Structure-Guided Development of Selective TbcatB Inhibitors

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• 作者：Jeremy P. Mallari ; Anang A. Shelat ; Aaron Kosinski ; Conor R. Caffrey ; Michele Connelly ; Fangyi Zhu ; James H. McKerrow ; R. Kiplin Guy
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：October 22, 2009
• 年：2009
• 卷：52
• 期：20
• 页码：6489-6493
• 全文大小：795K
• 年卷期：v.52,no.20(October 22, 2009)
• ISSN：1520-4804

文摘

The trypanosomal cathepsin TbcatB is essential for parasite survival and is an attractive therapeutic target. Herein we report the structure-guided development of TbcatB inhibitors with specificity relative to rhodesain and human cathepsins B and L. Inhibitors were tested for enzymatic activity, trypanocidal activity, and general cytotoxicity. These data chemically validate TbcatB as a drug target and demonstrate that it is possible to potently and selectively inhibit TbcatB relative to trypanosomal and human homologues.