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1
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Ivantcova PM, Kirsanova AA, Polshakov VI, Lyssenko KA, Kudryavtsev KV. Pyrrolidine/Azepane Ring Expansion via Intramolecular Ullmann-Type Annulation/Rearrangement Cascade: Synthesis of Highly Functionalized 1 H-Benzazepines. Org Lett 2023; 25:7573-7577. [PMID: 37801732 DOI: 10.1021/acs.orglett.3c03030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/08/2023]
Abstract
5-Arylpyrrolidine-2-carboxylates with an ortho-halogen substituent at 5-aryl and an electron-withdrawing group at the C4 position of the pyrrolidine ring were transformed into 1H-benzo[b]azepine-2-carboxylates under Cu(I) promotion and microwave activation. Reaction promoter copper(I) thiophene-2-carboxylate has been generated in situ in the reaction's environment from Cu2O and thiophene-2-carboxylic acid. Functionalized 1H-benzo[b]azepine-2-carboxylates were obtained in racemic and optically active forms in 67-89% yields. Subsequent stereoselective 1,3-dipolar cycloaddition and an Ullmann-type annulation/rearrangement cascade (UARC) ensure a synthetic route to oligomeric optically active benzazepine species with a well-defined 3D-structure.
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Affiliation(s)
- Polina M Ivantcova
- Sirius University of Science and Technology, Olympic Ave 1, 354340 Sochi, Russian Federation
| | - Anna A Kirsanova
- Department of Chemistry, City University of Hong Kong, Tat Chee Ave 83, Kowloon Tong, Hong Kong
| | - Vladimir I Polshakov
- Faculty of Fundamental Medicine, Lomonosov Moscow State University, Lomonosovsky Ave 31/5, 119991 Moscow, Russian Federation
| | - Konstantin A Lyssenko
- Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1/3, 119991 Moscow, Russian Federation
| | - Konstantin V Kudryavtsev
- Institute of Pharmacy and Medicinal Chemistry, Pirogov Russian National Research Medical University, Ostrovityanova Street 1, 117997 Moscow, Russian Federation
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2
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Shehzadi K, Saba A, Yu M, Liang J. Structure-Based Drug Design of RdRp Inhibitors against SARS-CoV-2. Top Curr Chem (Cham) 2023; 381:22. [PMID: 37318607 DOI: 10.1007/s41061-023-00432-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 05/15/2023] [Indexed: 06/16/2023]
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a worldwide pandemic since 2019, spreading rapidly and posing a significant threat to human health and life. With over 6 billion confirmed cases of the virus, the need for effective therapeutic drugs has become more urgent than ever before. RNA-dependent RNA polymerase (RdRp) is crucial in viral replication and transcription, catalysing viral RNA synthesis and serving as a promising therapeutic target for developing antiviral drugs. In this article, we explore the inhibition of RdRp as a potential treatment for viral diseases, analysing the structural information of RdRp in virus proliferation and summarizing the reported inhibitors' pharmacophore features and structure-activity relationship profiles. We hope that the information provided by this review will aid in structure-based drug design and aid in the global fight against SARS-CoV-2 infection.
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Affiliation(s)
- Kiran Shehzadi
- Key Laboratory of Medical Molecule Science and Pharmaceutical Engineering, Ministry of Industry and Information Technology, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing, 10081, China
| | - Afsheen Saba
- Key Laboratory of Medical Molecule Science and Pharmaceutical Engineering, Ministry of Industry and Information Technology, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing, 10081, China
| | - Mingjia Yu
- Key Laboratory of Medical Molecule Science and Pharmaceutical Engineering, Ministry of Industry and Information Technology, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing, 10081, China.
| | - Jianhua Liang
- Key Laboratory of Medical Molecule Science and Pharmaceutical Engineering, Ministry of Industry and Information Technology, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing, 10081, China.
- Yangtze Delta Region Academy of Beijing Institute of Technology, Jiaxing, 314019, China.
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3
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Zhou Z, Zhang J, Zhou E, Ren C, Wang J, Wang Y. Small molecule NS5B RdRp non-nucleoside inhibitors for the treatment of HCV infection: A medicinal chemistry perspective. Eur J Med Chem 2022; 240:114595. [PMID: 35868125 DOI: 10.1016/j.ejmech.2022.114595] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Revised: 07/01/2022] [Accepted: 07/05/2022] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus (HCV) infection has become a global health problem with enormous risks. Nonstructural protein 5B (NS5B) RNA-dependent RNA polymerase (RdRp) is a component of HCV, which can promote the formation of the viral RNA replication complex and is also an essential part of the replication complex itself. It plays a vital role in the synthesis of the positive and negative strands of HCV RNA. Therefore, the development of small-molecule inhibitors targeting NS5B RdRp is of great value for treating HCV infection-related diseases. Compared with NS5B RdRp nucleoside inhibitors, non-nucleoside inhibitors have more flexible structures, simpler mechanisms of action, and more predictable efficacy and safety of drugs in humans. Technological advances over the past decade have led to remarkable achievements in developing NS5B RdRp inhibitors. This review will summarize the non-nucleoside inhibitors targeting NS5B RdRp developed in the past decade and describe their structure optimization process and structure-activity relationship.
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Affiliation(s)
- Zhilan Zhou
- Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; State Key Laboratory of Biotherapy and Cancer Center, Department of Respiratory and Critical Care Medicine, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Jifa Zhang
- Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; State Key Laboratory of Biotherapy and Cancer Center, Department of Respiratory and Critical Care Medicine, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Tianfu Jincheng Laboratory, Chengdu, 610041, Sichuan, China
| | - Enda Zhou
- Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; State Key Laboratory of Biotherapy and Cancer Center, Department of Respiratory and Critical Care Medicine, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Changyu Ren
- Department of Pharmacy, Chengdu Fifth People's Hospital, Chengdu, Sichuan, 611130, China
| | - Jiaxing Wang
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, 38163, Tennessee, United States
| | - Yuxi Wang
- Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; State Key Laboratory of Biotherapy and Cancer Center, Department of Respiratory and Critical Care Medicine, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Tianfu Jincheng Laboratory, Chengdu, 610041, Sichuan, China.
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4
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Elfiky AA, Mahran HA, Ibrahim IM, Ibrahim MN, Elshemey WM. Molecular dynamics simulations and MM-GBSA reveal novel guanosine derivatives against SARS-CoV-2 RNA dependent RNA polymerase. RSC Adv 2022; 12:2741-2750. [PMID: 35425333 PMCID: PMC8979119 DOI: 10.1039/d1ra07447d] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 12/06/2021] [Indexed: 01/18/2023] Open
Abstract
According to the World Health Organization (WHO), SARS-CoV-2 is responsible for more than 5 M deaths and is reported in 223 countries infecting +250 M people.
