KINETIC AND BINDING-STUDIES ON [I-125] SDZ-283471, A RADIOLABELED INHIBITOR OF HIV-1 PROTEINASE

Kinetic and binding studies on a novel type of potent inhibitors of HIV-1 proteinase containing a 2-aminobenzyl substituted statine moiety as dipeptide mimetic are reported. The compounds were characterized as fast-binding competitive inhibitors of the enzyme. Using the radioiodinated derivative [I-125]SDZ-28371, monophasic association and dissociation curves were observed indicating a simple bimolecular reaction. While the association rate constant was similar to that of other inhibitors, the dissociation constant of SDZ-283471 was 20-500 times lower. Thus, the enzyme-inhibitor complex appears to be very stable in the case of the 2-aminobenzyl-statine compounds. Furthermore, we demonstrated that the inhibitors show appropriate specificity for HIV-1 and HIV-2 proteinases as compared to other aspartic proteinases. Using a competition assay, relative potencies of inhibitors modified in the P2 position were obtained and a preference for valine at this site was observed.