Potent new antiviral compound shows similar inhibition and structural interactions with drug resistant mutants and wild type HIV-1 protease

J Med Chem. 2007 Sep 6;50(18):4509-15. doi: 10.1021/jm070482q. Epub 2007 Aug 16.

Abstract

The potent new antiviral inhibitor GRL-98065 (1) of HIV-1 protease (PR) has been studied with PR variants containing the single mutations D30N, I50V, V82A, and I84V that provide resistance to the major clinical inhibitors. Compound 1 had inhibition constants of 17-fold, 8-fold, 3-fold, and 3-fold, respectively, for PR(D30N), PR(I50V), PR(V82A), and PR(I84V) relative to wild type PR. The chemically related darunavir had similar relative inhibition, except for PR(D30N), where inhibitor 1 was approximately 3-fold less potent. The high resolution (1.11-1.60 Angstrom) crystal structures of PR mutant complexes with inhibitor 1 showed small changes relative to the wild type enzyme. PR(D30N) and PR(V82A) showed compensating interactions with inhibitor 1 relative to those of PR, while reduced hydrophobic contacts were observed with PR(I50V) and PR(I84V). Importantly, inhibitor 1 complexes showed fewer changes relative to wild type enzyme than reported for darunavir complexes. Therefore, inhibitor 1 is a valuable addition to the antiviral inhibitors with high potency against resistant strains of HIV.

Publication types

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

MeSH terms

  • Crystallography, X-Ray
  • Darunavir
  • Drug Resistance, Viral*
  • HIV Protease / chemistry*
  • HIV Protease / genetics
  • HIV Protease Inhibitors / chemistry*
  • Models, Molecular*
  • Molecular Structure
  • Mutation
  • Sulfonamides / chemistry*

Substances

  • (2,8-dioxabicyclo(3.3.0)oct-6-yl)-N-(4-((3,4-methylenedioxyphenyl)sulfonyl-(2-methylpropyl)amino)-3-hydroxy-1-phenylbutan-2-yl) carbamate
  • HIV Protease Inhibitors
  • Sulfonamides
  • HIV Protease
  • Darunavir