Specific interaction between HIV-1 proteinase and 5'-phosphate peptidomimetic derivatives of nucleoside analogues

HIV-1 proteinase is shown to interact with 5'-(methoxyglycinyl-S-(N-methylcarbamoylmethyl))thiophosphat e derivatives of 3'-fluoro-3'-deoxythymidine (FLT), 3'-azido-3'-deoxythymidine (AZT) and of acyclovir (ACV). The enzyme is inhibited in vitro by micromolar concentrations of these compounds. The Ki-value for the FLT derivative was 15 microM. Other closely related 5'-phosphate derivatives of nucleoside analogues tested showed no effect on the enzymatic activity, indicating a high degree of specificity. This type of compound is unstable in buffer at alkaline pH and in cell culture resulting in inhibition of HIV replication. HIV proteinase does not catalyse the hydrolysis nor is it inhibited by the hydrolysis products. Modelling of the non-nucleoside moiety of the compounds show that they can adopt a low energy conformation which is similar to a pseudo C2 symmetric inhibitor of HIV-1 proteinase.