Institute of Immunology, New Delhi 110067, India
| | - Jeyaraman Jeyakanthan
- Department
of Bioinformatics, Alagappa University, karaikudi 630004, Tamil Nadu, India
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28
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Min JS, Kim GW, Kwon S, Jin YH. A Cell-Based Reporter Assay for Screening Inhibitors of MERS Coronavirus RNA-Dependent RNA Polymerase Activity. J Clin Med 2020; 9:E2399. [PMID: 32727069 PMCID: PMC7465106 DOI: 10.3390/jcm9082399] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 07/14/2020] [Accepted: 07/20/2020] [Indexed: 12/17/2022] Open
Abstract
Severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and coronavirus disease 2019 (COVID-19) are emerging zoonotic diseases caused by coronavirus (CoV) infections. The viral RNA-dependent RNA polymerase (RdRp) has been suggested as a valuable target for antiviral therapeutics because the sequence homology of CoV RdRp is highly conserved. We established a cell-based reporter assay for MERS-CoV RdRp activity to test viral polymerase inhibitors. The cell-based reporter system was composed of the bicistronic reporter construct and the MERS-CoV nsp12 plasmid construct. Among the tested nine viral polymerase inhibitors, ribavirin, sofosbuvir, favipiravir, lamivudine, zidovudine, valacyclovir, vidarabine, dasabuvir, and remdesivir, only remdesivir exhibited a dose-dependent inhibition. Meanwhile, the Z-factor and Z'-factor of this assay for screening inhibitors of MERS-CoV RdRp activity were 0.778 and 0.782, respectively. Ribavirin and favipiravir did not inhibit the MERS-CoV RdRp activity, and non-nucleoside HCV RdRp inhibitor, dasabuvir, partially inhibited MERS-CoV RdRp activity. Taken together, the cell-based reporter assay for MERS-CoV RdRp activity confirmed remdesivir as a direct inhibitor of MERS-CoV RdRp in cells. A cell-based MERS-CoV RdRp activity reporter assay is reliable and accurate for screening MERS-CoV RdRp-specific inhibitors. It may provide a valuable platform for developing antiviral drugs for emerging CoV infections.
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Affiliation(s)
- Jung Sun Min
- Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Korea; (J.S.M.); (G.-W.K.)
- Center for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon 34114, Korea
| | - Geon-Woo Kim
- Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Korea; (J.S.M.); (G.-W.K.)
- Center for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon 34114, Korea
| | - Sunoh Kwon
- Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Korea; (J.S.M.); (G.-W.K.)
- Center for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon 34114, Korea
| | - Young-Hee Jin
- Center for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon 34114, Korea
- KM Application Center, Korea Institute of Oriental Medicine, Daegu 41062, Korea
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29
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Tsertsvadze T, Gamkrelidze A, Nasrullah M, Sharvadze L, Morgan J, Shadaker S, Gvinjilia L, Butsashvili M, Metreveli D, Kerashvili V, Ezugbaia M, Chkhartishvili N, Abutidze A, Kvaratskhelia V, Averhoff F. Treatment outcomes of patients with chronic hepatitis C receiving sofosbuvir-based combination therapy within national hepatitis C elimination program in the country of Georgia. BMC Infect Dis 2020; 20:30. [PMID: 31924172 PMCID: PMC6954615 DOI: 10.1186/s12879-019-4741-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Accepted: 12/27/2019] [Indexed: 12/25/2022] Open
Abstract
Background Georgia has one of the highest HCV prevalence in the world and launched the world’s first national HCV elimination programs in 2015. Georgia set the ambitious target of diagnosing 90% of people living with HCV, treating 95% of those diagnosed and curing 95% of treated patients by 2020. We report outcomes of Sofosbuvir (SOF) based treatment regimens in patients with chronic HCV infection in Georgia. Methods Patients with cirrhosis, advanced liver fibrosis and severe extrahepatic manifestations were enrolled in the treatment program. Initial treatment consisted of SOF plus ribavirin (RBV) with or without pegylated interferon (INF). Sustained virologic response (SVR) was defined as undetectable HCV RNA at least 12 weeks after the end of treatment. SVR were calculated using both per-protocol and modified intent-to-treat (mITT) analysis. Results for patients who completed treatment through 31 October 2018 were analyzed. Results Of the 7342 patients who initiated treatment with SOF-based regimens, 5079 patients were tested for SVR. Total SVR rate was 82.1% in per-protocol analysis and 74.5% in mITT analysis. The lowest response rate was observed among genotype 1 patients (69.5%), intermediate response rate was achieved in genotype 2 patients (81.4%), while the highest response rate was among genotype 3 patients (91.8%). Overall, SOF/RBV regimens achieved lower response rates than IFN/SOF/RBV regimen (72.1% vs 91.3%, P < 0.0001). In multivariate analysis being infected with HCV genotype 2 (RR =1.10, CI [1.05–1.15]) and genotype 3 (RR = 1.14, CI [1.11–1.18]) were associated with higher SVR. Patients with cirrhosis (RR = 0.95, CI [0.93–0.98]), receiving treatment regimens of SOF/RBV 12 weeks, SOF/RBV 20 weeks, SOF/RBV 24 weeks and SOF/RBV 48 weeks (RR = 0.85, CI [0.81–0.91]; RR = 0.86, CI [0.82–0.92]; RR = 0.88, CI [0.85–0.91] and RR = 0.92, CI [0.87–0.98], respectively) were less likely to achieve SVR. Conclusions Georgia’s real world experience resulted in high overall response rates given that most patients had severe liver damage. Our results provide clear evidence that SOF plus IFN and RBV for 12 weeks can be considered a treatment option for eligible patients with all three HCV genotypes. With introduction of next generation DAAs, significantly improved response rates are expected, paving the way for Georgia to achieve HCV elimination goals.
