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Structure-based design of a novel series of azetidine inhibitors of the hepatitis C virus NS3/4A serine protease

Authors
Journal
Bioorganic & Medicinal Chemistry Letters
0960-894X
Publisher
Elsevier
Publication Date
Volume
24
Issue
18
Identifiers
DOI: 10.1016/j.bmcl.2014.08.002
Keywords
  • Hepatitis C
  • Hcv Ns3/4A Protease Inhibitors
  • Macrocycle
Disciplines
  • Biology
  • Chemistry
  • Design
  • Medicine

Abstract

Abstract Structural homology between thrombin inhibitors and the early tetrapeptide HCV protease inhibitor led to the bioisosteric replacement of the P2 proline by a 2,4-disubstituted azetidine within the macrocyclic β-strand mimic. Molecular modeling guided the design of the series. This approach was validated by the excellent activity and selectivity in biochemical and cell based assays of this novel series and confirmed by the co-crystal structure of the inhibitor with the NS3/4A protein (PDB code: 4TYD).

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