Modular synthesis of antibiotic and anticancer classes of natural products

项目摘要/摘要 这份提案总结了我们实验室正在进行的专注于天然产品类别的项目 有希望的生物活性，但背负着限制，使他们无法达到他们的 治疗潜力。这些类在结构上很复杂，而且修改它们的 半合成和生物合成方法。我们的目标是开发完全合成的路线，从简单的 构建块，使化学修饰能够克服它们的限制。这些努力的依据是 每个类别的绑定数据(X射线或冷冻-EM)。在此概述项目的主要目标是1)扩展 每一类重要分子的结构-功能关系，以及2)发现有效的类似物 适合于从点击到领先的优化或用作研究生物系统的工具。另外， 合成路线本身的发展是高度创新的，而且往往伴随着发展 在化学中广泛适用的方法。这些努力反映了我们对链球菌素和 兰卡西丁抗生素，这是我们早期研究人员Mira(R35GM128656)的主要关注点，并领导 到结构重新分配，到体内具有抗耐药菌株活性的有效化合物。 这项工作的大部分生物学工作将通过合作来实现。本文总结的五个项目 专注于开发针对核糖体和膜蛋白的新型抗生素。由于我们的 在这一领域正在进行的工作，我们有几个合作到位，以评估体内的抗菌活性 功效，以及新类似物的目标参与度。除了抗生素，我们还建议合成和衍生化 针对Hsp90(抗癌目标)和eEF1A(抗癌和抗病毒目标)的类。评估 这些用于抑制活性、异构体选择性和结合的化合物将通过新的合作而成为可能， 扩大我们的研究范围。随着化学创新和强有力的生物研究的结合，我们 预计这里概述的工作将导致在化学合成方面的令人兴奋的发现和这一发现 用于治疗细菌感染、癌症和SARS-CoV-2的Hit化合物。

Project Summary/Abstract This proposal summarizes ongoing projects in our laboratory focused on natural product classes that have promising biological activity but are burdened with limitations that have prevented them from reaching their therapeutic potential. These classes are structurally complex and modification of their is challenging by semisynthetic and biosynthetic methods. We aim to develop fully synthetic routes to these classes from simple building blocks, enabling chemical modification to overcome their limitations. These efforts are informed by binding data (X-ray or cryo-EM) for each class. The primary goals of project outlined herein are to 1) expand structure–function relationships for each of these important classes of molecules, and 2) discover potent analogs that are suitable for hit-to-lead optimization or for use as tools to study biological systems. Additionally, development of the synthetic routes themselves is highly innovative, and is often accompanied by development of methods that are broadly applicable in chemistry. These efforts mirror our work on streptogramin and lankacidin antibiotics, which was a primary focus in our Early Stage Investigator MIRA (R35GM128656), and led to structural reassignments and to a potent hit compound with activity against resistant strains in vivo. Much of the biology for this work will be enabled by collaboration. Five of the projects summarized herein focus on the development of novel antibiotics that target the ribosome and membrane proteins. Due to our ongoing work in this area, we have several collaborations in place to evaluate the antimicrobial activity, in vivo efficacy, and target engagement of new analogs. Beyond antibiotics, we propose to synthesize and derivatize classes that target Hsp90, an anticancer target, and eEF1A, an anticancer and antiviral target. Evaluation of these compounds for inhibitory activity, isoform selectivity, and binding will be enabled by new collaborations, expanding the scope of our research. With chemical innovation paired with strong biological investigation, we anticipate that the work outlined herein will lead to exciting discoveries in chemical synthesis and to the discovery of hit compounds for the treatment of bacterial infections, cancer, and SARS-CoV-2.