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GS-9131 IS A NOVEL NRTI WITH ACTIVITY AGAINST NRTI-RESISTANT HIV-1
Kirsten L. White1, Nicolas Margot1, Kirsten Stray1, Helen Yu1, George Stepan1, Constantine Boojamra1, Richard Mackman1, Adrian Ray1, Michael D. Miller1, Tomas Cihlar1
1Gilead Scis, Inc, Foster City, CA, USA
There remains a need for an NRTI with potent activity against HIV-1 virus with NRTI resistance. GS-9131 is a monoamidate prodrug of the nucleotide analog GS-9148 (phosphonomethoxy-2'-fluoro-2',3'-dideoxydidehydroadenosine). GS-9131 undergoes conversion in lymphocytes to GS-9148 diphosphate, a potent inhibitor of HIV-1 RT. GS-9148 has a low potential for mitochondrial toxicity and renal accumulation. Here we report on the antiviral activity and resistance profile of GS-9131.
GS-9131 was subjected to extensive in vitro evaluation of antiviral activity and resistance profile. The PhenoSense HIV assay was used to compare the activity of GS-9131 and the NRTIs (ZDV, ddI, d4T, FTC, ABC, and TFV) against HIV-1 variants with all major types of NRTI resistance mutations. GS-9131 activity was also determined against 14 HIV-1 clinical isolates and 1 HIV-2 isolate in peripheral blood mononuclear cells.
GS-9131 had potent activity against laboratory strains of HIV-1 both in primary cells and T-cell lines (EC50 = 25-200 nM) and exhibited potent antiretroviral activity against HIV-1 isolates of subtypes A, B, C, D, E, F, group O and N (EC50 0.29-113 nM). GS-9131 also had potent activity against HIV-2 (EC50 = 21 nM) and showed low cytotoxicity in multiple cell types including renal cells (CC50 > 100 µM). The activity of GS-9131 was not affected by the presence of RT mutations K65R, L74V, M184V or their combinations (EC50 fold change < 1). Viruses with 4 or more thymidine analog mutations (TAMs), including one with the T69-insertion, showed minimal changes (0.68 to 1.5-fold) in susceptibility to GS-9131, a change smaller than any other tested NRTI. Passaging of HIV-1 in the presence of the parent drug GS-9148 selected for a primary K70E mutation in combination with D123N and T165I, or the poorly fit Q151L mutation in combination with K70E, L74I, and L187F/M in RT; these variants conferred <3-fold and 50-fold reduced susceptibility to GS-9131, respectively. GS-9131 (GS-9148) was synergistic in combination studies with AZT, FTC, ABC, efavirenz, the integrase inhibitors bictegravir and dolutegravir, and the PI lopinavir, and additive with TFV and TAF.
GS-9131 exhibits potent in vitro antiretroviral activity and a favorable resistance profile including lower levels of resistance than approved NRTIs. GS-9131 is an attractive candidate for further clinical development with a potential for once daily dosing and efficacy in patients with NRTI resistance.