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Affiliation(s)
- Tengiz Tsertsvadze
- Infectious Diseases, AIDS and Clinical Immunology Research Center, Tbilisi, Georgia. .,Ivane Javakhishvili Tbilisi State University, Faculty of Medicine, Tbilisi, Georgia.
| | - Amiran Gamkrelidze
- National Center for Disease control and public health, 99, Kakheti highway, 0198, Tbilisi, Georgia
| | - Muazzam Nasrullah
- Emerging Infections Program, Centers for Disease Control and Prevention (CDC), Division of Viral Hepatitis National Center for HIV, Hepatitis, STD&TB Prevention, Atlanta, USA
| | - Lali Sharvadze
- Infectious Diseases, AIDS and Clinical Immunology Research Center, Tbilisi, Georgia.,Ivane Javakhishvili Tbilisi State University, Faculty of Medicine, Tbilisi, Georgia.,Hepatology Clinic HEPA, Tbilisi, Georgia
| | - Juliette Morgan
- Emerging Infections Program, Centers for Disease Control and Prevention (CDC), Division of Viral Hepatitis National Center for HIV, Hepatitis, STD&TB Prevention, Atlanta, USA
| | - Shaun Shadaker
- Emerging Infections Program, Centers for Disease Control and Prevention (CDC), Division of Viral Hepatitis National Center for HIV, Hepatitis, STD&TB Prevention, Atlanta, USA
| | - Lia Gvinjilia
- CDC Foundation, Georgia Hepatitis C Elimination Program, Tbilisi, Georgia
| | | | | | - Vakhtang Kerashvili
- Infectious Diseases, AIDS and Clinical Immunology Research Center, Tbilisi, Georgia
| | - Marina Ezugbaia
- Infectious Diseases, AIDS and Clinical Immunology Research Center, Tbilisi, Georgia
| | | | - Akaki Abutidze
- Infectious Diseases, AIDS and Clinical Immunology Research Center, Tbilisi, Georgia
| | | | - Francisco Averhoff
- Emerging Infections Program, Centers for Disease Control and Prevention (CDC), Division of Viral Hepatitis National Center for HIV, Hepatitis, STD&TB Prevention, Atlanta, USA
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30
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Han J, Lee HW, Jin Y, Khadka DB, Yang S, Li X, Kim M, Cho WJ. Molecular design, synthesis, and biological evaluation of bisamide derivatives as cyclophilin A inhibitors for HCV treatment. Eur J Med Chem 2020; 188:112031. [PMID: 31923861 DOI: 10.1016/j.ejmech.2019.112031] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 12/20/2019] [Accepted: 12/31/2019] [Indexed: 12/25/2022]
Abstract
Hepatitis C virus (HCV) is a major cause of end-stage liver diseases. Direct-acting antivirals (DAAs), including inhibitors of nonstructural proteins (NS3/4A protease, NS5A, and NS5B polymerase), represent key components of anti-HCV treatment. However, some DAAs are associated with increased drug resistance and undesired side effects. Previous reports have shown that bisamides could be a novel class of cyclophilin A (CypA) inhibitors for treating HCV as a member of combinational therapies. To fully elucidate structure-activity relationships of bisamide derivatives and find a better hit compound with diverse binding modes, 16 biamides were designed with the help of docking program. They were then synthesized using one-pot four-component Ugi reaction. 7e with selectivity index of more than 18.9 (50% effective concentration of 5.3 μM, but no cytotoxicity at 100 μM) and unique binding mode that could be dived into gatekeeper pocket was selected as a new hit compound. Surface plasmon resonance experiments revealed that 7e is able to bind to CypA with a KD of 3.66 μM. Taken together, these results suggest that 7e as a CypA inhibitor could be used as an alternative anti-HCV agent in combinational therapy in the future.
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Affiliation(s)
- Jinhe Han
- College of Pharmacy, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - Hye Won Lee
- Virus Research Group, Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea
| | - Yifeng Jin
- College of Pharmacy, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - Daulat B Khadka
- College of Pharmacy, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - Suhui Yang
- College of Pharmacy, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - Xiaoli Li
- College of Pharmacy, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - Meehyein Kim
- Virus Research Group, Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea.
| | - Won-Jea Cho
- College of Pharmacy, Chonnam National University, Gwangju, 61186, Republic of Korea.
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Rabaan AA, Al-Ahmed SH, Bazzi AM, Alfouzan WA, Alsuliman SA, Aldrazi FA, Haque S. Overview of hepatitis C infection, molecular biology, and new treatment. J Infect Public Health 2019; 13:773-783. [PMID: 31870632 DOI: 10.1016/j.jiph.2019.11.015] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Revised: 07/08/2019] [Accepted: 11/18/2019] [Indexed: 12/13/2022] Open
Abstract
The World Health Organization estimates that 71 million people worldwide have chronic hepatitis C viral infection. A major challenge is overall lack of public awareness of hepatitis C, particularly among infected people of their infection status. Chronic hepatitis C infection is associated with advanced liver disease, is the main cause of hepatocellular carcinoma and causes many extra-hepatic manifestations. The existence of seven viral genotypes complicates targeting of treatment. Recent years have seen the approval of many direct acting antivirals targeted at hepatitis C virus non-structural proteins. These have revolutionized therapy as they allow achievement of extremely high sustained virologic responses. Of great significance is the development of pan-genotypic drug combinations, including the NS3/4A-NS5A inhibitor combinations sofosbuvir-velpatasvir and glecaprevir-pibrentasvir. However, resistance-associated mutations can result in failure of these treatments in a small number of patients. This, combined with the high costs of treatment, highlights the importance of continued research into effective anti-hepatitis C therapies, for example aimed at viral entry. Recent developments include identification of the potential of low-cost anti-histamines for repurposing as inhibitors of hepatitis C viral entry. In this review we focus on molecular biology of hepatitis C virus, and the new developments in hepatitis C treatment.
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Affiliation(s)
- Ali A Rabaan
- Molecular Diagnostic Laboratory, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia.
