The long-term objective is to develop clinically effective antiviral agents. Previous efforts for development of antiviral agents were directed towards the inhibition of herpesvirus, however for the pat few years a major thrust has been developed of compounds for inhibition of HIV-1, the virus responsible for AIDS. Our early efforts produced the clinically useful FDA approved anti-herpetic agent Idoxuridine, and more recently we developed as an anti-HIV-1 agent (3'-deoxythymidin-2'-ene; d4T), a compound first synthesized by J. Horwitz and which we now have in phase 1 clinical trial. The current objectives include the synthesis of novel antiviral compounds, to evaluate their spectra of activity both singly and in combination, to determine the site of inhibition and molecular basis for their inhibitory activity, and to prepare adequate amounts for evaluation in viral infected animals by investigation at other institutions in collaboration. The methodologies for synthesis are well established in the literature, but the application will yield novel compounds such as (1) analogs of gossypol a natural product which we found to have a good antiviral activity against HIV-1, (2) boron-peptides to specifically inhibit the processing of HIV-1 protease, by preventing cleavage at the protease-reverse transcriptase junction of the HIV-1 polyprotein precursor, and (3) novel nucleoside analogs based on the structure of the naturally occuring exocyclic amino nucleoside, clitocine. The basis for this very productive program is the combined efforts of several disciplines - organic chemistry, biochemistry, virology and pharmacology. This combination has allowed maximal efficiency in the development of these therapeutic agents.
