Modular synthesis of antibiotic and anticancer classes of natural products

抗生素和抗癌类天然产物的模块化合成

• 批准号: 10551666
• 负责人: Ian Bass Seiple
• 金额: $ 42.74万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10551666
• 关键词: 2019-nCoV; Antibiotics; Area; Bacterial Infections; Binding; Biological; Biology; Chemicals; Chemistry; Collaborations; Complex; Cryoelectron Microscopy; Data; Derivation procedure; Development; Evaluation; Goals; Investigation; Laboratories; Malignant Neoplasms; Membrane Proteins; Methodology; Methods; Modification; Natural Products; Property; Protein Isoforms; Research; Research Personnel; Ribosomal Proteins; Roentgen Rays; Route; Streptogramins; Structure-Activity Relationship; Therapeutic; Viral; Work; analog; anti-cancer; antimicrobial; biological systems; chemical synthesis; in vivo; innovation; lead optimization; method development; novel; prevent; resistant strain; scaffold; tool

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.

项目总结/摘要 该提案总结了我们实验室正在进行的项目，重点是天然产品类别， 具有有希望的生物活性，但受到限制，使其无法达到其生物活性。 治疗潜力这些类在结构上很复杂，修改它们是一个挑战， 半合成和生物合成方法。我们的目标是开发这些类的完全合成路线， 构建模块，使化学修饰能够克服它们的局限性。这些努力的信息来自于 结合数据（X射线或冷冻EM）为每个类。本文概述的项目的主要目标是：1）扩大 这些重要类别分子的结构-功能关系，以及2）发现有效的类似物 其适合于命中-引导优化或用作研究生物系统的工具。此外，本发明还 合成路线本身的开发是高度创新的，并且通常伴随着开发 广泛应用于化学的方法。这些努力反映了我们在链阳性菌素方面的工作， lankacidin抗生素，这是我们早期研究者MIRA（R35 GM 128656）的主要焦点，并导致 涉及结构重建和具有体内抗抗性菌株活性的有效命中化合物。 这项工作的大部分生物学将通过合作实现。本文概述的五个项目 专注于开发针对核糖体和膜蛋白的新型抗生素。由于我们 在这一领域正在进行的工作中，我们有几个合作的地方，以评估抗菌活性，在体内 功效和新类似物的靶向接合。除了抗生素，我们还建议合成和衍生 靶向Hsp 90（抗癌靶点）和eEF 1A（抗癌和抗病毒靶点）的类别。评价 这些化合物的抑制活性、异构体选择性和结合将通过新的合作而实现， 扩大我们的研究范围。随着化学创新与强大的生物学研究相结合，我们 我预计，本文概述的工作将导致令人兴奋的发现，在化学合成和发现 用于治疗细菌感染、癌症和SARS-CoV-2的热门化合物。