Designing HTA therapy for drug resistant malaria

描述(申请人提供)：最近，在阐明氯喹抗性的遗传学和生物化学以及氯喹与其主要靶标--未结晶血红素之间的原子水平相互作用方面取得了重大进展。在前者，Wellems实验室取得的突破性进展已经扩展到我们的实验室以及其他在短时间内产生大量数据的实验室进行的一系列详细研究。在后者中，该联盟的成员最近在使用新的溶液核磁共振方法以及尖端的固体核磁共振方法定义喹啉-血红素相互作用的物理化学方面取得了重大进展。在集体分析这些数据时，有助于设计喹啉和吖啶类抗疟疾药物的新概念(以前未被认识)变得显而易见。利用这些，同时保持在抗疟疾药物成本限制内，还需要在合成化学方面取得重大进展，包括开发高度化学和区域选择性的交叉偶联反应。在过去的18个月里，我们在合成血红素靶向抗疟疾(HTA)药效团方面取得了重大进展。我们在这方面的讨论和合作已经发展成为研究人员Roepe博士和De Dios博士的实验室之间高度协同的药物发现活动。我们将结合我们团队中独特的遗传、生化、物理化学和合成化学专业知识来设计、合成和解决HTA新药的药物靶标结构。利用我们联合体中存在的独特的药物筛选能力，我们将分析这些大型库中的抗疟疾活性，包括单独和联合使用。我们的长期目标是确定治疗抗药性疟疾的新的、廉价的、有效的治疗方法。

DESCRIPTION (provided by applicant): Recently, major advances have been made in elucidating both the genetics and biochemistry of chloroquine resistance as well as in elucidating the atomic level interactions between chloroquine and its principle target, uncrystallized heme. In the former, groundbreaking advances by the Wellems lab have expanded into a series of detailed studies conducted in our laboratories, as well as by others that have generated enormous data in a short period of time. In the later, major advances have very recently been made by members of this consortium in defining the physical chemistry of quinoline - heme interactions using both new solution NMR methods as well as cutting edge solid state NMR methods. In collectively analyzing these data new (previously unrecognized) concepts that assist the design of quinoline and acridine based antimalarial drugs become evident. Capitalizing on these, while remaining within antimalarial drug cost limitations, also requires significant advances in synthetic chemistry, including developing highly chemo- and regioselective cross-coupling reactions. Over the past 18 months, we have pioneered major advances in the synthesis of heme-targeted antimalarial (HTA) pharmacophores. Our discussions and collaborations in this regard have developed into highly synergistic drug discovery activities between the laboratories of the investigator, Dr. Roepe, and Dr. de Dios. We will combine the unique genetic, biochemical, physical chemical and synthetic chemistry expertise present among our groups to design, synthesize, and solve drug - target structures for new HTA drugs. Using the unique drug screening capabilities present in our consortium, we will analyze large libraries of these for antimalarial activity, both alone and in combinations. Our long term goal is the identification of novel, inexpensive, efficacious therapy for treating drug resistant malaria.