Discovery of Oxaboroles as New Antimalarial Agents

描述（由申请人提供）：非常需要治疗疟疾的新药。该计划旨在开发新的含硼小分子作为抗疟疾药物。我们的初步结果表明，新型含硼小分子（氧杂硼杂环戊烯）具有有效的抗疟活性，重要的是，可能符合新药的标准药代动力学和安全性标准，也符合抗疟药的独特要求。我们假设，一个系统的药物发现计划将确定优化的oxaboroles是相对简单的生产，并满足新的抗疟药的既定标准。此外，我们将采用系统的方法来确定一种特定的抗疟药物， 氧杂硼杂环戊烯的作用机制。对作用机制的理解将有助于药物优化和对耐药性的理解。具体来说，我们将测试假设 抗疟疾氧杂硼杂环戊烯抑制疟原虫亮氨酰tRNA合成酶（LeuRS）。该假设基于其他氧杂硼杂环戊烯对真菌或细菌LeuRS的特异性活性。此外，我们还将评估耐药机制。我们的计划将需要硼化学领域的世界领导者Anacor与加州大学旧金山分校弗朗西斯科的一个疟疾研究小组之间的持续合作，该研究小组在抗疟药物发现方面拥有近二十年的经验。我们计划的具体目标是1）发现氧杂硼杂环戊烯抗疟药，2）优化氧杂硼杂环戊烯抗疟药，3）表征氧杂硼杂环戊烯铅的作用机制和耐药性。我们预计，在该项目的时间范围内，我们将确定一种候选的氧硼杂环戊烯抗疟药用于开发，我们将获得对这些化合物的抗疟作用机制的重要见解。

DESCRIPTION (provided by applicant): New drugs for malaria are greatly needed. This program is directed toward the development of new boron-containing small molecules as antimalarial drugs. Our preliminary results suggest that novel boron-containing small molecules (oxaboroles) have potent antimalarial activity and, importantly, are likely to meet standard pharmacokinetic and safety criteria for new drugs and also the unique requirements for antimalarials. We hypothesize that a systematic drug discovery program will identify optimized oxaboroles that are relatively simple to produce and meet established criteria for new antimalarial agents. Further, we will use a systematic approach to identify a specific antimalarial mechanism of action for oxaboroles. Appreciation of the mechanism of action will aid in drug optimization and in the understanding of drug resistance. Specifically, we will test the hypothesis that antimalarial oxaboroles inhibit a plasmodial leucyl tRNA synthetase (LeuRS). This hypothesis is based on specific activity of other oxaboroles against fungal or bacterial LeuRS. In addition, we will assess mechanisms of resistance. Our program will entail continued collaboration between Anacor, the world leader in boron chemistry and a malaria research group at the University of California, San Francisco with nearly two decades experience in antimalarial drug discovery. Specific aims of our program will be 1) hit-to-lead discovery of oxaborole antimalarials, 2) lead optimization of oxaborole antimalarials, and 3) characterization of the mechanisms of action and resistance for lead oxaboroles. We anticipate that, within the time-frame of this project, we will identify a candidate oxaborole antimalarial for development and that we will gain important insights into the antimalarial mechanisms of action of these compounds.