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

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