Antiviral characteristics of GSK1265744, an HIV integrase inhibitor dosed orally or by long-acting injection.
Tomokazu Yoshinaga, Masanori Kobayashi, Takahiro Seki, Shigeru Miki, Chiaki Wakasa-Morimoto, Akemi Suyama-Kagitani, Shinobu Kawauchi-Miki, Teruhiko Taishi, Takashi Kawasuji, Brian A Johns, Mark R Underwood, Edward P Garvey, Akihiko Sato, Tamio Fujiwara
Index: Antimicrob. Agents Chemother. 59(1) , 397-406, (2014)
Full Text: HTML
Abstract
GSK1265744 is a new HIV integrase strand transfer inhibitor (INSTI) engineered to deliver efficient antiviral activity with a once-daily, low-milligram dose that does not require a pharmacokinetic booster. The in vitro antiviral profile and mechanism of action of GSK1265744 were established through integrase enzyme assays, resistance passage experiments, and cellular assays with site-directed molecular (SDM) HIV clones resistant to other classes of anti-HIV-1 agents and earlier INSTIs. GSK1265744 inhibited HIV replication with low or subnanomolar efficacy and with a selectivity index of at least 22,000 under the same culture conditions. The protein-adjusted half-maximal inhibitory concentration (PA-EC50) extrapolated to 100% human serum was 102 nM. When the virus was passaged in the presence of GSK1265744, highly resistant mutants with more than a 10-fold change (FC) in EC50 relative to that of the wild-type were not observed for up to 112 days of culture. GSK1265744 demonstrated activity against SDM clones containing the raltegravir (RAL)-resistant Y143R, Q148K, N155H, and G140S/Q148H signature variants (FC less than 6.1), while these mutants had a high FC in the EC50 for RAL (11 to >130). Either additive or synergistic effects were observed when GSK1265744 was tested in combination with representative anti-HIV agents, and no antagonistic effects were seen. These findings demonstrate that, similar to dolutegravir, GSK1265744 is differentiated as a new INSTI, having a markedly distinct resistance profile compared with earlier INSTIs, RAL, and elvitegravir (EVG). The collective data set supports further clinical development of GSK1265744. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
Related Compounds
Related Articles:
2015-04-01
[Br. J. Pharmacol. 172(7) , 1713-27, (2015)]
2014-10-01
[Food Chem. Toxicol. 72 , 13-9, (2014)]
2014-06-01
[Food Chem. Toxicol. 68 , 117-27, (2014)]
2014-09-01
[Antimicrob. Agents Chemother. 58(9) , 5036-46, (2014)]
Species differences and substrate specificity of CYP3A heteroactivation by efavirenz.
2015-04-01
[Xenobiotica 45(4) , 345-52, (2015)]