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Special Issue: 酶化学

• Review •

HCV Non-Nucleoside NS5B Polymerase Inhibitors

Wu Daochun, He Yanping   

  1. Key Laboratory of Medicinal Chemistry for Natural Resources, Ministry of Education, School of Chemical Science and Technology, Yunnan University, Kunming 650091, China
  • Received: Revised: Online: Published:
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Hepatitis C virus (HCV) infection has emerged as a significant global public health problem, with an estimated 170 million chronically infected individuals worldwide, and a leading cause of liver transplantation. Currently neither a vaccine nor a therapy with effective broad spectrum mode of action against all genotypes of HCV is available. Current HCV therapy comprising of pegylated interferon α (PEGeIFN-α) in combination with ribavirin has found limited patient compliance due to severe adverse effects. In the past two decades, several approaches have been adopted to inhibit non-structural viral proteins. RNA dependent RNA polymerase coded by NS5B protein is an attractive therapeutic target, since it plays an important role in replicating the HCV RNA genome and the host lacks its functional equivalent. According to its function mechanism and chemical structure, NS5B inhibitors mainly divided into nucleoside inhibitors(NIs) and non-nucleoside inhibitors(NNIs), the latter can bind to less conserved sites outside the active site and impair the enzyme’s catalytic efficiency. Scince the benzimidazole-based compounds were identified as NS5B NNIs, several inhibitors targeting various known binding sites within HCV NS5B polymerase have demonstrated useful efficacy in clinical trials. In this article, the recent progress of NS5B NNIs, such as benzothiadiazines, benzimidazoles, indole analogs, thiophene carboxylic acids, isoquinoline and quinolones, dihydropyranones, diketo acids and so on, is reviewed to provide some useful information for the further research and development of HCV polymerase inhibitors. Contents
1 Introduction
1.1 Gene structure and replicative cycle of HCV
1.2 Structure of HCV NS5B polymerase and its relation ship of activity with RdRp
1.3 NS5B polymerase as an anti-HCV drug target
2 Non-nucleoside inhibitors of HCV NS5B polymerase
2.1 Benzothiadiazine analogs
2.2 Benzimidazole analogs
2.3 Indole analogs
2.4 Thiophene carboxylic acid analogs
2.5 Isoquinoline and quinolone analogs
2.6 Dihydropyranone analogs
2.7 Diketo acid analogs
2.8 The other non-nucleoside inhibitors
3 Conclusion
Key words: HCV, specifically targeted antiviral drugs, NS5B polymerase, non-nucleoside inhibitors Contents

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. Anticancer Activity of Indolocarbazoles [J]. Progress in Chemistry, 2008, 20(0203): 368-374.
[9] Yang Xiaogai|Yang Xiaoda|Wang Kui**. Trends and Problems in Studies of Rare-Earths-Based Drugs [J]. Progress in Chemistry, 2007, 19(0203): 201-204.
[10] Gang Xu,Yubo Cui,Kai Cui,Shaohua Gou**. Progress on the Study of Non-Platinum Metallic Drugs in Antitumor [J]. Progress in Chemistry, 2006, 18(01): 107-113.
[11] Guizhao Liang1,Hu Mei1,Yuan Zhou1,Zhiliang Li 1,2*. Modeling Techniques of Multidimensional Quantitative Structure-Activity Relationship in Computer-Aided Drug Design [J]. Progress in Chemistry, 2006, 18(01): 120-130.
[12] Feng Song,He Xuchang,Bai Donglu*. Studies of Secretase Inhibitors of Amyloid-β Protein [J]. Progress in Chemistry, 2004, 16(05): 791-.
[13] Shen Tao,Zhang Tianle,Liu Changlin*. Inorganic Biochemistry on CuZn Superoxide Dismutase Mutants and Neurodegenerative Diseases [J]. Progress in Chemistry, 2004, 16(05): 813-.
[14] Wang Baolei,Li Zhengming*,Cang Hongjun. Influence of Genomics on Structure-based Drug Design [J]. Progress in Chemistry, 2003, 15(06): 505-.
[15] Sun Hongzhe,Chen Rong,Che Chiming*. Metals in Biology and Medicine [J]. Progress in Chemistry, 2002, 14(04): 257-.