Potent antiviral HIV-1 protease inhibitor combats highly drug resistant mutant PR20

Biochem Biophys Res Commun. 2019 Oct 29;519(1):61-66. doi: 10.1016/j.bbrc.2019.08.126. Epub 2019 Aug 29.

Abstract

Drug-resistance threatens effective treatment of HIV/AIDS. Clinical inhibitors, including darunavir (1), are ineffective for highly resistant protease mutant PR20, however, antiviral compound 2 derived from 1 with fused tricyclic group at P2, extended amino-benzothiazole P2' ligand and two fluorine atoms on P1 shows 16-fold better inhibition of PR20 enzyme activity. Crystal structures of PR20 and wild-type PR complexes reveal how the extra groups of 2 counteract the expanded ligand-binding pocket, dynamic flaps, and faster dimer dissociation of PR20.

Keywords: Antiretroviral inhibitor; Drug resistance; HIV protease; Structure-based design; X-ray crystallography.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Crystallography, X-Ray
  • Drug Resistance, Viral / drug effects*
  • HIV Protease / metabolism*
  • HIV Protease Inhibitors / chemistry
  • HIV Protease Inhibitors / pharmacology*
  • HIV-1 / drug effects*
  • Humans
  • Kinetics
  • Models, Molecular
  • Molecular Conformation
  • Mutation

Substances

  • Antiviral Agents
  • HIV Protease Inhibitors
  • HIV Protease