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
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Research Support, N.I.H., Extramural
MeSH terms
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Drug Design
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Enzyme Activation / drug effects
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / pharmacology*
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Guanosine Triphosphate / pharmacology
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Monomeric GTP-Binding Proteins / antagonists & inhibitors*
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Monomeric GTP-Binding Proteins / chemistry
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SAM Domain and HD Domain-Containing Protein 1
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Small Molecule Libraries
Substances
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Enzyme Inhibitors
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Small Molecule Libraries
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Guanosine Triphosphate
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SAM Domain and HD Domain-Containing Protein 1
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SAMHD1 protein, human
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Monomeric GTP-Binding Proteins