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Antimicrobial Agents and Chemotherapy, March 2009, p. 1194-1203, Vol. 53, No. 3
0066-4804/09/$08.00+0     doi:10.1128/AAC.00984-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Preclinical Evaluation of GS-9160, a Novel Inhibitor of Human Immunodeficiency Virus Type 1 Integrase{triangledown} ,{dagger}

Gregg S. Jones, Fang Yu, Ameneh Zeynalzadegan, Joseph Hesselgesser, Xiaowu Chen, James Chen, Haolun Jin, Choung U. Kim, Matthew Wright, Romas Geleziunas, and Manuel Tsiang*

Gilead Sciences, Foster City, California 94404

Received 23 July 2008/ Returned for modification 24 August 2008/ Accepted 16 December 2008

GS-9160 is a novel and potent inhibitor of human immunodeficiency virus type 1 (HIV-1) integrase (IN) that specifically targets the process of strand transfer. It is an authentic inhibitor of HIV-1 integration, since treatment of infected cells results in an elevation of two-long terminal repeat circles and a decrease of integration junctions. GS-9160 has potent and selective antiviral activity in primary human T lymphocytes producing a 50% effective concentration (EC50) of ~2 nM, with a selectivity index (50% cytotoxic concentration/EC50) of ~2,000. The antiviral potency of GS-9160 decreased by 6- to 10-fold in the presence of human serum. The antiviral activity of GS-9160 is synergistic in combination with representatives from three different classes of antiviral drugs, namely HIV-1 protease inhibitors, nonnucleoside reverse transcriptase inhibitors, and nucleotide reverse transcriptase inhibitors. Viral resistance selections performed with GS-9160 yielded a novel pattern of mutations within the catalytic core domain of IN; E92V emerged initially, followed by L74M. While E92V as a single mutant conferred 12-fold resistance against GS-9160, L74M had no effect as a single mutant. Together, these mutations conferred 67-fold resistance to GS-9160, indicating that L74M may potentiate the resistance caused by E92V. The pharmacokinetic profile of GS-9160 in healthy human volunteers revealed that once-daily dosing was not likely to achieve antiviral efficacy; hence, the clinical development of this compound was discontinued.

* Corresponding author. Mailing address: Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404. Phone: (650) 522-5860. Fax: (650) 522-5143. E-mail: MTsiang{at}gilead.com

{triangledown} Published ahead of print on 22 December 2008.

{dagger} Supplemental material for this article may be found at http://aac.asm.org/.

Antimicrobial Agents and Chemotherapy, March 2009, p. 1194-1203, Vol. 53, No. 3
0066-4804/09/$08.00+0     doi:10.1128/AAC.00984-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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