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Affiliation(s)
- Abdo A. Elfiky
- Biophysics Department, Faculty of Science, Cairo University, Giza, Egypt
| | - Hanan A. Mahran
- Biophysics Department, Faculty of Science, Cairo University, Giza, Egypt
| | - Ibrahim M. Ibrahim
- Biophysics Department, Faculty of Science, Cairo University, Giza, Egypt
| | - Mohamed N. Ibrahim
- Clinical Laboratories Department, College of Applied Medical Sciences, Jouf University, Sakakah, Kingdom of Saudi Arabia
- Microbiology Department, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Wael M. Elshemey
- Biophysics Department, Faculty of Science, Cairo University, Giza, Egypt
- Physics Department, Faculty of Science, Islamic University in Madinah, KSA
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5
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Designing an HCV diagnostic kit for common genotypes of the virus in Iran based on conserved regions of core, NS3-protease, NS4A/B, and NS5A/B antigens: an in silico approach. Biologia (Bratisl) 2020. [DOI: 10.2478/s11756-020-00566-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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6
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Elfiky AA, Azzam EB. Novel guanosine derivatives against MERS CoV polymerase: An in silico perspective. J Biomol Struct Dyn 2020; 39:2923-2931. [PMID: 32306854 PMCID: PMC7189410 DOI: 10.1080/07391102.2020.1758789] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The Middle East Respiratory Syndrome Coronavirus (MERS CoV), also termed camel flu, is a new viral infection that first reported in the year 2012 in the Middle East region and further spread during the last seven years. MERS CoV is characterized by its high mortality rate among different human coronaviruses. MERS CoV polymerase shares more than 20% sequence identity with the Hepatitis C Virus (HCV) Non-structural 5b (NS5b) RNA dependent RNA polymerase (RdRp). Despite the low sequence identity, the active site is conserved between the two proteins, with two consecutive aspartates that are crucial in the nucleotide transfer reaction. In this study, seven nucleotide inhibitors have been tested against MERS CoV RdRp using molecular modeling and docking simulations, from which four are novel compounds. Molecular Dynamics Simulation for 260 nanoseconds is performed on the MERS CoV RdRp model to test the effect of protein dynamics on the binding affinities to the tested nucleotide inhibitors. Results support the hypothesis of using the anti-polymerases (Anti-HCV drugs) against MERS CoV RdRp as a potent candidates. Besides four novel compounds are suggested as a seed for high performance inhibitors against MERS CoV RdRp.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Abdo A Elfiky
- Biophysics Department, Faculty of Sciences, Cairo University, Giza, Egypt
| | - Eman B Azzam
- Biophysics Section of Physics Department, Faculty of Sciences, Helwan University, Cairo, Egypt
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7
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Elfiky AA. Novel guanosine derivatives against Zika virus polymerase in silico. J Med Virol 2020; 92:11-16. [PMID: 31436327 PMCID: PMC7166851 DOI: 10.1002/jmv.25573] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 08/17/2019] [Indexed: 01/06/2023]
Abstract
The Zika virus (ZIKV) outbreak, which started in the year 2015, is considered the fastest and most widely spread outbreak reported for this flavivirus. The polymerase domain of the NS5 protein has been targeted in other viral infections and is recognized as a suitable target in ZIKV infection. Different novel modified compounds against ZIKV NS5 have been tested in silico. A few structures have been solved for ZIKV polymerase and deposited in the protein data bank website. Two of these solved structures (with a resolution of less than 1.9 A) are used in this study to test the binding of 74 novel compounds in silico. Molecular docking is used to quantify the binding affinities of ZIKV polymerase and compare it to the hepatitis C virus NS5B. A total of 19 novel compounds revealed results that are either similar to or better than the physiological molecule, guanosine triphosphate. Water molecules are found to facilitate the binding of the compounds to ZIKV RNA-dependent RNA polymerase (RdRp) structures. The presented 19 novel compounds represent good binders to ZIKV RdRp and could be suitable candidates for developing a new and effective anti-ZIKV polymerase nucleotide inhibitor.
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Affiliation(s)
- Abdo A. Elfiky
- Biophysics Department, Faculty of SciencesCairo UniversityGizaEgypt
- Quantitative Life Science SectionThe Abdus Salam International Center for Theoretical Physics (ICTP), Strada CostieraTriesteItaly
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8
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Abstract
Aim: Mucormycosis (zygomycosis) is a rare fungal infection that affects humans (40–100% mortality). Rhizopus oryzae is the primary fungus responsible for 70% of mucormycosis cases. RNA-dependent RNA polymerase (RdRp) is a vital enzyme accountable for the RNA polymerization process in different organisms, including R. oryzae. Blocking this enzyme has been previously reported as a successful strategy to eradicate viral infections. Materials & methods: AutoDock Vina is utilized for the calculation of binding affinities of Sofosbuvir, Ribavirin and uridine triphosphate nucleotide to the fungal RdRp model built by homology modeling (no solved structures available). Results: Sofosbuvir shows excellent binding affinity to the fungal RdRp in silico. Conclusion: In this study, R. oryzae RdRp is suggested to be a possible protein target against the nucleotide inhibitor, Sofosbuvir.
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Affiliation(s)
- Abdo A Elfiky
- Biophysics Department, Faculty of Sciences, Cairo University, Giza, Egypt
- College of Applied Medical Sciences, University of Al-Jouf, Sakakah, Saudi Arabia
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9
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Duan Y, Zeng M, Jiang B, Zhang W, Wang M, Jia R, Zhu D, Liu M, Zhao X, Yang Q, Wu Y, Zhang S, Liu Y, Zhang L, Yu Y, Pan L, Chen S, Cheng A. Flavivirus RNA-Dependent RNA Polymerase Interacts with Genome UTRs and Viral Proteins to Facilitate Flavivirus RNA Replication. Viruses 2019; 11:v11100929. [PMID: 31658680 PMCID: PMC6832647 DOI: 10.3390/v11100929] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Accepted: 10/08/2019] [Indexed: 12/16/2022] Open
Abstract
Flaviviruses, most of which are emerging and re-emerging human pathogens and significant public health concerns worldwide, are positive-sense RNA viruses. Flavivirus replication occurs on the ER and is regulated by many mechanisms and factors. NS5, which consists of a C-terminal RdRp domain and an N-terminal methyltransferase domain, plays a pivotal role in genome replication and capping. The C-terminal RdRp domain acts as the polymerase for RNA synthesis and cooperates with diverse viral proteins to facilitate productive RNA proliferation within the replication complex. Here, we provide an overview of the current knowledge of the functions and characteristics of the RdRp, including the subcellular localization of NS5, as well as the network of interactions formed between the RdRp and genome UTRs, NS3, and the methyltransferase domain. We posit that a detailed understanding of RdRp functions may provide a target for antiviral drug discovery and therapeutics.
