1. Small Molecule Inhibition of SAMHD1 dNTPase by Tetramer Destabilization
- Author
-
Namandjé N. Bumpus, Kyle J. Seamon, Anastasia P. Kadina, James T. Stivers, Erik C Hansen, Boris A. Kashemirov, and Charles E. McKenna
- Subjects
Stereochemistry ,Allosteric regulation ,Methylene bridge ,01 natural sciences ,Biochemistry ,Catalysis ,SAM Domain and HD Domain-Containing Protein 1 ,Small Molecule Libraries ,03 medical and health sciences ,chemistry.chemical_compound ,Colloid and Surface Chemistry ,Non-competitive inhibition ,Tetramer ,Enzyme Inhibitors ,Monomeric GTP-Binding Proteins ,030304 developmental biology ,0303 health sciences ,010405 organic chemistry ,Chemistry ,Communication ,General Chemistry ,Phosphate ,Small molecule ,3. Good health ,0104 chemical sciences ,Enzyme Activation ,Drug Design ,Biophysics ,Guanosine Triphosphate ,Active enzyme ,SAMHD1 - 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.
- Published
- 2014