The high rate of mutation associated with HIV replication has necessitated the continuing search for new viral targets and drugs which can circumvent this obstacle to effective drug therapies. In searching for novel drug targets that could be used in anti-HIV approaches, the P.I. has described the nuclear localization signal in the HIV-1 matrix protein as a critical determinant responsible for viral replication in macrophages. Mutations in the NLS, when combined with defects in another HIV-1 protein, Vpr, resulted in the inability of the virus to deliver its genome into the nucleus of macrophages, thus effectively blocking viral replication at a pre-integration stage. This proposal describes a series of new compounds that have been designed to chemically react with the HIV-1 Matrix NLS and which efficiently inhibit translocation of HIV-1 to the nucleus of an infected monocyte, thereby reducing viral replication in monocyte cultures. Compounds from this series demonstrated a very low toxicity in vitro and good bioavailability in the experiments with mice, thus making them good candidates for development as potential therapeutic agents. The proposed studies are to characterize in detail the molecular mechanisms of action of NLS-targeting compounds. They will also investigate the structure-relationships within compounds of this series with a goal to synthesize compounds with higher anti-viral activity. They will analyze anti-viral effects of these compounds in different cell targets using various activation conditions. These studies are expected to lay a foundation for introducing anti-NLS compounds as new anti-HIV drugs.