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Affiliation(s)
- YanPing Duan
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang District, Chengdu 611130, China.
| | - Miao Zeng
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang District, Chengdu 611130, China.
| | - Bowen Jiang
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang District, Chengdu 611130, China.
| | - Wei Zhang
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang District, Chengdu 611130, China.
| | - Mingshu Wang
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang District, Chengdu 611130, China.
- Institute of Preventive Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang District, Chengdu 611130, China.
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Wenjiang District, Chengdu 611130, China.
| | - Renyong Jia
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang District, Chengdu 611130, China.
- Institute of Preventive Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang District, Chengdu 611130, China.
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Wenjiang District, Chengdu 611130, China.
| | - Dekang Zhu
- Institute of Preventive Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang District, Chengdu 611130, China.
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Wenjiang District, Chengdu 611130, China.
| | - Mafeng Liu
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang District, Chengdu 611130, China.
- Institute of Preventive Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang District, Chengdu 611130, China.
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Wenjiang District, Chengdu 611130, China.
| | - Xinxin Zhao
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang District, Chengdu 611130, China.
- Institute of Preventive Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang District, Chengdu 611130, China.
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Wenjiang District, Chengdu 611130, China.
| | - Qiao Yang
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang District, Chengdu 611130, China.
- Institute of Preventive Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang District, Chengdu 611130, China.
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Wenjiang District, Chengdu 611130, China.
| | - Ying Wu
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang District, Chengdu 611130, China.
- Institute of Preventive Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang District, Chengdu 611130, China.
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Wenjiang District, Chengdu 611130, China.
| | - ShaQiu Zhang
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang District, Chengdu 611130, China.
- Institute of Preventive Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang District, Chengdu 611130, China.
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Wenjiang District, Chengdu 611130, China.
| | - YunYa Liu
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang District, Chengdu 611130, China.
| | - Ling Zhang
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang District, Chengdu 611130, China.
| | - YanLing Yu
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang District, Chengdu 611130, China.
| | - Leichang Pan
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang District, Chengdu 611130, China.
| | - Shun Chen
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang District, Chengdu 611130, China.
- Institute of Preventive Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang District, Chengdu 611130, China.
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Wenjiang District, Chengdu 611130, China.
| | - Anchun Cheng
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang District, Chengdu 611130, China.
- Institute of Preventive Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang District, Chengdu 611130, China.
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Wenjiang District, Chengdu 611130, China.
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10
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Therapeutic strategies to target the Ebola virus life cycle. Nat Rev Microbiol 2019; 17:593-606. [DOI: 10.1038/s41579-019-0233-2] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/18/2019] [Indexed: 02/07/2023]
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Elfiky AA, Ismail AM. Molecular docking revealed the binding of nucleotide/side inhibitors to Zika viral polymerase solved structures. SAR AND QSAR IN ENVIRONMENTAL RESEARCH 2018; 29:409-418. [PMID: 29652194 DOI: 10.1080/1062936x.2018.1454981] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/15/2023]
Abstract
A new Zika virus (ZIKV) outbreak started in 2015. According to the World Health Organization, 84 countries confirmed ZIKV infection. RNA-dependent RNA polymerase (RdRp) was an appealing target for drug designers during the last two decades. Through molecular docking, we screened 16 nucleotide/side inhibitors against ZIKV RdRp. While the mode of interaction with ZIKV is different from that in the hepatitis C virus (HCV), nucleotide/side inhibitors in this study (mostly anti-HCV) showed promising binding affinities (-6.2 to -9.7 kcal/mol calculated by AutoDock Vina) to ZIKV RdRp. Setrobuvir, YAK and, to a lesser extent, IDX-184 reveal promising results compared to other inhibitors in terms of binding ZIKV RdRp. These candidates would be powerful anti-ZIKV drugs.
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Affiliation(s)
- A A Elfiky
- a Biophysics Department, Faculty of Sciences , Cairo University , Giza , Egypt
- b Quantitative Life Science Department, The Abdus Salam International Center for Theoretical Physics , Strada Costiera , Trieste , Italy
- c Faculty of Pharmacy and Pharmaceutical Sciences , University of Alberta , Edmonton , AB , Canada
| | - A M Ismail
- a Biophysics Department, Faculty of Sciences , Cairo University , Giza , Egypt
- d Biochemistry Department, Faculty of Medicine and Dentistry , University of Alberta , Edmonton , AB , Canada
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Li E, Wang Y, Yu W, Lv Z, Peng Y, Liu B, Li S, Ho W, Wang Q, Li H, Chang J. Synthesis and biological evaluation of a novel β-D-2'-deoxy-2'-α-fluoro-2'-β-C-(fluoromethyl)uridine phosphoramidate prodrug for the treatment of hepatitis C virus infection. Eur J Med Chem 2017; 143:107-113. [PMID: 29172078 DOI: 10.1016/j.ejmech.2017.11.024] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Revised: 11/01/2017] [Accepted: 11/08/2017] [Indexed: 12/15/2022]
Abstract
A novel β-D-2'-deoxy-2'-α-fluoro-2'-β-C-(fluoromethyl)uridine phosphoramidate prodrug (1) has been synthesized. This compound exhibits submicromolar-level antiviral activity in vitro against HCV genotypes 1b, 1a, 2a, and S282T replicons (EC50 = 0.18-1.13 μM) with low cytotoxicity (CC50 > 1000 μM). Administered orally, prodrug 1 is well tolerated at doses of up to 4 g/kg in mice, and produces a high level of the corresponding triphosphate in rat liver.
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Affiliation(s)
- Ertong Li
- College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, China
| | - Yafeng Wang
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA
| | - Wenquan Yu
- College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, China
| | - Zhigang Lv
- College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, China
| | - Youmei Peng
- Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, China
| | - Bingjie Liu
- School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang 453007, China
| | - Shiliang Li
- Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Wenzhe Ho
- Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA
| | - Qingduan Wang
- Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, China
| | - Honglin Li
- Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Junbiao Chang
- College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, China.
