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

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

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

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-phosphonylmethoxy-ethyl)-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 α and β while showing weaker activity against mitochondrial DNA polymerase γ (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.

Original languageEnglish (US)
Pages (from-to)2777-2784
Number of pages8
JournalAntimicrobial agents and chemotherapy
Volume53
Issue number7
DOIs
StatePublished - Jul 1 2009

Fingerprint

Prodrugs
Guanine
Nucleotides
Cottontail rabbit papillomavirus
Nucleic Acid Synthesis Inhibitors
Diphosphates
Papilloma
DNA-Directed DNA Polymerase
Mitochondrial DNA
S Phase
Nucleosides
GS-9191
Animal Models
Apoptosis
Cell Line
Skin
DNA
Enzymes
Growth

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Wolfgang, Grushenka H.I. ; Shibata, Riri ; Wang, Jianying ; Ray, Adrian S. ; Wu, Sylvia ; Doerrfler, Edward ; Reiser, Hans ; Lee, William A. ; Birkus, Gabriel ; Christensen, Neil D. ; Andrei, Graciela ; Snoeck, Robert. / 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. In: Antimicrobial agents and chemotherapy. 2009 ; Vol. 53, No. 7. pp. 2777-2784.
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abstract = "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-phosphonylmethoxy-ethyl)-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 α and β while showing weaker activity against mitochondrial DNA polymerase γ (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.",
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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. / Wolfgang, Grushenka H.I.; Shibata, Riri; Wang, Jianying; Ray, Adrian S.; Wu, Sylvia; Doerrfler, Edward; Reiser, Hans; Lee, William A.; Birkus, Gabriel; Christensen, Neil D.; Andrei, Graciela; Snoeck, Robert.

In: Antimicrobial agents and chemotherapy, Vol. 53, No. 7, 01.07.2009, p. 2777-2784.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 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

AU - Wolfgang, Grushenka H.I.

AU - Shibata, Riri

AU - Wang, Jianying

AU - Ray, Adrian S.

AU - Wu, Sylvia

AU - Doerrfler, Edward

AU - Reiser, Hans

AU - Lee, William A.

AU - Birkus, Gabriel

AU - Christensen, Neil D.

AU - Andrei, Graciela

AU - Snoeck, Robert

PY - 2009/7/1

Y1 - 2009/7/1

N2 - 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-phosphonylmethoxy-ethyl)-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 α and β while showing weaker activity against mitochondrial DNA polymerase γ (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.

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