title: Small molecule inhibition of SAMHD1 dNTPase by tetramer destabilization.
abstract: SAMHD1 is a GTP-activated nonspecific dNTP triphosphohydrolase that depletes dNTP pools in resting CD4+ T cells and macrophages and effectively restricts infection by HIV-1. We have designed a nonsubstrate dUTP analogue with a methylene bridge connecting the α phosphate and 5' carbon that potently inhibits SAMHD1. Although pppCH2dU shows apparent competitive inhibition, it acts by a surprising allosteric mechanism that destabilizes active enzyme tetramer.
authors.affiliation: Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine , 725 North Wolfe Street, Baltimore, Maryland 21205-2185, United States.
authors.forename: Kyle J
authors.initials: KJ
authors.lastname: Seamon
authors.forename: Erik C
authors.initials: EC
authors.lastname: Hansen
authors.forename: Anastasia P
authors.initials: AP
authors.lastname: Kadina
authors.forename: Boris A
authors.initials: BA
authors.lastname: Kashemirov
authors.forename: Charles E
authors.initials: CE
authors.lastname: McKenna
authors.forename: Namandjé N
authors.initials: NN
authors.lastname: Bumpus
authors.forename: James T
authors.initials: JT
authors.lastname: Stivers
mesh_terms: D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006160:Guanosine Triphosphate / Q000494:pharmacology; D020559:Monomeric GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000076106:SAM Domain and HD Domain-Containing Protein 1; D054852:Small Molecule Libraries
chemical_list: D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D006160:Guanosine Triphosphate; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D020559:Monomeric GTP-Binding Proteins