title: The antiviral drug ribavirin is a selective inhibitor of S-adenosyl-L-homocysteine hydrolase from Trypanosoma cruzi.
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.
authors.affiliation: Department of Molecular Biosciences, The University of Kansas, Lawrence, KS 66045, USA.
authors.forename: Sumin
authors.initials: S
authors.lastname: Cai
authors.forename: Qing-Shan
authors.initials: QS
authors.lastname: Li
authors.forename: Ronald T
authors.initials: RT
authors.lastname: Borchardt
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Kuczera
authors.forename: Richard L
authors.initials: RL
authors.lastname: Schowen
mesh_terms: D043383:Adenosylhomocysteinase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000302:isolation & purification; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008968:Molecular Conformation; D009243:NAD / Q000737:chemistry / Q000187:drug effects; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000302:isolation & purification; D012254:Ribavirin / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D013329:Structure-Activity Relationship; D013997:Time Factors; D014349:Trypanosoma cruzi / Q000201:enzymology*
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D009243:NAD; D012254:Ribavirin; D043383:Adenosylhomocysteinase