Journal ArticleDOI
NS5B RNA Dependent RNA Polymerase Inhibitors: The Promising Approach to Treat Hepatitis C Virus Infections
Ravindra Ramesh Deore,Chern Jw +1 more
TLDR
This review summarizes the lead identification, structure activity relationship (SAR) studies leading to the most potent NS5B inhibitors with subgenomic replicon activity.Abstract:
Hepatitis C virus (HCV), a causative agent for non-A and non-B hepatitis, has infected approximately 3% of world's population. The current treatment option of ribavirin in combination with pegylated interferon possesses lower sustained virological response rates, and has serious disadvantages. Unfortunately, no prophylactic vaccine has been approved yet. Therefore, there is an unmet clinical need for more effective and safe anti-HCV drugs. HCV NS5B RNA dependent RNA polymerase is currently pursued as the most popular target to develop safe anti-HCV agents, as it is not expressed in uninfected cells. More than 25 pharmaceutical companies and some research groups have developed ≈50 structurally diverse scaffolds to inhibit NS5B. Here we provide comprehensive account of the drug development process of these scaffolds. NS5B polymerase inhibitors have been broadly classified in nucleoside and non nucleoside inhibitors and are sub classified according to their mechanism of action and structural diversities. With some additional considerations about the inhibitor bound NS5B enzyme X-ray crystal structure information and pharmacological aspects of the inhibitors, this review summarizes the lead identification, structure activity relationship (SAR) studies leading to the most potent NS5B inhibitors with subgenomic replicon activity.read more
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Functional Analysis of Two Cavities in Flavivirus NS5 Polymerase
Gang Zou,Yen Liang Chen,Hongping Dong,Chin Chin Lim,Li Jian Yap,Yin Hoe Yau,Susana Geifman Shochat,Julien Lescar,Pei Yong Shi +8 more
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A highly conserved G-rich consensus sequence in hepatitis C virus core gene represents a new anti-hepatitis C target.
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Independent Structural Domains in Paramyxovirus Polymerase Protein
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Mechanistic Insight Enables Practical, Scalable, Room Temperature Chan–Lam N-Arylation of N-Aryl Sulfonamides
Julien C. Vantourout,Julien C. Vantourout,Ling Li,Enrique Bendito-Moll,Enrique Bendito-Moll,Sonia Chabbra,Kenneth Arrington,Bela E. Bode,Albert Isidro-Llobet,John A. Kowalski,Mark G. Nilson,Katherine Wheelhouse,John L. Woodard,Shiping Xie,David C. Leitch,Allan J. B. Watson +15 more
TL;DR: In this paper, the authors present a solution to this problem via oxidative Cu-catalysis (Chan-Lam cross-coupling) via Narylation of primary and secondary N-arylsulfonamide pharmacophore.
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A cell-based assay for RNA synthesis by the HCV polymerase reveals new insights on mechanism of polymerase inhibitors and modulation by NS5A.
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