title: Small-molecule APOBEC3G DNA cytosine deaminase inhibitors based on a 4-amino-1,2,4-triazole-3-thiol scaffold.
abstract: 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 (3.9-8.2 μM) 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.
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota - Twin Cities, 717 Delaware Street S.E., Minneapolis, MN 55414, USA.
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Olson
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.forename: Reuben S
authors.initials: RS
authors.lastname: Harris
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Harki
mesh_terms: D001665:Binding Sites; D003564:Cytidine Deaminase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D017354:Point Mutation; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000494:pharmacology; D014230:Triazoles / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D011506:Proteins; D054852:Small Molecule Libraries; D013438:Sulfhydryl Compounds; D014230:Triazoles; C045575:1,2,4-triazole; C121399:APOBEC3A protein, human; D003564:Cytidine Deaminase