NIMBLE CHEMISTRY TO MATCH HIV PROTEASE EVOLUTION

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Small-molecule inhibitors of HIV protease (HIV Pr) have played a central role in both the treatment of the disease and in the evolution of the virus to achieve drug resistance. The moving nature of the target requires greater understanding of the ways in which resistance is achieved, as well as the ability to respond to such changes by creating new drugs to overcome the resistance mechanisms. We propose a program of chemical synthesis and analysis that services both directions of information flow, translating predictions of the structural details of resistance into molecules with which to challenge the evolving system, and allowing the evolving protein to produce molecular inhibitors that tell us where it has gone. First, we will prepare new libraries of candidate HIV Pr inhibitors using fragments either predicted or shown to bind at particular sites of the target. These fragment structures will come from other laboratories in the program consortium and from our own efforts to identify binding elements from peptide-based libraries. The resulting inhibitors will be tested by other members of the program, and the results fed back into the continuing loop of design and synthesis. In addition to this more traditional combinatorial approach, we will also allow wild-type and mutant forms of HIV Pr to assemble their own inhibitors from carefully chosen building blocks in a technique we call "click chemistry in situ." The method relies on the unique chemical properties of the azide and alkyne groups used to make the connections between blocks, and we have previously been successful in uncovering new protease active site inhibitors in this manner. Lastly, we will attempt to open up a connected area of investigation by making and screening candidates for binding to the polyprotein cleavage sites that are the substrates for HIV Pr. Recent reports in the literature suggest that this may represent an effective therapeutic approach, and it has fundamental relevance to our attempts to understand the development of drug resistance.