The thiocarboxanilide nonnucleoside inhibitor UC781 restores antiviral activity of 3 '-azido-3 '-deoxythymidine (AZT) against AZT-resistant human immunodeficiency virus type 1

N-[4-Chloro-3-(3-methyl-2-butenyloxy)phenyl]-2-methyl-3-furancarbothioamide (UC781) is an exceptionally potent nonnucleoside inhibitor of human immuno deficiency virus type 1 (HIV-1) reverse transcriptase. We found that a 1:1 molar combination of UC781 and 3'-azido-3'-deoxythymidine (AZT) showed high -level synergy in inhibiting the replication of AZT-resistant virus, implyi ng that UC781 can restore antiviral activity to AZT against AZT-resistant H IV-1. Neither the nevirapine plus AZT nor the 2',5'-bis-O-(t-butyldimethyls ilyl)-3'-spiro-5 "-(4 "-amino-1 ",2 "-osathiote-2 ",2 "-dioxide plus AZT co mbinations had this effect. Studies with purified HIV-1 reverse transcripta se (from a wild type and an AZT-resistant mutant) showed that UC781 was a p otent inhibitor of the pyrophosphorolytic cleavage of nucleotides from the 3' end of the DNA polymerization primer, a process that we have proposed to be critical for the phenotypic expression of AZT resistance. Combinations of UC781 plus AZT did not act in synergy to inhibit the replication of eith er wild-type virus or UC781-resistant HIV-1. Importantly, the time to the d evelopment of viral resistance to combinations of UC781 plus AZT is signifi cantly delayed compared to the time to the development of resistance to eit her drug alone.