| | - Shamsah H Al-Ahmed
- Specialty Paediatric Medicine, Qatif Central Hospital, Qatif, Saudi Arabia
| | - Ali M Bazzi
- Microbiology Laboratory, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia
| | - Wadha A Alfouzan
- Department of Microbiology, Faculty of Medicine, Kuwait University, Safat 13110, Kuwait; Faculty of Medicine, Kuwait University, Dasma 35153, Kuwait
| | - Shahab A Alsuliman
- Internal Medicine and Infectious Disease Department, Dammam Medical Complex, Dammam, Saudi Arabia
| | - Fatimah A Aldrazi
- Infection Control Department, Dammam Medical Complex, Dammam, Saudi Arabia
| | - Shafiul Haque
- Research and Scientific Studies Unit, College of Nursing & Allied Health Sciences, Jazan University, Saudi Arabia
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32
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Arabyan E, Kotsynyan A, Hakobyan A, Zakaryan H. Antiviral agents against African swine fever virus. Virus Res 2019; 270:197669. [DOI: 10.1016/j.virusres.2019.197669] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Revised: 07/15/2019] [Accepted: 07/16/2019] [Indexed: 02/03/2023]
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33
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Akher FB, Farrokhzadeh A, Ramharack P, Shunmugam L, Van Heerden FR, Soliman MES. Discovery of novel natural flavonoids as potent antiviral candidates against hepatitis C virus NS5B polymerase. Med Hypotheses 2019; 132:109359. [PMID: 31466018 DOI: 10.1016/j.mehy.2019.109359] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2019] [Revised: 07/28/2019] [Accepted: 08/11/2019] [Indexed: 12/13/2022]
Abstract
The non-structural 5B (NS5B) polymerase of hepatitis C virus (HCV) is an attractive target for antiviral intervention. Quercetagetin (Que) is a natural flavonoid, which has been exhibited to have anti-HCV property through inhibition of RNA binding to NS5B. The last few decades have witnessed a growing interest in the extraction of natural flavonoids with a plethora of different biological activities. Considering the high therapeutic potential of Que, the aim of this study is to explore wide structure entities with potent activity using Que as a prototype. A virtual screen protocol involving docking and molecular dynamics has been performed to examine the potency of forty-three natural flavonoids which recently extracted from plants for inhibition of NS5B. During two screening stages, two compounds 24 and 41 were identified to have more favorable binding affinity to NS5B as compared to Que. The comparative analysis showed that there is a significant difference in the binding free energy of Que and 41 (ΔΔGbind = -11.17 kcal/mol). It was revealed that van der Waals (vdW) interaction drives the binding process of both 24 and 41 and plays an important role in increasing their activities relative to Que. PHE162 serves as a crucial residue in both the NS5B-24 and NS5B-41 systems, contributing the most vdW energy by π-π interaction, suggesting that aromatic interactions are critical for the binding of 24 and 41 to NS5B. Moreover, hydrogen bond analysis indicates that the hydrogen bonds formed by LYS98, THR137, ASP164 and ARG168, can play important roles in the increased binding affinity of 41 to NS5B relative to Que. The findings of this study will provide useful structure-activity relationship (SAR) guidelines for the design of novel inhibitors with improved/enhanced therapeutic activities in the treatment of hepatitis C.
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Affiliation(s)
- Farideh Badichi Akher
- Department of Computer Science, University of Cape Town, Cape Town 7701, South Africa; Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4001, South Africa.
| | - Abdolkarim Farrokhzadeh
- School of Chemistry and Physics, University of KwaZulu-Natal, Private Bag X01, Pietermaritzburg 3209, South Africa; Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4001, South Africa
| | - Pritika Ramharack
- Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4001, South Africa
| | - Letitia Shunmugam
- Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4001, South Africa
| | - Fanie R Van Heerden
- School of Chemistry and Physics, University of KwaZulu-Natal, Private Bag X01, Pietermaritzburg 3209, South Africa
| | - Mahmoud E S Soliman
- Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4001, South Africa.
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Abstract
Over the past few years, nucleosides have maintained a prominent role as one of the cornerstones of antiviral and anticancer therapeutics, and many approaches to nucleoside drug design have been pursued. One such approach involves flexibility in the sugar moiety of nucleosides, for example, in the highly successful anti-HIV and HBV drug tenofovir. In contrast, introduction of flexibility to the nucleobase scaffold has only more recently gained significance with the invention of our fleximers. The history, development, and some biological relevance for this innovative class of nucleosides are detailed herein.
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Dellay B, Sexter A, Wang JH, Hess GP, Ray Kim W, Israni AK. Impact of Sofosbuvir-Based Therapy on Liver Transplant Candidates with Hepatitis C Virus Infection. Pharmacotherapy 2019; 39:424-432. [PMID: 30779203 DOI: 10.1002/phar.2237] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND Sofosbuvir use in patients with decompensated cirrhosis may be associated with reduced liver transplant waitlist mortality and reduced need for transplant. METHODS Data from the Scientific Registry of Transplant Recipients were linked with a national database of pharmacy claims. All adult patients on the liver transplant waitlist on January 1, 2014, or added to the list during 2014, with hepatitis C virus as reason for listing were identified (2009 patients). A subgroup of 1093 unique patients had consistent pharmacy claim capture and observations. We compared patients who were and were not treated with all sofosbuvir-based regimens. RESULTS During the study period, 154 patients received sofosbuvir-based regimens. These patients had lower model for end-stage liver disease scores and significantly longer waiting times. We found a trend toward significance for more sofosbuvir-treated than untreated patients being removed from the waitlist due to improved condition (4.54% vs 3.19%, p=0.03). In a propensity score-adjusted analysis, sofosbuvir-treated patients were less likely to undergo transplant (hazard ratio 0.57, 95% confidence interval 0.37-0.89, p=0.01). CONCLUSION During the study period reflecting early sofosbuvir use, few liver transplant candidates received sofosbuvir. Use was associated with lower incidence of transplant and a trend toward more waitlist removals due to improved condition.
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Affiliation(s)
| | - Anne Sexter
- Chronic Disease Research Group, Hennepin Healthcare Research Institute, Minneapolis, Minnesota
| | - Jeffrey H Wang
- Department of Medicine, Hennepin Healthcare Systems, Minneapolis, Minnesota
| | - Gregory P Hess
- Scientific Studies & Projects Group, Symphony Health, Conshohocken, Pennsylvania.,Institute of Health Economics, University of Pennsylvania, Philadelphia, Pennsylvania
| | - W Ray Kim
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Palo Alto, California
| | - Ajay K Israni
- Department of Medicine, Hennepin Healthcare Systems, Minneapolis, Minnesota.,Department of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota
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Venkatesan A, Prabhu Dass J F. Review on chemogenomic approaches towards hepatitis C viral targets. J Cell Biochem 2019; 120:12167-12181. [PMID: 30887580 DOI: 10.1002/jcb.28581] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Revised: 01/09/2019] [Accepted: 01/14/2019] [Indexed: 12/18/2022]
Abstract
Hepatitis C virus (HCV) is the most prevalent viral pathogen that infects more than 185 million people worldwide. HCV infection leads to chronic liver diseases such as liver cirrhosis and hepatocellular carcinoma. Direct-acting antivirals (DAAs) are the recent combination therapy for HCV infection with reduced side effects than prior therapies. Sustained virological response (SVR) acts as a gold standard marker to monitor the success of antiviral treatment. Older treatment therapies attain 50-55% of SVR compared with DAAs which attain around 90-95%. The current review emphasizes the recent chemogenomic updates that have been unfolded through structure-based drug design of HCV drug target proteins (NS3/4A, NS5A, and NS5B) and ligand-based drug design of DAAs in achieving a stable HCV viral treatment strategies.
