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

描述（由申请人提供）：我们将应用核磁共振（NMR）波谱和x射线晶体学来研究甲基赤藓糖醇类异戊二烯（MEP）生物合成途径中的酶，该途径在多种病原体中是必需的，在人类中是缺失的。结合MEP靶点的片段的鉴定和生物物理特性将为合理设计用于MEP酶抑制的小分子先导物提供数据。通过迭代合成和结构测定，我们将把这些先导物开发成能够结合各种传染病生物的MEP酶的新化合物。这一努力的成功将导致第二阶段的集中合成和体外/体内效价测试，以证明有效性和推进这些化合物更接近临床。该项目的最终目标是为那些感染了耐药疟疾、结核病和其他微生物感染的人开发新的治疗方法，因为目前还没有批准用于临床使用的MEP途径抑制剂联合疗法

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.