Desai Prashant V, Patny Akshay, Gut Jiri, Rosenthal Philip J, Tekwani Babu, Srivastava Anuradha, Avery Mitchell
Department of Medicinal Chemistry, School of Pharmacy, P.O. Box 1848, University of Mississippi, University, Mississippi 38677-1848, USA.
J Med Chem. 2006 Mar 9;49(5):1576-84. doi: 10.1021/jm0505765.
The incidence of parasitic infections such as malaria, leishmaniasis, and trypanosomiasis has been steadily increasing. Since the existing chemotherapy of these diseases suffers from lack of safe and effective drugs and/or the presence of widespread drug resistance, there is an urgent need for development of potent, mechanism-based antiparasitic agents against these diseases. Cysteine proteases have been established as valid targets for this purpose. The Available Chemical Directory consisting of nearly 355,000 compounds was screened in silico against the homology models of plasmodial cysteine proteases, falcipain-2, and falcipain-3, to identify structurally diverse non-peptide inhibitors. The study led to identification of 22 inhibitors of parasitic cysteine proteases out of which 18 compounds were active against falcipain-2 and falcipain-3. Eight compounds exhibited dual activity against both enzymes. Additionally, four compounds were found to inhibit L. donovani cysteine protease. While one of the cysteine protease inhibitors also exhibited in vitro antiplasmodial activity with an IC50 value of 9.5 microM, others did not show noticeable antiplasmodial activity up to 20 microM. A model identifying important pharmacophoric features common to the structurally diverse falcipain-2 inhibitors has also been developed. Very few potent non-peptide inhibitors of the parasitic cysteine proteases have been reported so far, and identification of these novel and chemically diverse inhibitors should provide leads to be optimized into candidates to treat protozoal infections.
疟疾、利什曼病和锥虫病等寄生虫感染的发病率一直在稳步上升。由于这些疾病现有的化疗方法缺乏安全有效的药物和/或存在广泛的耐药性，因此迫切需要开发针对这些疾病的强效、基于机制的抗寄生虫药物。半胱氨酸蛋白酶已被确定为实现这一目标的有效靶点。利用包含近355,000种化合物的可用化学目录，针对疟原虫半胱氨酸蛋白酶、恶性疟原虫蛋白酶-2和恶性疟原虫蛋白酶-3的同源模型进行了虚拟筛选，以鉴定结构多样的非肽类抑制剂。该研究鉴定出22种寄生虫半胱氨酸蛋白酶抑制剂，其中18种化合物对恶性疟原虫蛋白酶-2和恶性疟原虫蛋白酶-3具有活性。8种化合物对这两种酶均表现出双重活性。此外，发现4种化合物可抑制杜氏利什曼原虫半胱氨酸蛋白酶。虽然其中一种半胱氨酸蛋白酶抑制剂在体外也表现出抗疟活性，IC50值为9.5 microM，但其他抑制剂在高达20 microM时未显示出明显的抗疟活性。还建立了一个模型，用于识别结构多样的恶性疟原虫蛋白酶-2抑制剂共有的重要药效特征。迄今为止，报道的寄生虫半胱氨酸蛋白酶的强效非肽类抑制剂非常少，这些新型且化学结构多样的抑制剂的鉴定应为优化成治疗原生动物感染的候选药物提供线索。