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Affiliation(s)
- Arthi Venkatesan
- Department of Integrative Biology, School of BioSciences and Technology (SBST), VIT, Vellore, Tamil Nadu, India
| | - Febin Prabhu Dass J
- Department of Integrative Biology, School of BioSciences and Technology (SBST), VIT, Vellore, Tamil Nadu, India
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Elfiky AA. Novel Guanosine Derivatives as Anti-HCV NS5b Polymerase: A QSAR and Molecular Docking Study. Med Chem 2019; 15:130-137. [PMID: 30324891 DOI: 10.2174/1573406414666181015152511] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2017] [Revised: 06/01/2018] [Accepted: 09/30/2018] [Indexed: 12/23/2022]
Abstract
BACKGROUND IDX-184 is a guanosine derivative having a potent inhibitory performance against HCV NS5b polymerase. OBJECTIVE To test three different groups of 2'C - modified analogues of guanosine nucleotide against HCV polymerase. METHOD Using combined Quantitative Structure-Activity Relationships (QSAR) and molecular docking, the suggested compounds are studied. RESULTS Examining the docked structures of the compounds with experimentally solved NS5b structure (PDB ID: 2XI3) revealed that most of the compounds have the same mode of interaction as that of guanosine nucleotide and hence, NS5b inhibition is possible. CONCLUSION It is revealed that sixteen modifications have a better binding affinity to NS5b compared to guanosine. In addition, seven more compounds are better in NS5b binding compared to the approved drug, sofosbuvir, and the compound under clinical trials, IDX-184. Hence, these compounds could be potent HCV NS5b inhibitors. Summary Points: Novel guanosine modifications were introduced in silico and optimized using QM. QSAR and docking calculations are performed to test the binding affinity of the compounds to HCV NS5b active site. Comparison between the binding affinities and the mode of interactions of the compounds and both GTP and IDX-184 is performed. Structural mining to quantify the mode of binding of the compounds to NS5b active site pocket.
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Affiliation(s)
- Abdo A Elfiky
- Biophysics Department, Faculty of Science, Cairo University, Giza, Egypt
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Viral RNA-Dependent RNA Polymerase Inhibitor 7-Deaza-2'- C-Methyladenosine Prevents Death in a Mouse Model of West Nile Virus Infection. Antimicrob Agents Chemother 2019; 63:AAC.02093-18. [PMID: 30642926 DOI: 10.1128/aac.02093-18] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Accepted: 01/04/2019] [Indexed: 12/22/2022] Open
Abstract
West Nile virus (WNV) is a medically important emerging arbovirus causing serious neuroinfections in humans and against which no approved antiviral therapy is currently available. In this study, we demonstrate that 2'-C-methyl- or 4'-azido-modified nucleosides are highly effective inhibitors of WNV replication, showing nanomolar or low micromolar anti-WNV activity and negligible cytotoxicity in cell culture. One representative of C2'-methylated nucleosides, 7-deaza-2'-C-methyladenosine, significantly protected WNV-infected mice from disease progression and mortality. Twice daily treatment at 25 mg/kg starting at the time of infection resulted in 100% survival of the mice. This compound was highly effective, even if the treatment was initiated 3 days postinfection, at the time of a peak of viremia, which resulted in a 90% survival rate. However, the antiviral effect of 7-deaza-2'-C-methyladenosine was absent or negligible when the treatment was started 8 days postinfection (i.e., at the time of extensive brain infection). The 4'-azido moiety appears to be another important determinant for highly efficient inhibition of WNV replication in vitro However, the strong anti-WNV effect of 4'-azidocytidine and 4'-azido-aracytidine was cell type dependent and observed predominantly in porcine kidney stable (PS) cells. The effect was much less pronounced in Vero cells. Our results indicate that 2'-C-methylated or 4'-azidated nucleosides merit further investigation as potential therapeutic agents for treating WNV infections as well as infections caused by other medically important flaviviruses.
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Zając M, Muszalska I, Sobczak A, Dadej A, Tomczak S, Jelińska A. Hepatitis C - New drugs and treatment prospects. Eur J Med Chem 2019; 165:225-249. [PMID: 30685524 DOI: 10.1016/j.ejmech.2019.01.025] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 01/11/2019] [Accepted: 01/11/2019] [Indexed: 12/19/2022]
Abstract
Hepatitis C virus (HCV) affects approx. 3% of the world's population and accounts for ca 300 000 deaths per year. 80% of individuals with HCV develop chronic symptoms which, when untreated, may cause cirrhosis (27%) or hepatocellular carcinoma (25%). The hepatitis C virus is a (+)ssRNA enveloped virus of the family Flaviviridae. Seven major HCV genotypes and their subtypes (a, b) have been identified. In the 1990s, interferons alpha-2 were used in the treatment of HCV and in the next decade HCV therapy was based on pegylated interferon alpha-2 in combination with ribavirin. Since 2011, interferons alpha, DNA and RNA polymerase inhibitors, NS3/4A RNA protease inhibitors, NS5 RNA serine protease inhibitors, NS5B RNA polymerase inhibitors have been approved for clinical use. Monotherapy is avoided in medication due to rapidly developing viral resistance. A total of 113 papers were included comprising original publications and reviews. The paper reviews the molecular targets and chemical structures of drugs used in HCV treatment. Indications and contraindications for anti-HCV drugs are also discussed together with application regimens.
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Affiliation(s)
- Marianna Zając
- Poznan University of Medicinal Sciences, Department of Pharmaceutical Chemistry, Grunwaldzka Str. 6, 60-780, Poznań, Poland
| | - Izabela Muszalska
- Poznan University of Medicinal Sciences, Department of Pharmaceutical Chemistry, Grunwaldzka Str. 6, 60-780, Poznań, Poland.
