INHIBITION OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 WILD-TYPE AND MUTANT REVERSE TRANSCRIPTASES BY THE PHENYL ETHYL THIAZOLYL THIOUREA DERIVATIVES TROVIRDINE AND MSG-127

A new class of very potent and selective non-nucleoside inhibitors of HIV reverse transcriptase (RT) has recently been identified, The proto type compound trovirdine (LY 300046 HCl) and one analogue, MSG-127, ha ve been studied with respect to inhibition of wild-type HIV-1 RT and R T with various mutations known to give rise to resistance to other non -nucleoside RT inhibitors, namely Leu(100) --> Ile (Ile(100))), GlU(13 8) --> Arg (Arg(138)), Tyr(181) --> Cys (CyS(181)) and Tyr(188) --> Hi s (His(188)). The inhibition of HIV-1 RT by trovirdine and MSG-127 was reversible and template dependent. Trovirdine inhibited HIV-1 RT with an IC50 of 0.007 mu M when employing heterapolymeric primer/template (oligo-DNA/ribosomal RNA) and dGTP as substrate. Enzyme kinetic studie s showed that inhibition of RT by trovirdine was non-competitive with regard to deoxynucleoside triphosphates and uncompetitive with respect to varied primer/template under steady-state conditions. The amino ac id changes Leu(100), Tyr(181) and Tyr(188) gave rise to 25-, 147- and 12-fold decrease in inhibition by trovirdine. Enzyme-kinetic studies o n trovirdine have been carried out using various RT mutants and compar ed to the properties of the earlier reported non-nucleoside RT inhibit ors 9-Cl-TIBO, nevirapine and L-697,661.