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Hepatitis C replication inhibitors that target the viral NS4B protein.

Authors
  • And 4 more
Type
Published Article
Journal
Journal of Medicinal Chemistry
1520-4804
Publisher
American Chemical Society
Publication Date
Volume
57
Issue
5
Pages
2107–2120
Identifiers
DOI: 10.1021/jm400125h
PMID: 23544424
Source
Medline
License
Unknown

Abstract

We describe the preclinical development and in vivo efficacy of a novel chemical series that inhibits hepatitis C virus replication via direct interaction with the viral nonstructural protein 4B (NS4B). Significant potency improvements were realized through isosteric modifications to our initial lead 1a. The temptation to improve antiviral activity while compromising physicochemical properties was tempered by the judicial use of ligand efficiency indices during lead optimization. In this manner, compound 1a was transformed into (+)-28a which possessed an improved antiviral profile with no increase in molecular weight and only a modest elevation in lipophilicity. Additionally, we employed a chimeric "humanized" mouse model of HCV infection to demonstrate for the first time that a small molecule with high in vitro affinity for NS4B can inhibit viral replication in vivo. This successful proof-of-concept study suggests that drugs targeting NS4B may represent a viable treatment option for curing HCV infection.

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