抗病毒药物利巴韦林是克氏锥虫S-腺苷-L-高半胱氨酸水解酶的选择性抑制剂。
The antiviral drug ribavirin is a selective inhibitor of S-adenosyl-L-homocysteine hydrolase from Trypanosoma cruzi.
作者信息
Cai Sumin, Li Qing-Shan, Borchardt Ronald T, Kuczera Krzysztof, Schowen Richard L
机构信息
Department of Molecular Biosciences, The University of Kansas, Lawrence, KS 66045, USA.
出版信息
Bioorg Med Chem. 2007 Dec 1;15(23):7281-7. doi: 10.1016/j.bmc.2007.08.029. Epub 2007 Aug 24.
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.
摘要
利巴韦林（1,2,4-三唑-3-羧酰胺核糖苷）是一种著名的抗病毒药物。据报道，利巴韦林还能抑制人S-腺苷-L-高半胱氨酸水解酶（Hs-SAHH），该酶催化S-腺苷-L-高半胱氨酸转化为腺苷和高半胱氨酸。我们现在报道，结构与腺苷相似的利巴韦林会导致Hs-SAHH和克鲁斯锥虫SAHH（Tc-SAHH）发生时间依赖性失活。利巴韦林与两种SAHH的腺苷结合位点结合，并将NAD(+)辅因子还原为NADH。利巴韦林与Hs-SAHH和Tc-SAHH的可逆结合步骤具有相似的K(I)值（分别为266和194 microM），但Tc-SAHH的缓慢失活步骤快5倍。利巴韦林可为设计更具选择性的Tc-SAHH抑制剂作为潜在抗寄生虫药物提供结构线索。
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