Kraus James M, Verlinde Christophe L M J, Karimi Mandana, Lepesheva Galina I, Gelb Michael H, Buckner Frederick S
Department of Chemistry, University of Washington, Seattle, Washington 98195-7185, USA.
J Med Chem. 2009 Mar 26;52(6):1639-47. doi: 10.1021/jm801313t.
Chagas disease is one of the major neglected diseases of the world. Existing drug therapies are limited, ineffective, and highly toxic. We describe a novel strategy of drug discovery of adapting an existing clinical compound with excellent pharmaceutical properties to target a pathogenic organism. The protein farnesyltransferase (PFT) inhibitor tipifarnib, now in phase III anticancer clinical trials, was previously found to kill Trypanosoma cruzi by blocking sterol 14 alpha-demethylase (14DM). We rationally developed tipifarnib analogues that display reduced affinity for human PFT to reduce toxicity while increasing affinity for parasite 14DM. The lead compound has picomolar activity against cultured T. cruzi and is efficacious in a mouse model of acute Chagas disease.
恰加斯病是世界上主要的被忽视疾病之一。现有的药物疗法有限、无效且毒性很高。我们描述了一种药物发现的新策略，即采用一种具有优异药学特性的现有临床化合物来靶向致病生物体。蛋白法尼基转移酶（PFT）抑制剂替匹法尼布目前正处于抗癌三期临床试验阶段，此前发现它可通过阻断甾醇14α-脱甲基酶（14DM）杀死克氏锥虫。我们合理开发了替匹法尼布类似物，这些类似物对人PFT的亲和力降低，以降低毒性，同时增加对寄生虫14DM的亲和力。先导化合物对培养的克氏锥虫具有皮摩尔活性，并且在急性恰加斯病小鼠模型中有效。