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13
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Jin G, Lee J, Lee K. Chemical genetics-based development of small molecules targeting hepatitis C virus. Arch Pharm Res 2017; 40:1021-1036. [PMID: 28856597 DOI: 10.1007/s12272-017-0949-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Accepted: 08/20/2017] [Indexed: 12/21/2022]
Abstract
Hepatitis C virus (HCV) infection is a major worldwide problem that has emerged as one of the most significant diseases affecting humans. There are currently no vaccines or efficient therapies without side effects, despite today's advanced medical technology. Currently, the common therapy for most patients (i.e. genotype 1) is combination of HCV-specific direct-acting antivirals (DAAs). Up to 2011, the standard of care (SOC) was a combination of peg-IFNα with ribavirin (RBV). After approval of NS3/4A protease inhibitor, SOC was peg-IFNα and RBV with either the first-generation DAAs boceprevir or telaprevir. In the past several years, various novel small molecules have been discovered and some of them (i.e., HCV polymerase, protease, helicase and entry inhibitors) have undergone clinical trials. Between 2013 and 2016, the second-generation DAA drugs simeprevir, asunaprevir, daclatasvir, dasabuvir, sofosbuvir, and elbasvir were approved, as well as the combinational drugs Harvoni®, Zepatier®, Technivie®, and Epclusa®. A number of reviews have been recently published describing the structure-activity relationship (SAR) in the development of HCV inhibitors and outlining current therapeutic approaches to hepatitis C infection. Target identification involves studying a drug's mechanism of action (MOA), and a variety of target identification methods have been developed in the past few years. Chemical biology has emerged as a powerful tool for studying biological processes using small molecules. The use of chemical genetic methods is a valuable strategy for studying the molecular mechanisms of the viral lifecycle and screening for anti-viral agents. Two general screening approaches have been employed: forward and reverse chemical genetics. This review reveals information on the small molecules in HCV drug discovery by using chemical genetics for targeting the HCV protein and describes successful examples of targets identified with these methods.
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Affiliation(s)
- Guanghai Jin
- College of Pharmacy, Dongguk University-Seoul, Goyang, 10326, Republic of Korea
| | - Jisu Lee
- College of Pharmacy, Dongguk University-Seoul, Goyang, 10326, Republic of Korea
| | - Kyeong Lee
- College of Pharmacy, Dongguk University-Seoul, Goyang, 10326, Republic of Korea.
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14
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Elfiky AA, Ismail AM. Molecular modeling and docking revealed superiority of IDX-184 as HCV polymerase inhibitor. Future Virol 2017. [DOI: 10.2217/fvl-2017-0027] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Aim: IDX-184 is a nonstructural 5b nucleoside inhibitor (NI) that was under clinical trials against HCV. This work adopts a molecular modeling approach in order to study the interaction between IDX-184 and HCV polymerase from four different genotypes. Methods: Comparisons to the native nucleotide (Guanosine triphosphate) and other NIs were performed using interaction descriptors, calculated using semiempirical quantum mechanics and molecular docking. Results: IDX-184 shows potent binding to the active site of the polymerases. In addition, IDX-184 was better than Sofosbuvir and Ribavirin when docked into polymerase active site (even with experimentally solved structure). Conclusion: Analysis of the interaction descriptors and docking complexes suggests IDX-184 as a superior NI against the studied HCV subtypes.
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Affiliation(s)
- Abdo A Elfiky
- Biophysics Department, Faculty of Sciences, Cairo University, PO Box 12613, Giza, Egypt
- Quantitative Life Science Department, The Abdus Salam International Center for Theoretical Physics, Strada Costiera, 11 I34151, Trieste, Italy
| | - Alaa M Ismail
- Biophysics Department, Faculty of Sciences, Cairo University, PO Box 12613, Giza, Egypt
- Biochemistry Department, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, T6G 2R3, AB, Canada
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15
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Yu W, Li E, Lv Z, Liu K, Guo X, Liu Y, Chang J. Synthesis and Anti-HCV Activity of a Novel 2',3'-Dideoxy-2'-α-fluoro-2'-β- C-methyl Guanosine Phosphoramidate Prodrug. ACS Med Chem Lett 2017. [PMID: 28626533 DOI: 10.1021/acsmedchemlett.7b00174] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
A novel 2',3'-dideoxy-2'-α-fluoro-2'-β-C-methyl-6-methoxy guanosine (8) and its phosphoramidate prodrug (1) have been designed and synthesized. Their biological activity was evaluated in both cytotoxicity and cell-based HCV replicon assays. Neither compounds exhibited cytotoxicity up to the highest concentration tested (100 μM) in the Huh-7 cell line. The prodrug (1) displayed nanomolar level antiviral activity (EC50 = 0.39-1.1 μM) against the HCV genotype (GT) 1a, 1b, 2a, and 1b S282T replicons.
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Affiliation(s)
- Wenquan Yu
- College
of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, Henan 450001, P. R. China
| | - Ertong Li
- College
of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, Henan 450001, P. R. China
| | - Zhigang Lv
- College
of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, Henan 450001, P. R. China
| | - Ke Liu
- College
of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, Henan 450001, P. R. China
| | - Xiaohe Guo
- High & New Technology Research Center of Henan Academy of Sciences, Zhengzhou, Henan 450002, P. R. China
| | - Yuan Liu
- College
of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, Henan 450001, P. R. China
| | - Junbiao Chang
- College
of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, Henan 450001, P. R. China
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16
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Rajkumar V, Babu SA, Padmavathi R. Regio- and diastereoselective construction of a new set of functionalized pyrrolidine, spiropyrrolidine and spiropyrrolizidine scaffolds appended with aryl- and heteroaryl moieties via the azomethine ylide cycloadditions. Tetrahedron 2016. [DOI: 10.1016/j.tet.2016.07.053] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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17
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Identification of Peptide Leads to Inhibit Hepatitis C Virus: Inhibitory Effect of Plectasin Peptide Against Hepatitis C Serine Protease. Int J Pept Res Ther 2016. [DOI: 10.1007/s10989-016-9544-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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18
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Mohamed MS, Sayed AI, Khedr MA, Soror SH. Design, synthesis, assessment, and molecular docking of novel pyrrolopyrimidine (7-deazapurine) derivatives as non-nucleoside hepatitis C virus NS5B polymerase inhibitors. Bioorg Med Chem 2016; 24:2146-57. [PMID: 27052365 DOI: 10.1016/j.bmc.2016.03.046] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Revised: 03/16/2016] [Accepted: 03/27/2016] [Indexed: 12/16/2022]
Abstract
Hepatitis C virus (HCV) infection is highly persistent and presents an unmet medical need requiring more effective treatment options. This has spurred intensive efforts to discover novel anti-HCV agents. The RNA-dependent RNA polymerase (RdRp), NS5B of HCV, constitutes a selective target for drug discovery due to its absence in human cells; also, it is the centerpiece for viral replication. Here, we synthesized novel pyrrole, pyrrolo[2,3-d]pyrimidine and pyrrolo[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine derivatives. The non-toxic doses of these compounds on Huh 7.5 cell line were determined and their antiviral activity against HCVcc genotype 4a was examined. Compounds 7j, 7f, 5c, 12i and 12f showed significant anti HCV activity. The percent of reduction for the non-toxic doses of 7j, 7f, 5c, 12i and 12f were 90%, 76.7±5.8%, 73.3±5.8%, 70% and 63.3±5.8%, respectively. The activity of these compounds was interpreted by molecular docking against HCV NS5B polymerase enzyme.
