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Antimicrobial Agents and Chemotherapy, March 2008, p. 901-908, Vol. 52, No. 3
0066-4804/08/$08.00+0     doi:10.1128/AAC.01218-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The Naphthyridinone GSK364735 Is a Novel, Potent Human Immunodeficiency Virus Type 1 Integrase Inhibitor and Antiretroviral

Departments of Virology,¹ Medicinal Chemistry, Infectious Diseases Center of Excellence for Drug Discovery,² Department of Discovery Technology Group, Molecular Discovery Research, GlaxoSmithKline, Research Triangle Park, North Carolina 27709,³ Shionogi Research Laboratories, Shionogi and Company, Ltd., Mishima, Settsu-shi, Osaka 556-0022, Japan⁴

Received 14 September 2007/ Returned for modification 19 November 2007/ Accepted 14 December 2007

The naphthyridinone GSK364735 potently inhibited recombinant human immunodeficiency virus type 1 (HIV-1) integrase in a strand transfer assay (mean 50% inhibitory concentration ± standard deviation, 8 ± 2 nM). As expected based on the structure of the drug, it bound competitively with another two-metal binding inhibitor (K_d [binding constant], 6 ± 4 nM). In a number of different cellular assays, GSK364735 inhibited HIV replication with potency at nanomolar concentrations (e.g., in peripheral blood mononuclear cells and MT-4 cells, 50% effective concentrations were 1.2 ± 0.4 and 5 ± 1 nM, respectively), with selectivity indexes of antiviral activity versus in-assay cytotoxicity of at least 2,200. When human serum was added, the antiviral potency decreased (e.g., a 35-fold decrease in the presence of 100% human serum was calculated by extrapolation from the results of the MT-4 cell assay). In cellular assays, GSK364735 blocked viral DNA integration, with a concomitant increase in two-long-terminal-repeat circles. As expected, this integrase inhibitor was equally active against wild-type viruses and mutant viruses resistant to approved drugs targeting either reverse transcriptase or protease. In contrast, some but not all viruses resistant to other integrase inhibitors were resistant to GSK364735. When virus was passaged in the presence of the inhibitor, we identified resistance mutations within the integrase active site that were the same as or similar to mutations arising in response to other two-metal binding inhibitors. Finally, either additive or synergistic effects were observed when GSK364735 was tested in combination with approved antiretrovirals (i.e., no antagonistic effects were seen). Thus, based on all the data, GSK364735 exerted potent antiviral activity through the inhibition of viral DNA integration by interacting at the two-metal binding site within the catalytic center of HIV integrase.

Published ahead of print on 26 December 2007.