| | - Agnieszka Sobczak
- Poznan University of Medicinal Sciences, Department of Pharmaceutical Chemistry, Grunwaldzka Str. 6, 60-780, Poznań, Poland
| | - Adrianna Dadej
- Poznan University of Medicinal Sciences, Department of Pharmaceutical Chemistry, Grunwaldzka Str. 6, 60-780, Poznań, Poland
| | - Szymon Tomczak
- Poznan University of Medicinal Sciences, Department of Pharmaceutical Chemistry, Grunwaldzka Str. 6, 60-780, Poznań, Poland
| | - Anna Jelińska
- Poznan University of Medicinal Sciences, Department of Pharmaceutical Chemistry, Grunwaldzka Str. 6, 60-780, Poznań, Poland
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High sustained virologic response rate using generic directly acting antivirals in the treatment of chronic hepatitis C virus Egyptian patients: single-center experience. Eur J Gastroenterol Hepatol 2018; 30:1194-1199. [PMID: 30096091 DOI: 10.1097/meg.0000000000001228] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND Hepatitis C virus (HCV) is a major health problem in Egypt, with a high prevalence of genotype 4. AIM This study aimed to evaluate the safety and efficacy of generic sofosbuvir (SOF) plus generic daclatasvir (DAC) with or without ribavirin in the treatment of Egyptian chronic HCV patients compared with the use of brand drugs. MATERIALS AND METHODS An observational study that included 234 Egyptian chronic HCV patients was carried out. Patients were classified into two groups: group A (101 patients) received brand SOF 400 mg plus brand DAC 60 mg and group B (134 patients) received generic SOF 400 mg plus generic DAC 60 mg with or without ribavirin for 12 weeks. The end point was a sustained virological response at 12 weeks after treatment. RESULTS Thirty-eight (37.2%) patients in group A were treatment experienced compared with 12 (9.02%) patients in group B; there were 39 (38%) cirrhotic patients in group A and 22 (16.5%) cirrhotic patients in group B. In group A, 50% of patients received ribavirin, while in group B, 42.1% of patients received ribavirin. All patients were followed up; all of them attended their week 12 post-treatment visit with negative HCV RNA, with achievement of sustained virological response at 12 in 100% of patients receiving generic drugs (group B) and 99% of patients receiving brand drugs (group A). Generic SOF and DAC were well tolerated, with mild adverse events including fatigue and headache. CONCLUSION Use of generic SOF and DAC with or without ribavirin is an extremely effective and a well-tolerated treatment for Egyptian chronic HCV patients.
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Brown LV, Gaffney EA, Wagg J, Coles MC. Applications of mechanistic modelling to clinical and experimental immunology: an emerging technology to accelerate immunotherapeutic discovery and development. Clin Exp Immunol 2018; 193:284-292. [PMID: 30240512 PMCID: PMC6150250 DOI: 10.1111/cei.13182] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/31/2018] [Indexed: 12/15/2022] Open
Abstract
The application of in-silico modelling is beginning to emerge as a key methodology to advance our understanding of mechanisms of disease pathophysiology and related drug action, and in the design of experimental medicine and clinical studies. From this perspective, we will present a non-technical discussion of a small number of recent and historical applications of mathematical, statistical and computational modelling to clinical and experimental immunology. We focus specifically upon mechanistic questions relating to human viral infection, tumour growth and metastasis and T cell activation. These exemplar applications highlight the potential of this approach to impact upon human immunology informed by ever-expanding experimental, clinical and 'omics' data. Despite the capacity of mechanistic modelling to accelerate therapeutic discovery and development and to de-risk clinical trial design, it is not utilized widely across the field. We outline ongoing challenges facing the integration of mechanistic modelling with experimental and clinical immunology, and suggest how these may be overcome. Advances in key technologies, including multi-scale modelling, machine learning and the wealth of 'omics' data sets, coupled with advancements in computational capacity, are providing the basis for mechanistic modelling to impact on immunotherapeutic discovery and development during the next decade.
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Affiliation(s)
- L. V. Brown
- Wolfson Centre for Mathematical BiologyMathematical InstituteUniversity of OxfordOxfordUK
| | - E. A. Gaffney
- Wolfson Centre for Mathematical BiologyMathematical InstituteUniversity of OxfordOxfordUK
| | - J. Wagg
- Pharmaceutical Sciences, Clinical PharmacologyRoche Innovation CenterBaselSwitzerland
| | - M. C. Coles
- Kennedy Institute of RheumatologyUniversity of OxfordOxfordUK
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Rivero-Juarez A, Brieva T, Frias M, Rivero A. Pharmacodynamic and pharmacokinetic evaluation of the combination of daclatasvir/sofosbuvir/ribavirin in the treatment of chronic hepatitis C. Expert Opin Drug Metab Toxicol 2018; 14:901-910. [PMID: 30058394 DOI: 10.1080/17425255.2018.1506765] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION The combination of daclatasvir (DCV), sofosbuvir (SOF), and ribavirin (RBV) is a direct-acting antiviral (DAA) regimen for the treatment of hepatitis C virus (HCV) infection. The inclusion of newer effective DAAs such as SOF and DCV with high efficacy and excellent tolerance introduced a new scenario in HCV infection therapy: high rates of sustained virological response (SVR), shorter therapies, less toxicity, and interferon-free treatments. This combination was approved for the treatment of HCV in treatment-naive or treatment-experienced patients with chronic HCV genotype 1 or 3 infection. Areas covered: This review summarizes the pharmacokinetics, pharmacodynamics, efficacy, and safety of DCV plus SOF and RBV therapy in the treatment of HCV infection. The topics include data regarding drug absorption, distribution, metabolism, excretion, and antiviral activity strategies, such as clinical dose selection and treatment duration. Expert opinion: This combination, taken orally with or without food, has an excellent pharmacokinetic and pharmacodynamic profile. DAC/SOF/RBV achieves very high rates of SVR in treatment-naive and treatment-experienced patients with chronic HCV infection, including difficult-to-treat patients such as those with compensated cirrhosis, post-transplant recurrence, or HIV-1 co-infection.
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Affiliation(s)
- Antonio Rivero-Juarez
- a Unidad de Enfermedades Infecciosas, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC) , Hospital Universitario Reina Sofía de Córdoba, Universidad de Córdoba , Cordoba , Spain
| | - Teresa Brieva
- a Unidad de Enfermedades Infecciosas, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC) , Hospital Universitario Reina Sofía de Córdoba, Universidad de Córdoba , Cordoba , Spain
| | - Mario Frias
- a Unidad de Enfermedades Infecciosas, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC) , Hospital Universitario Reina Sofía de Córdoba, Universidad de Córdoba , Cordoba , Spain
| | - Antonio Rivero
- a Unidad de Enfermedades Infecciosas, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC) , Hospital Universitario Reina Sofía de Córdoba, Universidad de Córdoba , Cordoba , Spain
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Lu NT, Liu NM, Patel D, Vu JQ, Liu L, Kim CY, Cho P, Khachatoorian R, Patel N, Magyar CE, Ganapathy E, Arumugaswami V, Dasgupta A, French SW. Oncoprotein Stathmin Modulates Sensitivity to Apoptosis in Hepatocellular Carcinoma Cells During Hepatitis C Viral Replication. J Cell Death 2018; 11:1179066018785141. [PMID: 30034249 PMCID: PMC6047100 DOI: 10.1177/1179066018785141] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Accepted: 05/28/2018] [Indexed: 01/28/2023] Open
Abstract
Patients with chronic hepatitis C virus (HCV) infection risk complications of
cirrhosis, liver failure, and hepatocellular carcinoma (HCC). Previously, our
proteomic examination of hepatocytes carrying a HCV-replicon revealed that
deregulation of cytoskeletal dynamics may be a potential mechanism of
viral-induced HCC growth. Here, we demonstrate the effect of HCV replication on
the microtubule regulator stathmin (STMN1) in HCC cells. We further explore how
the altered activity or synthesis of stathmin affects cellular proliferation and
sensitivity to apoptosis in control HCC cells (Huh7.5) and experimental
HCV-replicon harboring HCC cells (R-Huh7.5). The HCV-replicon harboring HCC
cells (R-Huh 7.5) lack viral structural genes/proteins for acute infectivity and
thus is the standard model for in vitro chronic infection study. Knockdown of
endogenous stathmin reduced sensitivity to apoptosis in replicon cells.
