Small-Molecule APOBEC3G DNA Cytosine Deaminase Inhibitors Based on a 4-Amino-1,2,4-triazole-3-thiol Scaffold

Margaret E. Olson, Ming Li, Reuben S. Harris, Daniel A. Harki

Resultado de la investigación: Articlerevisión exhaustiva

31 Citas (Scopus)


APOBEC3G (A3G) is a single-stranded DNA cytosine deaminase that functions in innate immunity against retroviruses and retrotransposons. Although A3G can potently restrict Vif-deficient HIV-1 replication by catalyzing excessive levels of G→A hypermutation, sublethal levels of A3G-catalyzed mutation may contribute to the high level of HIV-1 fitness and its incurable prognosis. To chemically modulate A3G catalytic activity with the goal of decreasing the HIV-1 genomic mutation rate, we synthesized and biochemically evaluated a class of 4-amino-1,2,4-triazole-3-thiol small-molecule inhibitors identified by high-throughput screening. This class of compounds exhibits low-micromolar (3.9-8.2μM) inhibitory potency and remarkable specificity for A3G versus the related cytosine deaminase, APOBEC3A. Chemical modification of inhibitors, A3G mutational screening, and thiol reactivity studies implicate C321, a residue proximal to the active site, as the critical A3G target for this class of molecules.

Idioma originalEnglish (US)
Páginas (desde-hasta)112-117
Número de páginas6
EstadoPublished - ene 2013
Publicado de forma externa

ASJC Scopus subject areas

  • Drug Discovery
  • Molecular Medicine
  • Biochemistry
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Pharmacology
  • Organic Chemistry


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