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Antimicrobial Agents and Chemotherapy, February 2008, p. 648-654, Vol. 52, No. 2
0066-4804/08/$08.00+0     doi:10.1128/AAC.01209-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Intracellular Metabolism of the Nucleotide Prodrug GS-9131, a Potent Anti-Human Immunodeficiency Virus Agent{triangledown}

Adrian S. Ray,* Jennifer E. Vela, Constantine G. Boojamra, Lijun Zhang, Hon Hui, Christian Callebaut, Kirsten Stray, Kuei-Ying Lin, Ying Gao, Richard L. Mackman, and Tomas Cihlar

Gilead Sciences, Inc., Foster City, California 94404

Received 12 September 2007/ Returned for modification 25 October 2007/ Accepted 19 November 2007

GS-9131 is a phosphonoamidate prodrug of the novel ribose-modified phosphonate nucleotide analog GS-9148 that demonstrates potent anti-human immunodeficiency virus type 1 (HIV-1) activity and an excellent resistance profile in vitro. Prodrug moieties were optimized for the efficient delivery of GS-9148 and its active diphosphate (DP) metabolite to lymphoid cells following oral administration. To understand the intracellular pharmacology of GS-9131, incubations were performed with various types of lymphoid cells in vitro. The intracellular accumulation and antiviral activity levels of GS-9148 were limited by its lack of cellular permeation, and GS-9131 increased the delivery of GS-9148-DP by 76- to 290-fold relative to that of GS-9148. GS-9131 activation was saturable at high extracellular concentrations, potentially due to a high-affinity promoiety cleavage step. Once inside the cells, GS-9148 was efficiently phosphorylated, forming similar amounts of anabolites in primary lymphoid cells. The levels of GS-9148-DP formed in peripheral blood mononuclear cells infected with HIV-1 were similar to that in uninfected PBMCs, and approximately equivalent intracellular concentrations of GS-9148-DP and tenofovir (TVF)-DP were required to inhibit viral replication by 90%. Once it was formed, GS-9148-DP was efficiently retained in activated CD4+ cells, with a half-life of 19 h. In addition, GS-9131 showed a low potential for drug interactions with other adenine nucleoside/nucleotide reverse transcriptase inhibitors, based on the lack of competition for anabolism between suprapharmacologic concentrations of GS-9148 and TVF and the lack of activity of GS-9131 metabolites against purine nucleoside phosphorylase, an enzyme involved in the clearance of 2',3'-dideoxyinosine. Together, these observations elucidate the cellular pharmacology of GS-9131 and illustrate its efficient loading of lymphoid cells, resulting in a prolonged intracellular exposure to the active metabolite GS-9148-DP.

* Corresponding author. Mailing Address: Department of Drug Metabolism, Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA 94404. Phone: (650) 522-5536. Fax: (650) 522-1892. E-mail: adrian.ray{at}gilead.com

{triangledown} Published ahead of print on 3 December 2007.

Antimicrobial Agents and Chemotherapy, February 2008, p. 648-654, Vol. 52, No. 2
0066-4804/08/$08.00+0     doi:10.1128/AAC.01209-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Cihlar, T., LaFlamme, G., Fisher, R., Carey, A. C., Vela, J. E., Mackman, R., Ray, A. S. (2009). Novel Nucleotide Human Immunodeficiency Virus Reverse Transcriptase Inhibitor GS-9148 with a Low Nephrotoxic Potential: Characterization of Renal Transport and Accumulation. Antimicrob. Agents Chemother. 53: 150-156 [Abstract] [Full Text]  
  • Cihlar, T., Ray, A. S., Boojamra, C. G., Zhang, L., Hui, H., Laflamme, G., Vela, J. E., Grant, D., Chen, J., Myrick, F., White, K. L., Gao, Y., Lin, K.-Y., Douglas, J. L., Parkin, N. T., Carey, A., Pakdaman, R., Mackman, R. L. (2008). Design and Profiling of GS-9148, a Novel Nucleotide Analog Active against Nucleoside-Resistant Variants of Human Immunodeficiency Virus Type 1, and Its Orally Bioavailable Phosphonoamidate Prodrug, GS-9131. Antimicrob. Agents Chemother. 52: 655-665 [Abstract] [Full Text]  


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