Design of Mutation-Resistant HIV Protease Inhibitors With the Substrate Envelope Hypothesis

摘要

The introduction of human immunodeficiency virus protease (HIVP) inhibi-tors as therapeutic agents against HIV has considerably improved survivalrate of acquired immunodeficiency syndrome (AIDS) patients. However,treatment using these inhibitors is hampered by the emergence of resistancemutations within the viral protease that decrease inhibitor affinity. Thus, toretain efficacy as anti-HIV drugs, the inhibitors must retain the ability tobind to HIVP despite the presence of mutations in the enzyme. This articlereports on the use of the so-called "substrate envelope hypothesis" as anapproach to search for inhibitors of HIVP that remain effective despite thepresence of resistance mutations. The natural substrates of the HIVP (i.e.,sites in the Gag-Pol polyprotein that are cleaved by the protease) all occupyessentially the same area of the substrate binding site despite having differ-ing amino acid sequences. Importantly, mutations that give rise to inhibitorresistance mostly lie outside this substrate envelope, presumably becausemutations within the envelope would compromise the essential cleavage ofthe viral polyprotein. Thus, an inhibitor that fits within the envelope shouldbe immune to resistance mutations. The investigators designed a combinato-rial chemical library using computational methods and based on the hydrox-yethylaminosulfonamide scaffold (Fig. 1) as a blueprint of the HIVPinhibitors. Additionally, the authors used combined docking and substrateenvelope scores to identify and synthesize two compounds that were testedagainst wild-type and mutant HIV-1 protease for inhibitory activities (Fig.2). The two compounds were determined to have considerable affinityagainst HIVP mutants, although lower than that of Amprenavir, which isbetter fitted to the conformation of the substrate envelope.