1. Academic Validation
  2. Antiviral characteristics of GSK1265744, an HIV integrase inhibitor dosed orally or by long-acting injection

Antiviral characteristics of GSK1265744, an HIV integrase inhibitor dosed orally or by long-acting injection

  • Antimicrob Agents Chemother. 2015 Jan;59(1):397-406. doi: 10.1128/AAC.03909-14.
Tomokazu Yoshinaga 1 Masanori Kobayashi 2 Takahiro Seki 2 Shigeru Miki 2 Chiaki Wakasa-Morimoto 2 Akemi Suyama-Kagitani 2 Shinobu Kawauchi-Miki 2 Teruhiko Taishi 3 Takashi Kawasuji 2 Brian A Johns 4 Mark R Underwood 4 Edward P Garvey 4 Akihiko Sato 2 Tamio Fujiwara 5
Affiliations

Affiliations

  • 1 Discovery Research Laboratory for Core Therapeutic Area, Shionogi & Co., Ltd., Osaka, Japan tomokazu.yoshinaga@shionogi.co.jp.
  • 2 Discovery Research Laboratory for Core Therapeutic Area, Shionogi & Co., Ltd., Osaka, Japan.
  • 3 Strategic Development Department, Shionogi & Co., Ltd., Osaka, Japan.
  • 4 GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
  • 5 Global Development, Shionogi & Co., Ltd., Osaka, Japan.
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.

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