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Affiliation(s)
- Mosaad S Mohamed
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Helwan University, Ain Helwan, Cairo, Egypt
| | - Amira I Sayed
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Helwan University, Ain Helwan, Cairo, Egypt
| | - Mohammed A Khedr
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Ain Helwan, Cairo, Egypt
| | - Sameh H Soror
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy, Helwan University, Ain Helwan, University Campus, 11795 Cairo, Egypt; Center for Scientific Excellence 'Helwan Structural Biology Research (HSBR)', Cairo, Egypt.
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19
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New pseudodimeric aurones as palm pocket inhibitors of Hepatitis C virus RNA-dependent RNA polymerase. Eur J Med Chem 2016; 115:217-29. [PMID: 27017550 DOI: 10.1016/j.ejmech.2016.03.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2015] [Revised: 03/01/2016] [Accepted: 03/02/2016] [Indexed: 12/14/2022]
Abstract
The NS5B RNA-dependent RNA polymerase (RdRp) is a key enzyme for Hepatitis C Virus (HCV) replication. In addition to the catalytic site, this enzyme is characterized by the presence of at least four allosteric pockets making it an interesting target for development of inhibitors as potential anti-HCV drugs. Based on a previous study showing the potential of the naturally occurring aurones as inhibitors of NS5B, we pursued our efforts to focus on pseudodimeric aurones that have never been investigated so far. Hence, 14 original compounds characterized by the presence of a spacer between the benzofuranone moieties were synthesized and investigated as HCV RdRp inhibitors by means of an in vitro assay. The most active inhibitor, pseudodimeric aurone 4, induced high inhibition activity (IC50 = 1.3 μM). Mutagenic and molecular modeling studies reveal that the binding site for the most active derivatives probably is the palm pocket I instead of the thumb pocket I as for the monomeric derivatives.
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20
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Elfiky AA, Elshemey WM. IDX-184 is a superior HCV direct-acting antiviral drug: a QSAR study. Med Chem Res 2016; 25:1005-1008. [PMID: 32214769 PMCID: PMC7080126 DOI: 10.1007/s00044-016-1533-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2015] [Accepted: 02/10/2016] [Indexed: 01/21/2023]
Abstract
Abstract Quantitative structure-activity relationship (QSAR) parameters are good indicators for the reactivity of direct-acting antiviral drugs. Since molecular structure is related to molecular function, careful selection of molecular substitutions will result in more drugs that are potent. In this work, QSAR parameters are selected in order to compare the four drugs used as nucleotide inhibitors (NIs) for non-structural 5B (NS5B) RNA-dependent RNA polymerase (RdRp) of hepatitis C virus (HCV). These drugs are: ribavirin (widely used over the last 20 years), sofosbuvir (approved on December 2013 by FDA), and finally IDX-184 and R7128 (phase IIb of clinical trial drugs). The nucleotide analogues uracil (U), guanine (G), and cytosine (C) from which these drugs are fabricated are also compared to that group of drugs. QSAR parameters suggested that the drug IDX-184 is the best among all of the studied NIs. It also shows that NIs are always more reactive than their parent nucleotide. Graphical Abstract The active site environment of 12 amino acids coordinated with IDX-184 through two Mg2+. The interaction with HCV subtypes 1a, 2b, and 3b is better than 4a subtype.
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Affiliation(s)
- Abdo A Elfiky
- 1Biophysics Department, Faculty of Sciences, Cairo University, Giza, Egypt.,2Biochemistry and Structural Biology, Center of Molecular Protein Science CMPS, Lund University, Lund, Sweden
| | - Wael M Elshemey
- 1Biophysics Department, Faculty of Sciences, Cairo University, Giza, Egypt
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21
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Afrasiabi M, Hosseini SY, Yaghobi R, Fattahi MR, Ardebili M, Khodadad M. Analysis of Naturally Occurring Resistant Mutations to Hepatitis C Virus NS3 Protease Inhibitors: A Preliminary Study in South of Iran. Jundishapur J Microbiol 2015; 8:e24965. [PMID: 26587218 PMCID: PMC4644313 DOI: 10.5812/jjm.24965] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Revised: 02/03/2015] [Accepted: 02/28/2015] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Exploring the rate of naturally occurring NS3 protease mutants in HCV infected population is influential in the future therapeutic approaches. OBJECTIVES This study explored naturally occurring resistant mutations to protease inhibitors in a pilot study. PATIENTS AND METHODS We analyzed NS3 gene sequences in 7 HCV infected patients, referred to the central liver center, south of Iran. The protease domain was amplified by PCR followed by product extraction. Amplified NS3 genes were cloned by TA/cloning system. For each patient, clonal-sequencing was performed to improve mutation detection sensitivity. Then, the obtained sequences were compared with the reference sequences and final phylogenic tree was constructed. Afterwards, the sequences were studied to investigate point mutations. RESULTS Phylogenetic analysis between reference and amplified sequences demonstrated high similarity of all sequences with genotype 1. Interestingly, crucial protease resistant mutations were detected in V36 and R155 positions in one patient's sequence. Checking different clones of this patient confirmed V36L, as the dominant mutation while R155K was detected only in a few cases. CONCLUSIONS As revealed, naturally occurring resistant mutations, especially R155K in protease sequence were identified in 1 out of the 7 patients, so the rate of such mutations is estimated to be high. It seems that checking HCV patients before protease inhibitor treatment are necessary in the region.
