Computer-guided drug repurposing: Identification of trypanocidal activity of clofazimine, benidipine and saquinavir
Computer-guided drug repurposing: Identification of trypanocidal activity of clofazimine, benidipine and saquinavir
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DOI：
10.1016/j.ejmech.2015.01.065
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发表时间：
2015-03-26
影响因子：
6.7
通讯作者：
Talevi, Alan
中科院分区：
文献类型：
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作者：
Bellera, Carolina L.;Balcazar, Dario E.;Talevi, Alan
尽管在克氏锥虫生物学知识方面取得了显着进展，但在过去40年中没有批准治疗恰加斯病的药物，近800万人仍然受到感染。由于公共部门和非营利组织在南美锥虫病的研究工作中发挥着重要作用，因此必须实施促进基础研究转化为临床实践的研究战略。最近的国际公私举措涉及药物重新定位的潜力（即发现已知药物的第二或进一步的医疗用途），这可以大大提高临床试验的成功率和制药领域的创新。在这项工作中，我们提出了批准药物氯法齐明的计算机辅助识别，贝尼地平和沙奎那韦作为潜在的杀锥虫化合物，并测试它们在不同寄生虫阶段的生物化学和细胞水平上的作用。根据所获得的结果，我们讨论了生物制药，毒理学和病理生理学标准应用于决定移动氯法齐明和贝尼地平进入临床前阶段，在急性感染模型。这篇文章阐述了计算机引导的药物重新定位整合和优化药物发现和临床前开发的潜力;它还提出了合理的规则，以选择重新定位的候选药物中的哪一个应该进入研究药物状态，并提供了对氯法齐明和贝尼地平作为南美锥虫病候选治疗的新见解。我们提出了三种已批准药物的计算机引导药物重新定位，作为南美锥虫病的潜在新治疗方法，整合了计算机辅助药物筛选和生化，细胞和临床试验。(C)2015年Elsevier Masson SAS。All rights reserved.
In spite of remarkable advances in the knowledge on Trypanosoma cruzi biology, no medications to treat Chagas disease have been approved in the last 40 years and almost 8 million people remain infected. Since the public sector and non-profit organizations play a significant role in the research efforts on Chagas disease, it is important to implement research strategies that promote translation of basic research into the clinical practice. Recent international public-private initiatives address the potential of drug repositioning (i.e. finding second or further medical uses for known-medications) which can substantially improve the success at clinical trials and the innovation in the pharmaceutical field.In this work, we present the computer-aided identification of approved drugs clofazimine, benidipine and saquinavir as potential trypanocidal compounds and test their effects at biochemical as much as cellular level on different parasite stages. According to the obtained results, we discuss biopharmaceutical, toxicological and physiopathological criteria applied to decide to move clofazimine and benidipine into preclinical phase, in an acute model of infection. The article illustrates the potential of computer-guided drug repositioning to integrate and optimize drug discovery and preclinical development; it also proposes rational rules to select which among repositioned candidates should advance to investigational drug status and offers a new insight on clofazimine and benidipine as candidate treatments for Chagas disease.One Sentence Summary: We present the computer-guided drug repositioning of three approved drugs as potential new treatments for Chagas disease, integrating computer-aided drug screening and biochemical, cellular and predinical tests. (C) 2015 Elsevier Masson SAS. All rights reserved.