Fragment based inhibitor discovery of the MEP pathway in infectious organisms.

描述(申请人提供)：我们将应用核磁共振波谱和X射线结晶学来研究甲基赤藓糖醇异戊二烯(MEP)生物合成途径中的酶，该途径在多种病原体中是必需的，在人类中是不存在的。与MEP靶标结合的片段的鉴定和生物物理特性将为合理设计MEP酶抑制的小分子先导提供数据。通过迭代合成和结构测定，我们将把这些先导化合物开发成能够结合来自各种传染病生物体的MEP酶的新化合物。这一努力的成功将导致集中合成和体外/体内效力测试的第二阶段提案，以证明有效性并使这些化合物更接近临床。这个项目的最终目标是为那些感染了疟疾、结核病和其他微生物感染的耐药菌株的人开发新的治疗方法，因为目前还没有MEP途径抑制剂的联合疗法被批准用于临床。 公共卫生相关性：该项目建议利用生物物理方法来发现与甲基赤藓糖醇异戊二烯(MEP)生物合成途径中的酶结合的先导化合物。该项目的最终目标是为那些感染了疟疾、结核病和其他微生物感染耐药菌株的人开发新的治疗方法，因为目前还没有MEP途径抑制剂的联合疗法被批准用于临床。

DESCRIPTION (provided by applicant): We will apply nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography to study enzymes from the methyl erythritol isoprenoid (MEP) biosynthetic pathway, which is essential in multiple pathogens and absent in humans. Identification and biophysical characterization of fragments which bind to MEP targets will generate data for the rational design of small molecule leads for MEP enzymatic inhibition. Through iterative synthesis and structure determination, we will develop these leads into novel compounds capable of binding MEP enzymes from a variety of infectious disease organisms. Success in this endeavor would lead to a Phase II proposal for focused synthesis and in vitro/in vivo potency testing to prove efficacy and advance these compounds closer to the clinic. The ultimate goal of this project is the development of novel treatments for those infected with drug-resistant strains of malaria, tuberculosis, and other microbial infections, as there are currently no MEP pathway inhibitor combination therapies approved for clinical usage PUBLIC HEALTH RELEVANCE: This project proposes to utilize biophysical methods to discover lead compounds that bind to enzymes from the methyl erythritol isoprenoid (MEP) biosynthetic pathway. The ultimate goal of this project is the development of novel treatments for those infected with drug-resistant strains of malaria, tuberculosis, and other microbial infections, as there are currently no MEP pathway inhibitor combination therapies approved for clinical usage.