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.

项目摘要/摘要 该提案总结了我们的实验室正在进行的项目，重点是自然产品类别 具有有希望的生物学活动 治疗潜力。这些课程在结构上很复杂，其修改受到挑战 半合成和生物合成方法。我们旨在从简单的 构建块，使化学修改能够克服其局限性。这些努力是由 每个类的绑定数据（X射线或冷冻EM）。本文概述的项目的主要目标是1）扩展 这些重要类别的分子的结构 - 功能关系，2）发现潜在的类似物 适用于命中率优化或用作研究生物系统的工具。此外， 合成路线本身的开发具有很高的创新性，并且经常伴随着发展 广泛适用于化学的方法。这些努力反映了我们在链链球菌素上的工作和 Lankacidin抗生素是我们早期研究员Mira（R35GM128656）的主要重点，并LED 结构性重新分配，并具有对体内抗性菌株的活性的潜在命中化合物。 这项工作的大部分生物学将通过协作启用。本文总结的五个项目 专注于靶向核糖体和膜蛋白的新型抗生素的发展。由于我们 在这一领域正在进行的工作，我们进行了几次合作来评估抗菌活性，体内 功效和新类似物的目标参与。除了抗生素之外，我们建议合成和衍生 靶向HSP90的类，抗癌靶标，EEF1A（抗癌和抗病毒靶标）。评估 这些用于抑制活性，同工型选择性和绑定的化合物将由新的合作启用， 扩大我们的研究范围。通过化学创新与强有力的生物学研究，我们 预计此处概述的工作将导致化学合成和发现的令人兴奋的发现 用于治疗细菌感染，癌症和SARS-COV-2的命中化合物的。