During the past year, the Retroviral Diseases Section has conducted research on human immunodeficiency virus (HIV) disease. We have been focusing on the HIV proteaseand the GagPol protease precursor. The first part of the project is exploring the feasibility of developing a novel therapy to HIV protease through inhibition of HIV protease dimerization. HIV protease is a dimer composed of two identical monomers. Our group previously found that glutathiolation of a conserved cysteine (Cys 95) at the HIV protease dimer interface abolishes HIV-1 protease activity. This suggested that the dimer interface and inhibition of dimerization could be a novel target for drug development. We showed that several peptides could be designed that interfered with HIV protease dimerization and that this peptide could block HIV viral production from infected cells. We are exploring the effect of these inhibitors on the Gag-Pol polyprotein, which needs to form a dimer and self-cleave itself to form active protease. Our hypothesis is that such dimerization inhibitors may be optimally directed at this initial dimerization of the Gag-Pol polyproteins. We are also exploring a number of small molecule inhibitors of HIV protease for their activity against Gag-Pol (especially the first step in GagPol autocleavage) and against dimerization, in part in collaboration with the laboratory of Dr. Mitsuya. We have developed an in vitro translation assay to study inhibitors of the first autocleavage of HIV GagProPol, and have found that it is modified by oxidation of cysteines in the protease sequence, although somewhat differently than mature protease. In addition, we are exploring the effects of various protease inhibitors on this first autocleavage step. We have found that the protease inhibitor darunavir also has activity in inhibiting HIV protease dimerization. In addition, we are testing several novel HIV protease inhibitors for activity against GagPol autocleavage. Also, we are studying some unexpected effects of P27, a peptide designed to inhibit the dimerization of HIV protease, on macropinocytosis. FInally, in collaboration with other investigators in the NCI, NIH, and FDA, we have been exploring the effects of HIV infection on immunologic parameters such as IL-15 production or other factors such as novekl ways to measure p24 antigen.
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|Davis, David A; Tebbs, Irene R; Daniels, Sarah I et al. (2009) Analysis and characterization of dimerization inhibition of a multi-drug-resistant human immunodeficiency virus type 1 protease using a novel size-exclusion chromatographic approach. Biochem J 419:497-506|