EMPIRICAL AND RATIONAL APPROACHES FOR DEVELOPMENT OF INHIBITORS OF THE HUMAN-IMMUNODEFICIENCY-VIRUS - HIV-1

The human immunodeficiency virus, HIV-1, is generally accepted to be r esponsible for AIDS. It is imperative that all approaches, empirical a nd rational, be taken for development of a drug for therapy of this di sease. These approaches are discussed, with emphasis on the direction being pursued in our laboratory. Empirically, we found 3'-deoxy-2',3'- didehydrothymidine, a compound first synthesized for potential antican cer activity by J. Horwitz in the 1960s, to be a potent inhibitor of H IV-1. It is now in Phase II/III clinical trials. We have also synthesi zed several 2,5'-anhydro pyrimidine nucleoside analogs, which have int eresting chemical and biological properties. We have evaluated a natur al product, gossypol and synthesized various derivatives for anti-HIV- 1 activity, but none were appreciably more inhibitory than the parent compound. More recently, we have taken the rational approach and synth esized a boron-modified tetrapeptide, Ac-Thr-Leu-Asn-boro-Phe, which c orresponds to the COOH-terminal of the Phe-Pro scissle bond of the gag /pol gene polyprotein product. Potent inhibition of the HIV-1 encoded protease was observed. These approaches and findings will be discussed .