Small molecule inhibition of SAMHD1 dNTPase by tetramer destabilization

Kyle J. Seamon, Erik C. Hansen, Anastasia P. Kadina, Boris A. Kashemirov, Charles E. McKenna, Namandjé N. Bumpus, James T. Stivers

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)9822-9825
Number of pages4
JournalJournal of the American Chemical Society
Issue number28
StatePublished - Jul 16 2014

ASJC Scopus subject areas

  • Catalysis
  • General Chemistry
  • Biochemistry
  • Colloid and Surface Chemistry


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