GS7340 (Tenofovir Alafenamide, TAF) is a novel oral prodrug of Tenofovir with improved antiviral activity [1].
Tenofovir (TFV) is an HIV-1 nucleotide reverse transcriptase (RT) inhibitor for the treatment of HIV infections [1].
GS7340 (Tenofovir Alafenamide, TAF) is a novel oral prodrug of Tenofovir. In peripheral blood mononuclear cells, TAF is mostly converted to TFV and achieved higher tenofovir diphosphate (TFV-DP) levels, compared with TDF. In MT-2 and MT-4 cells infected with HIV-1IIIB, TAF exhibited anti-HIV-1 activity with EC50 values of 5 nM, while with CC50 (50% cell death) values of 42 and 4.7 nM, respectively. In the 29 primary HIV-1 isolates tested in PBMCs, EC50 values of TAF ranged from 0.10 to 12.0 nM with mean EC50 of 3.5 nM. For the HIV-2 isolates, the mean EC50 value was 1.8 nM. In MT-2 cells, TAF maintained its antiviral activity after HS (human serum) pretreatment, suggesting its plasma stability. TAF is a potent inhibitor of immunodeficiency viruses, such as HIV and SIV, and a weak inhibitor of HSV-2 [1]. In HIV-1 isolates with NRTI resistance amino acid substitutions, TAF exhibited reduced activity [2]. In primary human hepatocytes, TAF resulted in high levels of tenofovir diphosphate (TFV-DP), which exhibited half-life of >24 h [3].
In dogs, TAF orally administration for 7 days increased the levels of TFV-DP in dog livers for the treatment of HBV infection [3].
References:
[1]. Callebaut C, Stepan G, Tian Y, et al. In Vitro Virology Profile of Tenofovir Alafenamide, a Novel Oral Prodrug of Tenofovir with Improved Antiviral Activity Compared to That of Tenofovir Disoproxil Fumarate. Antimicrob Agents Chemother, 2015, 59(10): 5909-5916.
[2]. Margot NA, Johnson A, Miller MD, et al. Characterization of HIV-1 Resistance to Tenofovir Alafenamide In Vitro. Antimicrob Agents Chemother, 2015, 59(10): 5917-5924.
[3]. Murakami E, Wang T, Park Y, et al. Implications of efficient hepatic delivery by tenofovir alafenamide (GS-7340) for hepatitis B virus therapy. Antimicrob Agents Chemother, 2015, 59(6): 3563-3569.