A ProTide of AZT Shows Activity Against Human Papillomaviruses

Nucleoside or nucleotide analogs with acyclic sugar moiety are commonly used to treat infections by DNA viruses. A prodrug of AZT was found to have detectable activity against Human papillomavirus strains in vitro. A typical known antiviral is shown on the left, and the prodrug is shown on the right, and in space-filling representation in the middle of the image.

Abstract

Infection by human papillomaviruses (HPV) can cause warts and tumors. So far, no small molecule antiviral has been approved for the treatment of infections with this DNA virus, although preclinical studies show activity for nucleosidic compounds, such as 9-(2-phosphonylmethoxy)ethylguanine (PMEG) or cidofovir. This prompted us to test new prodrug versions of the nucleoside analog 3’-azido-2’,3’-dideoxythymidine (AZT), known to be active against reverse transcriptases and approved for the treatment of HIV. Here we report the synthesis of an ethylbutyl alaninyl ester phosphosphoramidate prodrug of AZT, dubbed AZAEB, and its activity against HPV, a target not known to be sensitive to AZT. A methyl ester derivative was found to be inactive against this and three other DNA viruses, while the phosphoramidate prodrug AZAEB showed a modest inhibitory effect against HPV types 6, 11, 18 and 31. Our results open up new avenues of study for the treatment of diseases caused by members of the papillomaviridae family.

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