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Affiliation(s)
- Mozhgan Afrasiabi
- Gastroenterohepatology Research Center (GEHRC), Shiraz University of Medical Sciences, Shiraz, IR Iran
| | - Seyed Younes Hosseini
- Gastroenterohepatology Research Center (GEHRC), Shiraz University of Medical Sciences, Shiraz, IR Iran
| | - Ramin Yaghobi
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, IR Iran
| | - Mohammad-Reza Fattahi
- Gastroenterohepatology Research Center (GEHRC), Shiraz University of Medical Sciences, Shiraz, IR Iran
| | - Maryam Ardebili
- Gastroenterohepatology Research Center (GEHRC), Shiraz University of Medical Sciences, Shiraz, IR Iran
| | - Mahboobeh Khodadad
- Gastroenterohepatology Research Center (GEHRC), Shiraz University of Medical Sciences, Shiraz, IR Iran
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22
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Jácome R, Becerra A, Ponce de León S, Lazcano A. Structural Analysis of Monomeric RNA-Dependent Polymerases: Evolutionary and Therapeutic Implications. PLoS One 2015; 10:e0139001. [PMID: 26397100 PMCID: PMC4634563 DOI: 10.1371/journal.pone.0139001] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Accepted: 09/07/2015] [Indexed: 12/23/2022] Open
Abstract
The crystal structures of monomeric RNA-dependent RNA polymerases and reverse transcriptases of more than 20 different viruses are available in the Protein Data Bank. They all share the characteristic right-hand shape of DNA- and RNA polymerases formed by the fingers, palm and thumb subdomains, and, in many cases, “fingertips” that extend from the fingers towards the thumb subdomain, giving the viral enzyme a closed right-hand appearance. Six conserved structural motifs that contain key residues for the proper functioning of the enzyme have been identified in all these RNA-dependent polymerases. These enzymes share a two divalent metal-ion mechanism of polymerization in which two conserved aspartate residues coordinate the interactions with the metal ions to catalyze the nucleotidyl transfer reaction. The recent availability of crystal structures of polymerases of the Orthomyxoviridae and Bunyaviridae families allowed us to make pairwise comparisons of the tertiary structures of polymerases belonging to the four main RNA viral groups, which has led to a phylogenetic tree in which single-stranded negative RNA viral polymerases have been included for the first time. This has also allowed us to use a homology-based structural prediction approach to develop a general three-dimensional model of the Ebola virus RNA-dependent RNA polymerase. Our model includes several of the conserved structural motifs and residues described in other viral RNA-dependent RNA polymerases that define the catalytic and highly conserved palm subdomain, as well as portions of the fingers and thumb subdomains. The results presented here help to understand the current use and apparent success of antivirals, i.e. Brincidofovir, Lamivudine and Favipiravir, originally aimed at other types of polymerases, to counteract the Ebola virus infection.
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Affiliation(s)
- Rodrigo Jácome
- Facultad de Ciencias, Universidad Nacional Autónoma de México, Cd. Universitaria, México D.F., México
| | - Arturo Becerra
- Facultad de Ciencias, Universidad Nacional Autónoma de México, Cd. Universitaria, México D.F., México
| | - Samuel Ponce de León
- Dirección General de Investigación, Facultad de Medicina, Universidad Nacional Autónoma de México, Cd. Universitaria, México D.F., México
| | - Antonio Lazcano
- Facultad de Ciencias, Universidad Nacional Autónoma de México, Cd. Universitaria, México D.F., México
- Miembro de El Colegio Nacional, México D.F., México
- * E-mail:
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23
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Recent advances in bioactive pyrazoles. Eur J Med Chem 2015; 97:786-815. [DOI: 10.1016/j.ejmech.2014.11.059] [Citation(s) in RCA: 278] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2014] [Revised: 11/11/2014] [Accepted: 11/28/2014] [Indexed: 01/09/2023]
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24
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Cox R, Plemper RK. The paramyxovirus polymerase complex as a target for next-generation anti-paramyxovirus therapeutics. Front Microbiol 2015; 6:459. [PMID: 26029193 PMCID: PMC4428208 DOI: 10.3389/fmicb.2015.00459] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Accepted: 04/27/2015] [Indexed: 12/04/2022] Open
Abstract
The paramyxovirus family includes major human and animal pathogens, including measles virus, mumps virus, and human respiratory syncytial virus (RSV), as well as the emerging zoonotic Hendra and Nipah viruses. In the U.S., RSV is the leading cause of infant hospitalizations due to viral infectious disease. Despite their clinical significance, effective drugs for the improved management of paramyxovirus disease are lacking. The development of novel anti-paramyxovirus therapeutics is therefore urgently needed. Paramyxoviruses contain RNA genomes of negative polarity, necessitating a virus-encoded RNA-dependent RNA polymerase (RdRp) complex for replication and transcription. Since an equivalent enzymatic activity is absent in host cells, the RdRp complex represents an attractive druggable target, although structure-guided drug development campaigns are hampered by the lack of high-resolution RdRp crystal structures. Here, we review the current structural and functional insight into the paramyxovirus polymerase complex in conjunction with an evaluation of the mechanism of activity and developmental status of available experimental RdRp inhibitors. Our assessment spotlights the importance of the RdRp complex as a premier target for therapeutic intervention and examines how high-resolution insight into the organization of the complex will pave the path toward the structure-guided design and optimization of much-needed next-generation paramyxovirus RdRp blockers.
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Affiliation(s)
- Robert Cox
- Institute for Biomedical Sciences, Petit Science Center, Georgia State University, Atlanta, GA USA
| | - Richard K Plemper
- Institute for Biomedical Sciences, Petit Science Center, Georgia State University, Atlanta, GA USA
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25
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Ji H, Kozak RA, Biondi MJ, Pilon R, Vallee D, Liang BB, La D, Kim J, Van Domselaar G, Leonard L, Sandstrom P, Brooks J. Next generation sequencing of the hepatitis C virus NS5B gene reveals potential novel S282 drug resistance mutations. Virology 2015; 477:1-9. [PMID: 25600207 DOI: 10.1016/j.virol.2014.12.037] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Revised: 11/11/2014] [Accepted: 12/23/2014] [Indexed: 01/06/2023]
Abstract
Identifying HCV drug resistance mutations (DRMs) is increasingly important as new direct acting antiviral therapies (DAA) become available. Tagged pooled pyrosequencing (TPP) was originally developed as cost-effective approach for detecting low abundance HIV DRMs. Using 127 HCV-positive samples from a Canadian injection drug user cohort, we demonstrated the suitability and efficiency of TPP for evaluating DRMs in HCV NS5B gene. At a mutation identification threshold of 1%, no nucleoside inhibitor DRMs were detected among these DAA naïve subjects. Clinical NS5B resistance to non-nucleoside inhibitors and interferon/ribavirin was predicted to be low within this cohort. S282T mutation, the primary mutation selected by sofosbuvir in vitro, was not identified while S282G/C/R variants were detected in 9 subjects. Further characterization on these new S282 variants using in silico molecular modeling implied their potential association with resistance. Combining TPP with in silico analysis detects NS5B polymorphisms that may explain differences in treatment outcomes.
