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Antimicrobial Agents and Chemotherapy, July 2009, p. 2777-2784, Vol. 53, No. 7
0066-4804/09/$08.00+0     doi:10.1128/AAC.00103-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

GS-9191 Is a Novel Topical Prodrug of the Nucleotide Analog 9-(2-Phosphonylmethoxyethyl)Guanine with Antiproliferative Activity and Possible Utility in the Treatment of Human Papillomavirus Lesions{triangledown}

Grushenka H. I. Wolfgang,1* Riri Shibata,1 Jianying Wang,1 Adrian S. Ray,1 Sylvia Wu,1 Edward Doerrfler,1 Hans Reiser,1 William A. Lee,1 Gabriel Birkus,1 Neil D. Christensen,2 Graciela Andrei,3 and Robert Snoeck3

Gilead Sciences, Foster City, California,1 Gittlen Cancer Research Foundation, Hershey, Pennsylvania,2 Rega Institute for Medical Research, Katholieke Universiteit, Leuven, Belgium3

Received 15 January 2009/ Returned for modification 20 February 2009/ Accepted 21 April 2009

GS-9191 is a novel double prodrug of the nucleotide analog 9-(2-phosphonylmethoxyethyl)guanine (PMEG) designed as a topical agent to permeate skin and be metabolized to the active nucleoside triphosphate analog in the epithelial layer. The prodrug was shown to be metabolized intracellularly to 9-(2-phosphonylmethoxyethyl)-N6-cyclopropyl-2,6,diaminopurine (cPrPMEDAP) and subsequently deaminated to PMEG. The active form, PMEG diphosphate, was shown to be a potent inhibitor of DNA polymerase {alpha} and ß while showing weaker activity against mitochondrial DNA polymerase {gamma} (50% enzyme inhibition observed at 2.5, 1.6, and 59.4 µM, respectively). GS-9191 was markedly more potent than PMEG or cPrPMEDAP in a series of human papillomavirus (HPV)-positive cell lines, with effective concentrations to inhibit 50% cell growth (EC50) as low as 0.03, 207, and 284 nM, respectively. In contrast, GS-9191 was generally less potent in non-HPV-infected cells and primary cells (EC50s between 1 and 15 nM). DNA synthesis was inhibited by GS-9191 within 24 h of treatment; cells were observed to be arrested in S phase by 48 h and to subsequently undergo apoptosis (between 3 and 7 days). In an animal model (cottontail rabbit papillomavirus), topical GS-9191 was shown to decrease the size of papillomas in a dose-related manner. At the highest dose (0.1%), cures were evident at the end of 5 weeks, and lesions did not recur in a 30-day follow-up period. These data suggest that GS-9191 may have utility in the treatment of HPV-induced lesions.

* Corresponding author. Mailing address: Gilead Sciences, 333 Lakeside Drive, Foster City, CA. Phone: (650) 522-5993. Fax: (650) 522-5266. E-mail: gwolfgang{at}gilead.com

{triangledown} Published ahead of print on 27 April 2009.

Antimicrobial Agents and Chemotherapy, July 2009, p. 2777-2784, Vol. 53, No. 7
0066-4804/09/$08.00+0     doi:10.1128/AAC.00103-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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