Meanwhile, constitutively active stathmin increased sensitivity to apoptosis in
replicon cells. In addition, overexpression of constitutively active stathmin
reduced cell proliferation in both control and replicon cells. These findings
implicate, for the first time, a novel role for stathmin in viral
replication–related apoptosis. Stathmin’s potential role in HCV replication and
HCC make it a candidate for the future study of viral-induced malignancies.
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Affiliation(s)
- Nu T Lu
- Department of Pathology & Laboratory Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA.,Department of Hematology and Oncology, University of California, Los Angeles (UCLA), Los Angeles, CA, USA
| | - Natalie M Liu
- Department of Pathology & Laboratory Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA
| | - Darshil Patel
- Department of Pathology & Laboratory Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA
| | - James Q Vu
- Department of Pathology & Laboratory Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA
| | - Lisa Liu
- Department of Pathology & Laboratory Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA
| | - Chae Yeon Kim
- Department of Pathology & Laboratory Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA
| | - Peter Cho
- Department of Pathology & Laboratory Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA
| | - Ronik Khachatoorian
- Department of Pathology & Laboratory Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA
| | - Nikita Patel
- Department of Pathology & Laboratory Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA
| | - Clara E Magyar
- Department of Pathology & Laboratory Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA
| | - Ekambaram Ganapathy
- Department of Pathology & Laboratory Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA
| | - Vaithilingaraja Arumugaswami
- Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA.,Department of Surgery and Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Asim Dasgupta
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA, USA
| | - Samuel Wheeler French
- Department of Pathology & Laboratory Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA.,UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA
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Lin CK, Tseng CK, Liaw CC, Huang CY, Wei CK, Sheu JH, Lee JC. Lobohedleolide suppresses hepatitis C virus replication via JNK/c-Jun-C/EBP-mediated down-regulation of cyclooxygenase-2 expression. Sci Rep 2018; 8:8676. [PMID: 29875371 PMCID: PMC5989199 DOI: 10.1038/s41598-018-26999-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Accepted: 04/27/2018] [Indexed: 12/15/2022] Open
Abstract
Hepatitis C virus (HCV) chronically infects 2–3% people of the global population, which leads to liver cirrhosis and hepatocellular carcinoma. Drug resistance remains a serious problem that limits the effectiveness of US Food and Drug Administration (FDA)-approved direct-acting antiviral (DAA) drugs against HCV proteins. The objective of our study was to discover new antivirals from natural products to supplement current therapeutics. We demonstrated that lobohedleolide, isolated from the Formosan soft coral Lobophytum crassum, significantly reduced HCV replication in replicon cells and JFH-1 infection system, with EC50 values of 10 ± 0.56 and 22 ± 0.75 μM, respectively, at non-toxic concentrations. We further observed that the inhibitory effect of lobohedleolide on HCV replication is due to suppression of HCV-induced cyclooxygenase-2 (COX-2) expression. Based on deletion-mutant analysis of the COX-2 promoter, we identified CCAAT/enhancer-binding protein (C/EBP) as a key transcription factor for the down-regulation of COX-2 by lobohedleolide, through which lobohedleolide decreased the phosphorylation of c-Jun NH2-terminal protein kinase and c-Jun to suppress HCV-induced C/EBP expression. The combination treatment of lobohedleolide with clinically used HCV drugs synergistically reduced HCV RNA replication, indicating that lobohedleolide exhibited a high biomedical potential to be used as a supplementary therapeutic agent to control HCV infection.
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Affiliation(s)
- Chun-Kuang Lin
- Doctoral Degree Program in Marine Biotechnology, College of Marine Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.,Doctoral Degree Program in Marine Biotechnology, Academia Sinica, Taipei, Taiwan
| | - Chin-Kai Tseng
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chih-Chuang Liaw
- Doctoral Degree Program in Marine Biotechnology, College of Marine Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.,Department of Marine Biotechnology and Resources, College of Marine Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Chiung-Yao Huang
- Department of Marine Biotechnology and Resources, College of Marine Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Chih-Ku Wei
- Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jyh-Horng Sheu
- Doctoral Degree Program in Marine Biotechnology, College of Marine Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan. .,Department of Marine Biotechnology and Resources, College of Marine Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan. .,Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.
| | - Jin-Ching Lee
- Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan. .,Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. .,Research Center for Natural Products and Drug Development, Kaohsiung Medical University, Kaohsiung, Taiwan. .,Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
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Sofosbuvir inhibits hepatitis A virus replication in vitro assessed by a cell-based fluorescent reporter system. Antiviral Res 2018; 154:51-57. [DOI: 10.1016/j.antiviral.2018.04.007] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Revised: 03/28/2018] [Accepted: 04/08/2018] [Indexed: 02/07/2023]
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Attia D, El Saeed K, Elakel W, El Baz T, Omar A, Yosry A, Elsayed MH, Said M, El Raziky M, Anees M, Doss W, El Shazly Y, Wedemeyer H, Esmat G. The adverse effects of interferon-free regimens in 149 816 chronic hepatitis C treated Egyptian patients. Aliment Pharmacol Ther 2018; 47:1296-1305. [PMID: 29504152 DOI: 10.1111/apt.14538] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2017] [Revised: 10/30/2017] [Accepted: 01/07/2018] [Indexed: 12/14/2022]
Abstract
BACKGROUND Interferon-free regimens are associated with high sustained virological response; however, associated adverse effects have yet to be fully reported. AIM To evaluate the adverse effects associated with the different direct-acting antiviral drug (DAA) regimens in Egyptian patients. METHODS This multicenter retrospective study included all adverse effects during and after treatment with DAA regimens of 149 816 chronic hepatitis C treated Egyptian patients. Patients received sofosbuvir (SOF)/ribavirin (RBV) (n = 21 835), SOF/simeprevir (n = 24 215) SOF/daclatasvir (DCV) (n = 58 477), SOF/DCV/RBV (n = 45 188) and paritaprevir/ombitasvir/ritonavir/RBV (n = 101). The duration of treatment varied between 12 and 24 weeks. All changes in the treatment regimens, discontinuation, mortality, and serious side effects were reported. RESULTS Adverse effects developed in 2475 (1.7%) (mean age [54 ± 9], male gender [53%]) patients. Serious side effects developed in 68% of these patients, and SOF/RBV was the most common causing regimen (73%, P < 0.001). Anaemia and hyperbilirubinemia were the most common side effects (731/149816, 0.5% and 463/149816, 0.3%, respectively) and SOF/RBV (588/21835, 3% and 353/21835, 1.6%, respectively) showed the highest incidence in the treated patients. Hepatocellular carcinoma and mortality were reported in 0.02% and 0.06% of all treated patients, respectively. Patients with liver cirrhosis showed higher incidence of serious side effects (Log rank P = 0.045) and mortality (Log rank P = 0.025) than patients without liver cirrhosis. Male gender (P = 0.012), lower haemoglobin (P < 0.001), platelets (P < 0.001) and albumin (P = 0.001), higher bilirubin (P = 0.002) and cirrhosis (P < 0.001) were factors associated with serious side effects development. CONCLUSION Adverse effects associated with DAAs are few, anaemia being the most common. SOF/RBV regimen showed the highest rate of side effects while SOF/DCV showed the least.
