DDR SUBPRJ 5:FLEXIBLE PEPTIDE INHIBITORS INDUCING A STABLE CONFORMATION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Protease Inhibitors for HIV-1 protease have been developed in recent years. However, a major difficulty in the treatment with anti-HIV drugs has been the rapid mutations in the viral genome that result in resistance to the drug through changes in the protein target. Combination therapies and cocktails have developed in response to the resistance of the virus to protease inhibitors. Moreover, many resistant mutations can occur distant from the active site. These observations support a mechanism for drug resistance that is not specific to each inhibitor structure. Rather, they support a mechanism that affects a dynamic process of protease closure and conformational change upon ligand binding. The central hypothesis of this application is that the protease inhibitor should account for the dynamic process that occurs upon ligand binding. The inhibitors in this proposal have a "reduced" peptide bond and a phenylalanine group in the middle, and a naphthlylalanine on either end. We seek to prove our hypothesis through the specific aims of examining the NMR spectra of these peptides to determine their flexibility, and docking these inhibitors into HIV-1 protease performing computational molecular dynamic simulations. On the one hand, some flexibility is good in that the peptide can adapt to the active site of the enzyme in its open conformation. On the other hand, too rigid a peptide inhibitor will reduce the population of the best conformer and will be less able to adapt to the point mutations in the protease that affect its dynamics. The data accumulated in this investigation will lay the groundwork for the long range goals of this proposal to design more effective inhibitors that affect the dynamics of the HIV-1 protease in a manner that resist mutations in this enzyme.