Since the discovery of nucleoside reverse transcriptase inhibitors (NRTIs) for the treatment of HIV, efforts to improve the potency, resistance profile, and long term safety have continued. GS-7340 (tenofovir alafenamide, TAF) is a phosphonamidate prodrug of the acyclic NRTI tenofovir (TFV) that was recently approved for the treatment of HIV and HBV. Compared to the prodrug tenofovir disoproxil fumarate (TDF), GS-7340 preferentially delivers TFV to immune cells and tissues resulting in a lower oral dose and improved long term safety profile. There is also a need for new NRTIs with potent activity against HIV viral strains with NRTI resistance. GS-9131 is a phosphonamidate prodrug of a novel cyclic nucleoside phosphonate, GS-9148 (2’Fd4AP). GS-9131 demonstrates a superior resistance profile compared to all approved NRTIs and importantly a low potential for mitochondrial toxicity that supports its clinical development for treatment experienced patients with NRTI resistance mutations. The preclinical discovery and profiling of these prodrugs, along with clinical data supporting the approval of GS-7340 and the potential of GS-9131, will be presented. Additionally, there is an interest in application of nucleoside phosphonate antivirals toward RNA viruses. Aided by structural studies in HIV reverse transcriptase, the challenges associated with the extension of the class of nucleoside phosphonate inhibitors to RNA viruses will be discussed.

Phosphonamidate prodrugs GS-7340 (tenofovir alafenamide) and GS-9131 for the treatment of HIV

254th National Meeting (2017)

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