Approaches to the Design of Effective HIV-1 Protease Inhibitors

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 potential 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.

Design, synthesis and evaluation of a potent substrate analog inhibitor identified by scanning Ala/Phe mutagenesis, mimicking substrate co-evolution, against multidrug-resistant HIV-1 protease

“…HIV-1 protease is a homodimeric aspartyl protease [2] with two catalytic aspartic acid residues, Asp25 and Asp125. Due to the critical requirement of the protease in the life cycle of HIV-1, inhibition of HIV-1 protease for therapeutic intervention, has been evaluated using different strategies [3] – conventional competitive substrate mimics [4], protease dimerization inhibitors [5], allosteric inhibitors [6] and irreversible inhibitors [7] – of which, the conventional approach has been clinically the most successful to date. In fact, all the FDA approved PIs that are currently in clinical use were designed using the conventional approach and incorporate a unique hydroxyl group that mimics the tetrahedral reaction intermediate formed during substrate hydrolysis, resulting in enhanced affinity [8].…”

Modification and biological evaluation of novel 4-hydroxy-pyrone derivatives as non-peptidic HIV-1 protease inhibitors

“…In an attempt to develop new anti-HIV agents, numerous new and potent HIV PR inhibitors have been identified (Huff, 1991;Meek, 1992;Thaisrivongs, 1994;Leung et al, 2000), but most of them are peptidomimetic compounds and often associates with a low bioavailability and rapid clearance (West and Fairlie, 1995;Lebon and Ledecq, 2000). Thus, it is important to design and identify new non-peptidic structural inhibitors.…”

Target validation and ligand development for a pathogenic fungal profilin, using a knock‐down strain of pathogenic yeast Candida glabrata and structure‐based ligand design

“…The lead peptide will be converted either to or an alternative micro-antibody (Binz et al, 2005;Skerra, 2007) or to a pseudopeptide compound through the use of a peptidomimetics approach (Bursavich and Rich, 2002;Ripka and Rich, 1998) to refine the pharmacokinetics or its activity. These modified peptides can occasionally be put to practical use (Lebon and Ledecq, 2000).…”