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Antiviral drug ribavirin is a selective inhibitor of S‐adenosyl‐L‐homocysteine hydrolase from Trypanosoma cruzi
Author(s) -
Cai Sumin,
Li QingShan,
Schowen Richard L.,
Kuczera Krzysztof,
Borchardt Ronald T.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a896-a
Subject(s) - trypanosoma cruzi , ribavirin , enzyme , biochemistry , hydrolase , chemistry , biology , parasite hosting , world wide web , computer science , genotype , gene
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 ( AdoHcy) hydrolase. This enzyme catalyzes the conversion of AdoHcy to adenosine and Hcy. In this study, we report that ribavirin, which is structurally similar to adenosine, produces time‐dependent inactivation of the human and Trypanosoma cruzi AdoHcy hydrolases. Ribavirin inactivates the parasite enzyme approx. 5 times faster than the human enzyme. Fluorescence experiments indicate that ribavirin binds to the adenosine‐binding site of AdoHcy hydrolase and reduces the NAD + cofactor to NADH. Kinetic experiments showed that the human and parasite enzymes have similar affinities for ribaviran. Docking simulations with the MOE program predicted that ribavirin should bind to both the human and parasite enzymes. These results indicate that ribavirin is a promising structural lead for design of even more selective inhibitors of Trypanosoma cruzi AdoHcy hydrolase as potential anti‐parasitic drugs. This work was supported by a grant from the National Institutes of Health (GM‐29332).