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Updated: Apr 27, 2026

A High-Throughput Enzyme-Coupled Activity Assay to Probe Small Molecule Interaction with the dNTPase SAMHD1
Published on: April 16, 2021
Small molecule inhibition of SAMHD1 dNTPase by tetramer destabilization
Kyle J Seamon1, Erik C Hansen, Anastasia P Kadina
1Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine , 725 North Wolfe Street, Baltimore, Maryland 21205-2185, United States.
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.
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