Optimization of a Macromolecular Inhibitor of HIV-1 Protease

Abstract

HIV protease (HIV PR) has been identified as a key target in the treatment of HIV infection, and antiviral drugs that block its proteolytic activity have been developed. However, there are numerous ways in which a drug can lose effectiveness during long-term therapy. In particular several protease-mediated mechanisms result in reduced antiviral sensitivity of the various anti HIV protease inhibitors. As with inhibitors of reverse transcriptase, protease inhibitors have shown a sensitivity to variations in the protease that weaken drug affinities, both in cell culture and in vivo [1,2]. These include: 1) mutations of active site residues that are direct substrate specificity determinants; 2) mutations of non-active site residues that indirectly interfere with inhibitor binding through long range structural changes; 3) mutations that increase enzyme catalysis; 4) mutations that increase enzyme stability and half-life; and 5) mutations that provide new substrate specificities with corresponding mutations in the gag—pol polyprotein precursor substrate. Since the binding modes of both the natural substrates for HIV protease and the substrate analog class of inhibitors are similar, amino acid substitutions that occur in the substrate binding pocket are among the more common resistance mutations that arise in response to HIV protease inhibitors. However, the structural basis for the loss of sensitivity of a viral protease to a drug is not always obvious or predictable. This inability to anticipate the variety of mechanisms of viral resistance to new protease inhibitors complicates the task of designing more effective drugs. In this work, we consider the possibility of creating a new class of inhibitors that can pose a greater challenge to the development of protease-mediated viral resistance.