ALLOSTERIC INHIBITION OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 REVERSE-TRANSCRIPTASE BY HYDROIMIDAZO[4,5,1-JK][1,4]BENZODIAZEPIN-2(1H)-ONE AND THIONE COMPOUNDS

The reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) is present in virions and infected cells as an heterodimer (p6 6/p51). A new class of potent and selective HIV-1 inhibitors, the hydr oimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one and -thione (TIBO) deri vatives, were found to exert their antiviral activity by interacting w ith monomeric HIV-1 RT (p66) in a way different from that of previousl y studied RT inhibitors such as azidothymidine 5'-triphosphate. Upon e xamination of the kinetic properties of the heterodimeric HIV-1 RT and its inhibition by TIBO compounds, a positive cooperativity between th e subunits of the enzyme with regard to the 2'-deoxynucleoside observe d. The cooperativity with respect to the template/primer may result fr om a progressive dimerization in the presence of increasing concentrat ions of the template/primer, a process referred to as polysteric linka ge. Because the cooperativity of p66/p51 was abolished in the presence of TIBO, these compounds behave as allosteric inhibitors.