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Virological Profiling of GS 7340, a Next-generation Tenofovir Prodrug with Superior Potency over Tenofovir DF
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Reported by Jules Levin
52nd ICAAC 2012 Sept 9-12 SF
Christian Callebaut, Nicolas Margot, George Stepan, Yang Tian, and Michael D. Miller
Gilead Sciences
Program Abstract
Background: Tenofovir (TFV) is an HIV-1 nucleotide reverse transcriptase inhibitor (NtRTI), metabolized intracellularly to its active metabolite TFV-diphosphate (TFV-DP). Tenofovir disoproxil fumarate (TDF), an oral prodrug of TFV, is widely used for treatment of HIV-1 infection. GS-7340 is a novel oral prodrug of TFV that is more stable in human serum leading to enhanced delivery and conversion to TFV in lymphoid cells and increased TFV-DP in PBMCs. Phase 1 clinical studies showed that GS-7340 has more potent antiviral activity than TDF. Virological profiling of GS-7340 is described here.
Methods: Antiviral activity was evaluated in PBMCs against HIV-1 clinical isolates; compounds were also evaluated against a panel of other human viruses. Antiretroviral (ARV) drug combination studies were performed in MT-2 cells in a 384-well automated format. Potency experiments were performed in the presence of ARV drugs pre-incubated at 37ºC in human serum.
Results: GS-7340 showed high potency against a panel of 26 HIV-1 isolates from multiple subtypes (mean EC50 = 3.6 nM) and 3 HIV-2 isolates (mean EC50 = 1.8 nM). GS-7340 activity was highly specific for retroviruses with no significant activity detected against other viruses. Combination studies of GS-7340 or TFV with other ARV drugs, as well as the pharmaco-enhancer cobicistat, showed additive-to-synergistic interactions, and no antagonism. Although potency of the two prodrugs was similar without pretreatment, TDF potency was significantly reduced in the presence of human serum. Unlike TDF, GS-7340 maintained its potency after prolonged serum treatment, reflecting the greater plasma stability of GS-7340.
Conclusions: The next generation prodrug of TFV, GS-7340, has a virological profile similar to that of TFV regarding spectrum of activity and has in vitro synergy with other ARVs. GS-7340 demonstrated superior antiviral potency to TDF in vitro in the presence of human serum, consistent with the higher intracellular TFV-DP levels and greater antiviral potency seen in the clinical setting as compared to TDF.
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