Abstract
Ribavirin (1,2,4-triazole-3-carboxamide riboside) is a well-known antiviral drug. Ribavirin has also been reported to inhibit human S-adenosyl-L-homocysteine hydrolase (Hs-SAHH), which catalyzes the conversion of S-adenosyl-L-homocysteine to adenosine and homocysteine. We now report that ribavirin, which is structurally similar to adenosine, produces time-dependent inactivation of Hs-SAHH and Trypanosoma cruzi SAHH (Tc-SAHH). Ribavirin binds to the adenosine-binding site of the two SAHHs and reduces the NAD(+) cofactor to NADH. The reversible binding step of ribavirin to Hs-SAHH and Tc-SAHH has similar K(I) values (266 and 194 microM), but the slow inactivation step is 5-fold faster with Tc-SAHH. Ribavirin may provide a structural lead for design of more selective inhibitors of Tc-SAHH as potential anti-parasitic drugs.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adenosylhomocysteinase / antagonists & inhibitors*
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Adenosylhomocysteinase / biosynthesis
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Adenosylhomocysteinase / isolation & purification
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Animals
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Antiviral Agents / chemical synthesis
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Antiviral Agents / chemistry
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Antiviral Agents / pharmacology*
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Binding Sites
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Chromatography, High Pressure Liquid / methods
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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 / chemistry
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Enzyme Inhibitors / pharmacology*
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Humans
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Kinetics
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Molecular Conformation
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NAD / chemistry
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NAD / drug effects
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Recombinant Proteins / antagonists & inhibitors
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Recombinant Proteins / biosynthesis
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Recombinant Proteins / isolation & purification
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Ribavirin / chemical synthesis
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Ribavirin / chemistry
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Ribavirin / pharmacology*
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Spectrometry, Mass, Electrospray Ionization / methods
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Structure-Activity Relationship
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Time Factors
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Trypanosoma cruzi / enzymology*
Substances
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Antiviral Agents
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Enzyme Inhibitors
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Recombinant Proteins
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NAD
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Ribavirin
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Adenosylhomocysteinase