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Affiliation(s)
- D Attia
- Department of Hepatology, Gastroenterology and Endemic Medicine, Faculty of Medicine, Beni-suef University, Beni-suef, Egypt
| | - K El Saeed
- Department of Tropical Medicine, Ain Shams University, Cairo, Egypt
| | - W Elakel
- Department of Hepatology, Gastroenterology and Endemic Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - T El Baz
- Department of Hepatology, Gastroenterology and Endemic Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - A Omar
- Department of Hepatology, Gastroenterology and Endemic Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - A Yosry
- Department of Hepatology, Gastroenterology and Endemic Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - M H Elsayed
- National Committee of Viral Hepatitis MOH, Ain Shams University, Cairo, Egypt
| | - M Said
- Department of Hepatology, Gastroenterology and Endemic Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - M El Raziky
- Department of Hepatology, Gastroenterology and Endemic Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - M Anees
- Department of Tropical Medicine, Tanta University, Tanta, Egypt
| | - W Doss
- National Committee of Viral Hepatitis MOH, Cairo University, Cairo, Egypt
| | - Y El Shazly
- National Committee of Viral Hepatitis MOH, Ain Shams University, Cairo, Egypt
| | - H Wedemeyer
- Department of Hepatology, Gastroenterology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - G Esmat
- National Committee of Viral Hepatitis MOH, Cairo University, Cairo, Egypt
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Abdel-Aziz AM, Ibrahim MA, El-Sheikh AA, Kamel MY, Zenhom NM, Abdel-Raheim S, Abdelhaleem H. Effect of Sofosbuvir Plus Daclatasvir in Hepatitis C Virus Genotype-4 Patients: Promising Effect on Liver Fibrosis. J Clin Exp Hepatol 2018; 8:15-22. [PMID: 29743792 PMCID: PMC5938328 DOI: 10.1016/j.jceh.2017.06.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Accepted: 06/17/2017] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND/PURPOSE The effect of sofosbuvir and daclatasvir in treatment of genotype 4 Hepatitis C Virus (HCV) is not well documented. This study investigated the safety and efficacy of sofosbuvir plus daclatasvir with or without ribavirin in treatment of HCV genotype 4 patients. The impact of therapy on liver fibrosis as well as the role of IL18 polymorphism in therapeutic outcome was assessed. METHODS One hundred HCV genotype 4 patients were categorized into 2 groups. The group 1 comprised treatment naïve patients, with total serum bilirubin ≤ 1.2 mg/10-1 L, serum albumin ≥ 3.5 g/10-1 L, INR ≤ 1.2, and platelet count ≥ 150 × 109/L. This group was treated with sofosbuvir plus daclatasvir for 12 weeks. The group 2 included Peg-IFN-α-or sofosbuvir treatment experienced, or patients with at least 2 of the following findings: total serum bilirubin > 1.2 mg/10-1 L, serum albumin < 3.5 g/10-1 L, INR > 1.2, and platelet count < 150 × 109 L-1. Group 2 was treated with sofosbuvir-daclatasvir + ribavirin for 12 weeks, with the exception of sofosbuvir treatment experienced patients, who were treated with sofosbuvir/daclatasvir + ribavirin for 24 weeks. RESULTS Sustained Virological Response (SVR12) (undetectable viremia12 weeks post-treatment), was 93.3% in group 1 and 87.5% in group 2 (total = 91%). Such high efficacy was accompanied with tolerable adverse effects as well as with significant improvement in liver fibrosis. No significant association was observed between IL18 polymorphism (rs1946518) at position -607 and achievement of SVR12 in HCV patients after treatment. CONCLUSION Sofosbuvir plus daclatasvir, with or without ribavirin achieved high efficacy and safety in HCV genotype 4 patients. Their effects were accompanied with attenuation of liver fibrosis. Further wider-scale studies are needed to evaluate the actual role of IL18 polymorphisms in treatment response with sofosbuvir/daclatasvir.
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Key Words
- DAA, Direct Acting Anti-viral
- FIB 4, Fibrosis Score 4
- HCV
- HCV, Hepatitis C Virus
- IL-18 polymorphism
- IL-18, Interleukin 18
- INF, Interferon
- NS, Non-Structural
- PCR, Polymerase Chain Reaction
- RFLP, Restriction Fragment Length Polymorphism
- RNA, Ribonucleic Acid
- SNPs, Single-Nucleotide Polymorphisms
- SVR12, Sustained Virologic Response 12 Week Post Treatment
- daclatasvir
- sofosbuvir
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Affiliation(s)
- Asmaa M. Abdel-Aziz
- Department of Pharmacology, Faculty of Medicine, Minia University, 61511 Minia, Egypt
| | - Mohamed A. Ibrahim
- Department of Pharmacology, Faculty of Medicine, Minia University, 61511 Minia, Egypt,Address for correspondence: Mohamed Abdellah Ibrahim, Department of Pharmacology, Faculty of Medicine, Minia University, Minia 61511, Egypt. Tel.: +20 1023168222; fax: +20 862342813.
