title: Antiviral characteristics of GSK1265744, an HIV integrase inhibitor dosed orally or by long-acting injection.
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.
authors.affiliation: Discovery Research Laboratory for Core Therapeutic Area, Shionogi & Co., Ltd., Osaka, Japan tomokazu.yoshinaga@shionogi.co.jp.
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Yoshinaga
authors.affiliation: Discovery Research Laboratory for Core Therapeutic Area, Shionogi & Co., Ltd., Osaka, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Kobayashi
authors.affiliation: Discovery Research Laboratory for Core Therapeutic Area, Shionogi & Co., Ltd., Osaka, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Seki
authors.affiliation: Discovery Research Laboratory for Core Therapeutic Area, Shionogi & Co., Ltd., Osaka, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Miki
authors.affiliation: Discovery Research Laboratory for Core Therapeutic Area, Shionogi & Co., Ltd., Osaka, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Wakasa-Morimoto
authors.affiliation: Discovery Research Laboratory for Core Therapeutic Area, Shionogi & Co., Ltd., Osaka, Japan.
authors.forename: Akemi
authors.initials: A
authors.lastname: Suyama-Kagitani
authors.affiliation: Discovery Research Laboratory for Core Therapeutic Area, Shionogi & Co., Ltd., Osaka, Japan.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Kawauchi-Miki
authors.affiliation: Strategic Development Department, Shionogi & Co., Ltd., Osaka, Japan.
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Taishi
authors.affiliation: Discovery Research Laboratory for Core Therapeutic Area, Shionogi & Co., Ltd., Osaka, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kawasuji
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Johns
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Underwood
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
authors.forename: Edward P
authors.initials: EP
authors.lastname: Garvey
authors.affiliation: Discovery Research Laboratory for Core Therapeutic Area, Shionogi & Co., Ltd., Osaka, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Sato
authors.affiliation: Global Development, Shionogi & Co., Ltd., Osaka, Japan.
authors.forename: Tamio
authors.initials: T
authors.lastname: Fujiwara
mesh_terms: D019380:Anti-HIV Agents / Q000627:therapeutic use*; D002460:Cell Line; D024882:Drug Resistance, Viral / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D019427:HIV Integrase / Q000187:drug effects; D019428:HIV Integrase Inhibitors / Q000627:therapeutic use*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006575:Heterocyclic Compounds, 3-Ring / Q000627:therapeutic use; D006801:Humans; D008826:Microbial Sensitivity Tests; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones / Q000627:therapeutic use*; D015363:Quinolones / Q000627:therapeutic use; D000068898:Raltegravir Potassium / Q000627:therapeutic use; D014779:Virus Replication / Q000187:drug effects; D000099226:Dolutegravir; D054659:Diketopiperazines
chemical_list: D019380:Anti-HIV Agents; D019427:HIV Integrase; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D015363:Quinolones; D000068898:Raltegravir Potassium; D000099226:Dolutegravir; C509700:elvitegravir; C584914:cabotegravir; D054659:Diketopiperazines