Small molecule inhibition of SAMHD1 dNTPase by tetramer destabilization

J Am Chem Soc. 2014 Jul 16;136(28):9822-5. doi: 10.1021/ja5035717. Epub 2014 Jul 8.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Drug Design
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • Guanosine Triphosphate / pharmacology
  • Monomeric GTP-Binding Proteins / antagonists & inhibitors*
  • Monomeric GTP-Binding Proteins / chemistry
  • SAM Domain and HD Domain-Containing Protein 1
  • Small Molecule Libraries

Substances

  • Enzyme Inhibitors
  • Small Molecule Libraries
  • Guanosine Triphosphate
  • SAM Domain and HD Domain-Containing Protein 1
  • SAMHD1 protein, human
  • Monomeric GTP-Binding Proteins