| | - Azza A. El-Sheikh
- Department of Pharmacology, Faculty of Medicine, Minia University, 61511 Minia, Egypt,Basic Health Sciences Department, Faculty of Medicine, Princess Nourah Bint Abdulrahman University, 11671 Riyadh, Saudi Arabia
| | - Maha Y. Kamel
- Department of Pharmacology, Faculty of Medicine, Minia University, 61511 Minia, Egypt
| | - Nagwa M. Zenhom
- Department of Biochemistry, Faculty of Medicine, Minia University, 61511 Minia, Egypt
| | - Salam Abdel-Raheim
- Department of Biochemistry, Faculty of Medicine, Minia University, 61511 Minia, Egypt
| | - Hisham Abdelhaleem
- Department of Internal Medicine, Faculty of Medicine, Minia University, 61511 Minia, Egypt
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Eyer L, Nencka R, de Clercq E, Seley-Radtke K, Růžek D. Nucleoside analogs as a rich source of antiviral agents active against arthropod-borne flaviviruses. Antivir Chem Chemother 2018; 26:2040206618761299. [PMID: 29534608 PMCID: PMC5890575 DOI: 10.1177/2040206618761299] [Citation(s) in RCA: 104] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2017] [Accepted: 01/30/2018] [Indexed: 12/27/2022] Open
Abstract
Nucleoside analogs represent the largest class of small molecule-based antivirals, which currently form the backbone of chemotherapy of chronic infections caused by HIV, hepatitis B or C viruses, and herpes viruses. High antiviral potency and favorable pharmacokinetics parameters make some nucleoside analogs suitable also for the treatment of acute infections caused by other medically important RNA and DNA viruses. This review summarizes available information on antiviral research of nucleoside analogs against arthropod-borne members of the genus Flavivirus within the family Flaviviridae, being primarily focused on description of nucleoside inhibitors of flaviviral RNA-dependent RNA polymerase, methyltransferase, and helicase/NTPase. Inhibitors of intracellular nucleoside synthesis and newly discovered nucleoside derivatives with high antiflavivirus potency, whose modes of action are currently not completely understood, have drawn attention. Moreover, this review highlights important challenges and complications in nucleoside analog development and suggests possible strategies to overcome these limitations.
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Affiliation(s)
- Luděk Eyer
- Department of Virology, Veterinary Research Institute, Brno, Czech Republic
- Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, České Budějovice, Czech Republic
| | - Radim Nencka
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic
| | - Erik de Clercq
- Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | | | - Daniel Růžek
- Department of Virology, Veterinary Research Institute, Brno, Czech Republic
- Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, České Budějovice, Czech Republic
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Gao M, O'Boyle DR, Roberts S. HCV NS5A replication complex inhibitors. Curr Opin Pharmacol 2017; 30:151-157. [PMID: 27643675 DOI: 10.1016/j.coph.2016.07.014] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2016] [Revised: 07/21/2016] [Accepted: 07/25/2016] [Indexed: 01/29/2023]
Abstract
The development of anti-HCV drugs is one of the most successful stories of antiviral therapy. In fact, for the first time in human history we have the potential to eradicate a chronic viral infection using only orally administered direct antiviral agents (DAAs). HCV NS5A replication complex inhibitors, exemplified by Daclatasvir (DCV, BMS-790052, Daklinza®), are a new class of DAA. The astonishing in vitro potency of DCV (pM to low nM range) translated to remarkable efficacy in clinical trials, and 2nd generation NS5A inhibitors have become essential components of HCV combination therapies. The current cure rate of effective combination therapies exceeds 90% in most clinical trials. The extraordinary potency of NS5A inhibitors promoted significant efforts to understand their mechanism(s) of inhibition.
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Affiliation(s)
- Min Gao
- Bristol-Myers Squibb Company, Wallingford, CT 06492, USA.
| | | | - Susan Roberts
- Bristol-Myers Squibb Company, Wallingford, CT 06492, USA
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Siddique MS, Shoaib S, Saad A, Iqbal HJ, Durrani N. Rapid virological&End treatment response of patients treated with Sofosbuvir in Chronic Hepatitis C. Pak J Med Sci 2017; 33:813-817. [PMID: 29067045 PMCID: PMC5648944 DOI: 10.12669/pjms.334.12785] [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: 04/14/2017] [Revised: 05/03/2017] [Accepted: 08/03/2017] [Indexed: 12/26/2022] Open
Abstract
OBJECTIVE To determineRapid & End treatment response of patients treated with Sofosbuvir in Chronic Hepatitis C at tertiary care hospital. METHODS It was an observational study conducted at Memon Medical Institute from January 2016 to July 2017. The inclusion criteria for patients was 18 years of age or older, having chronic infection with HCV. Total=201 received sofosbuvir with or without interferon in our OPDs. Patients were categorized into Treatment naïve, treatment experienced and decompensated chronic liver disease. Pregnant patients and those not willing to participate were excluded. Initially genotyping and Quantitative HCV RNA test was done. RESULTS A total of 201 subjects were included in the study with mean age of the patients was 46.22± 14.41 years. Of 201 patients, n= 131 (65.2%) chronic hepatitis C, compensated cirrhosis n= 47(23.4%), and with decompensated cirrhosis n=23(11.4%). Most commonly genotype 3 n= 180 (89.6%) was present followed by genotype 1 n=9(4.5%), genotype 2 n=1(0.5%), genotype 4 n=1(0.5%). Of patients with genotype 3, 123 received dual therapy and 57 were given triple therapy. After one month of therapy HCV RNA by PCR, 200(99.5%) achieved RVR, 199(99%) achieved ETR and SVR achieved in 178(88.5%) while remaining 1 patient did not achieved RVR, 2 ETR and 12 patients did not achieved SVR and remaining 11 SVR lost follow up. CONCLUSION Sofosbuvir has shown to be very effective andsuccessfulwith achievement of virological response with little or no resistance in all genotypes mainly genotype 3 treated in our study population. The promising results of our study will aid in better outcomes and therefore help in eradication of the virus.
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Affiliation(s)
- Muhammad Shoaib Siddique
- Dr. Muhammad ShoaibSiddique, FCPS Gastroenterology. Consultant Gastroenterologists, Memon Medical Institute & Hospital, Karachi, Pakistan
| | - Sana Shoaib
- Dr. Sana Shoaib, FCPS Medicine. Consultant Medicine, Memon Medical Institute & Hospital, Karachi, Pakistan
| | - Alvia Saad
- Dr. AlviaSaad, FCPS Registrar General Medicine. Incharge Emergency, Memon Medical Institute & Hospital, Karachi, Pakistan
| | - Hamna Javed Iqbal
- HamnaJavedIqbal, Student, Research Coordinator, Memon Medical Hospital, Karachi, Memon Medical Institute & Hospital, Karachi, Pakistan
| | - Noureen Durrani
- NoureenDurrani, Statistician & Researcher, Memon Medical Institute & Hospital, Karachi, Pakistan
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