Small-molecule dimerization inhibitors of wild-type and mutant HIV protease: a focused library approach

J Am Chem Soc. 2004 Aug 18;126(32):9886-7. doi: 10.1021/ja048139n.

Abstract

We demonstrate that a focused library based on truncated, cross-linked interfacial peptides of HIV-1 protease produces effective dimerization inhibitors of the enzyme. By combining individual changes of the library into a single compound, we obtained a significantly more potent agent and found that an additive increase in inhibitor efficacy was obtained. The good activity of library members against an active-site drug-resistant protease mutant bodes well for dimerization inhibition as a complementary method to targeting the active site.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Binding Sites
  • Dimerization
  • Drug Resistance, Viral / genetics
  • HIV Protease / genetics
  • HIV Protease / metabolism*
  • HIV Protease Inhibitors / chemical synthesis
  • HIV Protease Inhibitors / chemistry*
  • HIV Protease Inhibitors / pharmacology*
  • Humans
  • Kinetics
  • Models, Molecular
  • Mutation
  • Structure-Activity Relationship

Substances

  • HIV Protease Inhibitors
  • HIV Protease