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Affiliation(s)
- Hezhao Ji
- National HIV & Retrovirology Laboratories, National Microbiology Laboratory, Public Health Agency of Canada, Ottawa, Canada
| | - Robert A Kozak
- Department of Pathobiology, University of Guelph, Guelph, Canada
| | - Mia J Biondi
- Arthur Labatt Family School of Nursing, Western University, London, Canada
| | - Richard Pilon
- National HIV & Retrovirology Laboratories, National Microbiology Laboratory, Public Health Agency of Canada, Ottawa, Canada
| | - Dominic Vallee
- National HIV & Retrovirology Laboratories, National Microbiology Laboratory, Public Health Agency of Canada, Ottawa, Canada
| | - Ben Binhua Liang
- Bioinformatics Core, National Microbiology Laboratory, Public Health Agency of Canada, Ottawa, Canada
| | - David La
- Bioinformatics Core, National Microbiology Laboratory, Public Health Agency of Canada, Ottawa, Canada
| | - John Kim
- National HIV & Retrovirology Laboratories, National Microbiology Laboratory, Public Health Agency of Canada, Ottawa, Canada
| | - Gary Van Domselaar
- Bioinformatics Core, National Microbiology Laboratory, Public Health Agency of Canada, Ottawa, Canada
| | - Lynne Leonard
- Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Canada
| | - Paul Sandstrom
- National HIV & Retrovirology Laboratories, National Microbiology Laboratory, Public Health Agency of Canada, Ottawa, Canada
| | - James Brooks
- National HIV & Retrovirology Laboratories, National Microbiology Laboratory, Public Health Agency of Canada, Ottawa, Canada.
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26
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Barnes-Seeman D, Boiselle C, Capacci-Daniel C, Chopra R, Hoffmaster K, Jones CT, Kato M, Lin K, Ma S, Pan G, Shu L, Wang J, Whiteman L, Xu M, Zheng R, Fu J. Design and synthesis of lactam–thiophene carboxylic acids as potent hepatitis C virus polymerase inhibitors. Bioorg Med Chem Lett 2014; 24:3979-85. [DOI: 10.1016/j.bmcl.2014.06.031] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2014] [Revised: 06/08/2014] [Accepted: 06/11/2014] [Indexed: 10/25/2022]
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27
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Hundt J, Li Z, Liu Q. Post-translational modifications of hepatitis C viral proteins and their biological significance. World J Gastroenterol 2013; 19:8929-8939. [PMID: 24379618 PMCID: PMC3870546 DOI: 10.3748/wjg.v19.i47.8929] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2013] [Accepted: 12/04/2013] [Indexed: 02/06/2023] Open
Abstract
Replication of hepatitis C virus (HCV) depends on the interaction of viral proteins with various host cellular proteins and signalling pathways. Similar to cellular proteins, post-translational modifications (PTMs) of HCV proteins are essential for proper protein function and regulation, thus, directly affecting viral life cycle and the generation of infectious virus particles. Cleavage of the HCV polyprotein by cellular and viral proteases into more than 10 proteins represents an early protein modification step after translation of the HCV positive-stranded RNA genome. The key modifications include the regulated intramembranous proteolytic cleavage of core protein, disulfide bond formation of core, glycosylation of HCV envelope proteins E1 and E2, methylation of nonstructural protein 3 (NS3), biotinylation of NS4A, ubiquitination of NS5B and phosphorylation of core and NS5B. Other modifications like ubiquitination of core and palmitoylation of core and NS4B proteins have been reported as well. For some modifications such as phosphorylation of NS3 and NS5A and acetylation of NS3, we have limited understanding of their effects on HCV replication and pathogenesis while the impact of other modifications is far from clear. In this review, we summarize the available information on PTMs of HCV proteins and discuss their relevance to HCV replication and pathogenesis.
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28
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Barakat KH, Law J, Prunotto A, Magee WC, Evans DH, Tyrrell DL, Tuszynski J, Houghton M. Detailed computational study of the active site of the hepatitis C viral RNA polymerase to aid novel drug design. J Chem Inf Model 2013; 53:3031-43. [PMID: 24116674 DOI: 10.1021/ci4003969] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
The hepatitis C virus (HCV) RNA polymerase, NS5B, is a leading target for novel and selective HCV drug design. The enzyme has been the subject of intensive drug discovery aimed at developing direct acting antiviral (DAA) agents that inhibit its activity and hence prevent the virus from replicating its genome. In this study, we focus on one class of NS5B inhibitors, namely nucleos(t)ide mimetics. Forty-one distinct nucleotide structures have been modeled within the active site of NS5B for the six major HCV genotypes. Our comprehensive modeling protocol employed 287 different molecular dynamics simulations combined with the molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) methodology to rank and analyze these structures for all genotypes. The binding interactions of the individual compounds have been investigated and reduced to the atomic level. The present study significantly refines our understanding of the mode of action of NS5B-nucleotide-inhibitors, identifies the key structural elements necessary for their activity, and implements the tools for ranking the potential of additional much needed novel inhibitors of NS5B.
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Affiliation(s)
- Khaled H Barakat
- Li Ka Shing Institute of Virology, Department of Medical Microbiology and Immunology, ⊥Department of Oncology, and ∥Department of Physics, University of Alberta , Edmonton, AB, Canada T6G 2E1
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29
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Schoenfeld RC, Bourdet DL, Brameld KA, Chin E, de Vicente J, Fung A, Harris SF, Lee EK, Le Pogam S, Leveque V, Li J, Lui AST, Najera I, Rajyaguru S, Sangi M, Steiner S, Talamas FX, Taygerly JP, Zhao J. Discovery of a novel series of potent non-nucleoside inhibitors of hepatitis C virus NS5B. J Med Chem 2013; 56:8163-82. [PMID: 24069953 DOI: 10.1021/jm401266k] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Hepatitis C virus (HCV) is a major global public health problem. While the current standard of care, a direct-acting antiviral (DAA) protease inhibitor taken in combination with pegylated interferon and ribavirin, represents a major advancement in recent years, an unmet medical need still exists for treatment modalities that improve upon both efficacy and tolerability. Toward those ends, much effort has continued to focus on the discovery of new DAAs, with the ultimate goal to provide interferon-free combinations. The RNA-dependent RNA polymerase enzyme NS5B represents one such DAA therapeutic target for inhibition that has attracted much interest over the past decade. Herein, we report the discovery and optimization of a novel series of inhibitors of HCV NS5B, through the use of structure-based design applied to a fragment-derived starting point. Issues of potency, pharmacokinetics, and early safety were addressed in order to provide a clinical candidate in fluoropyridone 19.
