Oxadaizols: Rationally designed compounds targeting HIV nuclear importation

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DESCRIPTION (provided by applicant): Despite recent progress in anti-HIV therapy, drug toxicity and emergence of drug-resistant isolates during long- term treatment of HIV-infected patients necessitate the search for new targets that can be used to develop novel anti-viral agents. One such target is the process of nuclear translocation of the HIV-1 pre-integration complex. In our preliminary studies, we identified a class of oxadiazol compounds that inhibit HIV-1 nuclear import by targeting the matrix protein (MA). These compounds were selected using computer-assisted drug design and are predicted to bind to MA near its nuclear localization signal (NLS) thus blocking MA-mediated nuclear import. The lead compound from this group, ITI-367, showed potent anti-HIV activity in cultures of T lymphocytes and macrophages, and also inhibited HIV-1 replication in ex vivo cultured lymphoid tissue. Real- time PCR analysis demonstrated that ITI-367 specifically inhibited nuclear import of viral DNA. In this application, we propose to further characterize the molecular mechanism of action of ITI-367 and to expand this analysis to other compounds related to ITI-367 in an attempt to identify the most potent inhibitor of HIV-1 replication. Towards these goals, the following Specific Aims will be pursued: 1. To produce and characterize the HIV-1 variants resistant to oxadiazol compounds. 2. To characterize interaction between oxadiazol derivatives and MA and analyze their anti-HIV activity. This exploratory proposal is fully consistent with the goals of this PA as it addresses an innovative concept in HIV research which has implications both for basic and clinical studies. Proposed experiments are expected to provide a direct test for the hypothesis regarding the mechanism of action of this new class of anti-HIV compounds. Upon completion, these studies are expected to define potent anti-HIV compounds working through a novel mechanism different from that of any other currently used drug. Studies proposed in this application will characterize a class of compounds aimed at a novel target in HIV life cycle: transport of the viral DNA to the nucleus. These studies are highly relevant to public health as they are expected to expand the repertoire of available anti-HIV drugs, thus providing an opportunity to fight drug resistance often seen in HIV-infected patients.