Suicide Inhibitors of Reverse Transcriptase in the Therapy of AIDS and OtherRetroviruses

摘要

This project was designed to develop antiviral agents by adapting new enzymaticand pharmacokinetic principles to inhibition of the HIV-reverse transcriptase. Towards this end, synthetic organic procedures were directed to synthesize compounds in the following categories. 3' Nucleosidee spiroxiranes and a series of related compounds having the potential to function as suicide inhibitors of reverse transcriptase through the 3' functional group. A series of sterol phosphonoformate analogs was designed to improve delivery of the active phosphonoformate (PFA) moiety to sites of viral replication; and a series of 5' sterol easter derivatives of azido thymidine was designed to improve the pharmacokinetics and blood half life of AZT. Synthetic compounds were tested for antiviral activity against HIV and EIAV in tissue culture, against purified HIV-reverse transcriptase in enzyme kinetic studies, where appropriate samples of synthetic analogs were supplied to the US Army Antiviral Program for screening against a battery of 10 viruses of interest as military disease hazards.