Pyrophosphate Analog HIV-1 Reverse Transcriptase Inhibitors

Description:

The invention relates to compounds that inhibit HIV-1 DNA synthesis mediated by reverse transcriptase (RT). HIV-1 DNA synthesis by RT utilizes deoxynucleoside 5’-triphosphate (dNTP) as substrate and like many other enzymes, the reaction is reversible. Pyrophosphate analogs like imidodiphosphate strongly promote reverse reaction dNTP products containing the imidodiphosphate group instead of the naturally occurring pyrophosphate group. This imidodiphosphate-containing dNTP was found to be a potent inhibitor of the forward RT reaction. Whereas pyrophosphorolysis is limited by a nonchemical step, replacing the bridging oxygen of pyrophosphate with an imido group resulted in a change in the rate-limiting step, so that the imidodiphosphate-dependent reverse reaction was limited by chemistry. There exists, then, the potential to use pyrophosphate analogs therapeutically.