Synthesis and anti-HIV activity of GS-9148 (2′-Fd4AP), a novel nucleoside phosphonate HIV reverse transcriptase inhibitor

Constantine G. Boojamra, Richard L. Mackman, David Y. Markevitch, Vidya Prasad, Adrian S. Ray, Janet Douglas, Deborah Grant, Choung U. Kim, Tomas Cihlar

Research output: Contribution to journalArticle

50 Scopus citations

Abstract

GS-9148 (2′-Fd4AP, 4) has been identified as a nucleoside phosphonate reverse transcriptase (RT) inhibitor with activity against wild-type HIV (EC50 = 12 μM). Unlike many clinical RT inhibitors, relevant reverse transcriptase mutants (M184V, K65R, 6-TAMs) maintain a susceptibility to 2′-Fd4AP that is similar to wild-type virus. The 2′-fluorine group was rationally designed into the molecule to improve the selectivity profile and in preliminary studies using HepG2 cells, compound 4 showed no measurable effect on mitochondrial DNA content indicating a low potential for mitochondrial toxicity.

Original languageEnglish (US)
Pages (from-to)1120-1123
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume18
Issue number3
DOIs
StatePublished - Feb 1 2008

Keywords

  • Antiviral
  • HIV
  • Phosphonate
  • Resistance

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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