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Affiliation(s)
- Ryan C Schoenfeld
- Pharma Research & Early Development, Hoffmann-La Roche Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States
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30
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Accounting for Target Flexibility and Water Molecules by Docking to Ensembles of Target Structures: The HCV NS5B Palm Site I Inhibitors Case Study. J Chem Inf Model 2013; 54:481-97. [DOI: 10.1021/ci400367m] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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31
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Elfiky AA, Elshemey WM, Gawad WA, Desoky OS. Molecular modeling comparison of the performance of NS5b polymerase inhibitor (PSI-7977) on prevalent HCV genotypes. Protein J 2013; 32:75-80. [PMID: 23322006 DOI: 10.1007/s10930-013-9462-9] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
The current available treatment for hepatitis C virus (HCV)-the causative of liver cirrhosis and development of liver cancer-is a dual therapy using modified interferon and ribavirin. While this regimen increases the sustained viral response rate up to 40-80 % in different genotypes, unfortunately, it is poorly tolerated by patients. PSI-7977, a prodrug for PSI-7409, is a Non-Structural 5b (NS5b) polymerase nucleoside inhibitor that is currently in phase III clinical trials. The activated PSI-7977 is a direct acting antiviral (DAA) drug that acts on NS5b polymerase of HCV through a coordination bond with the two Mg(+2) present at the GDD active site motif. The present work utilizes a molecular modeling approach for studying the interaction between the activated PSI-7977 and the 12 amino acids constituting a 5 Å region surrounding the GDD active triad motif for HCV genotypes 1a, 2b, 3b and 4a. The analysis of the interaction parameters suggests that PSI-7977 is probably a better DAA drug for HCV genotypes 1a and 3b rather than genotypes 2b and 4a.
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Affiliation(s)
- Abdo A Elfiky
- Biophysics Department, Faculty of Sciences, Cairo University, Giza, Egypt.
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Delaney WE. Molecular virology of chronic hepatitis B and C: parallels, contrasts and impact on drug development and treatment outcome. Antiviral Res 2013; 99:34-48. [PMID: 23602852 DOI: 10.1016/j.antiviral.2013.04.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2013] [Revised: 03/29/2013] [Accepted: 04/09/2013] [Indexed: 12/17/2022]
Abstract
Chronic infections with hepatitis B virus (HBV) and hepatitis C virus (HCV) are highly prevalent worldwide, causing significant liver disease and thus representing high unmet medical needs. Accordingly, substantial pharmaceutical and clinical research efforts have been made to develop and improve treatments for these viruses. While HBV and HCV are both hepatotropic viruses that can cause similar disease in chronically infected patients, they belong to different viral families. There are substantial differences in the molecular virology of HBV and HCV that have profound implications for therapeutic strategy. In particular, HBV has a long-lived nuclear form of its genome (covalently closed circular DNA) that is able to persist in the face of potent inhibition of viral replication. In contrast, HCV does not have a long-lived genome form and depends on active replication to maintain infection; HCV is therefore much more susceptible to eradication by potent antiviral agents. Additional differences between HBV and HCV with therapeutic implications include the size, structure and heterogeneity of their respective viral genomes. These factors influence the number of targets available for therapeutic intervention, response to therapy among viral genotypes and the emergence of viral resistance. Substantial progress has been made in treating each infection, but unique challenges remain. In this review, key differences in the molecular virology of hepatitis B and C will be presented, highlighting their impact on antiviral therapy (particularly with respect to direct-acting antivirals) and the challenges they present to the cure of each disease.
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Gu M, Rice CM. Structures of hepatitis C virus nonstructural proteins required for replicase assembly and function. Curr Opin Virol 2013; 3:129-36. [PMID: 23601958 DOI: 10.1016/j.coviro.2013.03.013] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2012] [Revised: 03/08/2013] [Accepted: 03/20/2013] [Indexed: 02/07/2023]
Abstract
Approximately 3% of the world population is infected with hepatitis C virus (HCV), causing a serious public health burden. Like other positive-strand RNA viruses, HCV assembles replicase complexes in association with cellular membranes and produces progeny RNA genomes through negative-strand intermediates. The viral proteins required for RNA replication are nonstructural (NS) proteins NS3 to NS5B. Owing to many obstacles and limitations in structural characterization of proteins and complexes with multiple transmembrane segments, attempts to understand the assembly and action of the HCV replicase complex have been challenging. Nevertheless, great progress has been made in obtaining structural information for several replicase components, providing insights into some aspects of the viral genome replication machinery.
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Affiliation(s)
- Meigang Gu
- Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, United States.
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Barreca ML, Manfroni G, Leyssen P, Winquist J, Kaushik-Basu N, Paeshuyse J, Krishnan R, Iraci N, Sabatini S, Tabarrini O, Basu A, Danielson UH, Neyts J, Cecchetti V. Structure-based discovery of pyrazolobenzothiazine derivatives as inhibitors of hepatitis C virus replication. J Med Chem 2013; 56:2270-82. [PMID: 23409936 DOI: 10.1021/jm301643a] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
The NS5B RNA-dependent RNA polymerase is an attractive target for the development of novel and selective inhibitors of hepatitis C virus replication. To identify novel structural hits as anti-HCV agents, we performed structure-based virtual screening of our in-house library followed by rational drug design, organic synthesis, and biological testing. These studies led to the identification of pyrazolobenzothiazine scaffold as a suitable template for obtaining novel anti-HCV agents targeting the NS5B polymerase. The best compound of this series was the meta-fluoro-N-1-phenyl pyrazolobenzothiazine derivative 4a, which exhibited an EC50 = 3.6 μM, EC90 = 25.6 μM, and CC50 > 180 μM in the Huh 9-13 replicon system, thus providing a good starting point for further hit evolution.
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Affiliation(s)
- Maria Letizia Barreca
- Dipartimento di Chimica e Tecnologia del Farmaco, Sezione di Chimica Farmaceutica II, Università degli Studi di Perugia, Via del Liceo 1, 06123 Perugia, Italy.
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35
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Abstract
During the last 30 years, significant progress has been made in the development of novel antiviral drugs, mainly crystallizing in the establishment of potent antiretroviral therapies and the approval of drugs inhibiting hepatitis C virus replication. Although major targets of antiviral intervention involve intracellular processes required for the synthesis of viral proteins and nucleic acids, a number of inhibitors blocking virus assembly, budding, maturation, entry or uncoating act on virions or viral capsids. In this review, we focus on the drug discovery process while presenting the currently used methodologies to identify novel antiviral drugs by using a computer-based approach. We provide examples illustrating structure-based antiviral drug development, specifically neuraminidase inhibitors against influenza virus (e.g. oseltamivir and zanamivir) and human immunodeficiency virus type 1 protease inhibitors (i.e. the development of darunavir from early peptidomimetic compounds such as saquinavir). A number of drugs in preclinical development acting against picornaviruses, hepatitis B virus and human immunodeficiency virus and their mechanism of action are presented to show how viral capsids can be exploited as targets of antiviral therapy.
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Affiliation(s)
- Luis Menéndez-Arias
- Centro de Biología Molecular "Severo Ochoa" (Consejo Superior de Investigaciones Científicas & Universidad Autónoma de Madrid), c/Nicolás Cabrera 1, Campus de Cantoblanco, 28049, Madrid, Spain,
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