Approaches to the Design of Effective HIV-1 Protease Inhibitors

F.      Lebon; M.      Ledecq

Abstract

Recently, western countries have recorded a decrease in the death rate imputed to AIDS. This success has been largely attributed to the presence on the market of chemotherapies that inhibit the infectivity of the predominant causative agent, the HIV-1 virus, by targeting essential viral enzymes. One of these is the protease (HIV-1 PR) whose activity is a prerequisite for viral replication. Two main sites have been identified as poten-tial targets for the inhibition of HIV-1 PR, the active site and the interface, the latter being largely responsible for the stabilization of the enzyme dimeric structure. The compounds that have reached clinical application so far target the active site of HIV-1 PR. These molecules act as transition state analogues and result from modifications of the peptidic scaffold into peptidomimetics. In order to improve their bioavailability, systematic biological screening and de novo design have been used to suggest new non-peptide inhibitors combining both antiviral potency and favorable pharmacokinetic properties. In parallel, compounds targeting other potential sites of inhibition have been tested. Peptides and peptidomimetics based on the terminal sequence of the enzyme, a site which is proposed to be less susceptible to mutations, have been shown to lead to HIV-1 PR inactivation. Cupric ion was described to bind a sequence on the protease surface, which includes cysteine and histidine residues, leading to the inhibition of the enzyme. In the future, these non-active site inhibitors could provide an alternative in anti-HIV drug combination strategies.

Keywords: protease inhibitors, acquired immunodeficiency syndrome AIDS, polyporteins gag m RNA, crystalographic structure, aspartic protease group, trystallographic complexes, non cleavable transition state, substrate based approach, substrate backbone, transition state isosteres, hydrohobicity, lipophilicity, difluoroketones, crystallographic studies, rational drug design, antifungal antibiotic cerulenin, HIV portease dimers, N terminus sequences, dimerization inhibitors, heterodimer formation, metal organic complexses, glutathionation experiments