BIOLOGICAL AND BIOCHEMICAL ANTI-HUMAN-IMMUNODEFICIENCY-VIRUS ACTIVITYOF UC-38, A NEW NONNUCLEOSIDE REVERSE-TRANSCRIPTASE INHIBITOR

UC 38, a simple analog of oxathin carboxanilide, UG 84, lacking the ox athin ring, was found to be a potent inhibitor of human immunodeficien cy virus (HIV)-1-induced cell killing and HIV replication in a variety of human cell fines, as well as in human peripheral blood lymphocytes and macrophages. UC 38 was active against a wide range of biologicall y diverse laboratory and clinical strains of HIV-1. However, UC 38 was inactive against HIV-2 and both nevirapine- and pyridinone-uesistant strains of HIV-1. UC 38 selectively inhibited HIV-1 reverse transcript ase (RT), but not HIV-2 RT. Combination of UC 38 with 3'-azido-3'-deox ythymidine synergistically, inhibited HIV-induced cell killing. An HIV -1 isolate resistant to UC 38 was selected in cell culture, and the mu tations in the RT nucleotide sequences were determined. Comparison wit h the wild-type RT sequence revealed an amino acid change at position 181 (Tyr to Cys). The UC 38-resistant virus was found to be cross-resi stant to a variety of structurally diverse non-nucleoside RT inhibitor s. UC 38 was susceptible to rapid degradation in vitro and in vive; ye t, nontoxic in vive concentrations of UC 38 many-fold in excess of the in vitro effective concentrations could be achieved and maintained af ter s.c. or p.o. administration in hamsters. These results establish U C 38 as a new chemotype within the general class of HIV-1-specific RT inhibitors. the favorable physical characteristics, lack of toxicity, potency and bioavailability of UC 38 may make it a candidate for combi nation chemotherapy of acquired immune deficiency syndrome.