Biosynthesis of the Leinamycin Family of Natural Products: Mechanistic Studies and Chemoenzymatic Analog Synthesis

莱纳霉素家族天然产物的生物合成：机理研究和化学酶法类似物合成

• 批准号: 9761034
• 负责人: Andrew Steele
• 金额: $ 6.12万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-16 至 2022-05-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761034
• 关键词: Acyl Carrier Protein; Address; Alkylating Agents; Anabolism; Area; Biochemical; Biochemistry; Biological; Biological Assay; Biological Testing; Breathing; Cancer Remission; Cells; Chemicals; Clinical; Clinical Treatment; Collaborations; Cysteine; DNA; DNA Alkylation; DNA Damage; Development; Diagnosis; Disease; Drug Utilization; Engineering; Enzymatic Biochemistry; Family; Financial Hardship; Future; Goals; Growth; Hydrolysis; In Vitro; Investigation; Ions; Knowledge; Lead; Learning; Letters; Life; Lyase; Malignant Neoplasms; Methylation; Modernization; Molecular Biology; Natural Products; Nature; Organism; Outcome; Parents; Pathway interactions; Pharmaceutical Preparations; Process; Production; Property; Proteins; Reaction; Reactive Oxygen Species; Resistance; Resistance development; Site; Societies; Streptomyces; Structure; Sulfhydryl Compounds; Sulfur; Therapeutic; Time; Work; analog; anti-cancer; anticancer activity; cancer cell; cancer therapy; chemical synthesis; chemotherapy; combinatorial; design; experimental study; improved; leinamycin; nanomolar; neoplastic cell; novel; professor; scaffold; side effect; stereochemistry; synthetic biology; training opportunity; tumor; tumor progression

PROJECT SUMMARY/ABSTRACT Chemotherapy has been the centerpiece of cancer treatment in modern society, and will remain so for the foreseeable future. DNA-damaging compounds have seen the most use historically in this regard, due to cancer cells’ increased rates of growth and proliferation relative to normal, healthy cells. However, these treatments often cause off-target effects and resistance development. Therefore, compounds that can damage cancer cell DNA in a selective fashion and with a mechanism complementary to current clinical treatments offer solutions to both of these issues. The natural product leinamycin (LNM) is a DNA-damaging compound that only elicits its DNA-damaging effects upon activation by thiols, and has nanomolar activity against tumor cells resistant to clinically utilized drugs. LNM E1 is an engineered LNM analog that upon activation by reactive oxygen species (ROS) exerts its antitumor activity via a mechanism orthogonal to LNM. A single scaffold that can be primed for DNA damage in two complementary ways is unique to this set of compounds, and sets the stage for further optimization of the LNM scaffold in terms of anticancer activity. The biosynthetic origin of LNM in Streptomyces has been an area of intense study, and many of the biosynthetic steps have been elucidated and led to discoveries involving unprecedented chemical steps. The long-term goals of this project are to harness the power of a mechanistic understanding of LNM biosynthesis to genetically alter producing organisms for production of analogs with improved therapeutic properties. This proposal contains two aims: (i) investigate the mechanism of a key biosynthetic step and (ii) access rationally-designed analogs of both LNM and LNM E1 to answer specific questions about the compounds’ biological activities. The central hypothesis of this proposal is that LNM compounds can be tuned and improved in both stability and potency through rational design. This hypothesis is rationalized by Nature’s ability to produce an array of LNM-type compounds, which have served as the inspiration for the structural changes proposed herein. The outcomes of this application will be a mechanistic understanding of one of the key steps of LNM biosynthesis and access to novel LNM analogs that can be used to answer key questions about LNM DNA-damaging and anticancer activity. These findings can be applied to the long-term goal of rational biosynthetic manipulation to produce targeted structural LNM analogs for further anticancer development.

项目摘要/摘要 化学疗法一直是现代社会癌症治疗的核心，并且将继续如此 可预见的未来。在这方面，DNA受损的化合物在历史上的使用率最多，因为 癌细胞相对于正常的健康细胞的生长和增殖率提高。但是，这些 治疗通常会导致靶向效果和抗性发展。因此，会损害的化合物 癌细胞DNA以选择性的方式，并具有当前临床治疗的机制完整性 为这两个问题提供解决方案。天然产物莱南霉素（LNM）是DNA损害化合物 这只会引起其对硫醇激活的DNA破坏作用，并且具有纳莫尔活性对肿瘤 细胞可抵抗临床使用的药物。 LNM E1是一种工程的LNM类似物，通过反应性激活后 氧（ROS）通过与LNM正交机制导出其抗肿瘤活性。一个脚手架 可以通过两种完整的方式对DNA损伤进行启动，这是这组化合物的独特之处，并设置 在抗癌活性方面进一步优化LNM支架的阶段。 LNM的生物合成起源 在链霉菌中，已经是一项激烈研究的领域，许多生物合成步骤已经阐明 并导致了涉及前所未有的化学步骤的发现。该项目的长期目标是 利用对LNM生物合成的机械理解的力量来改变生产 生产具有改善治疗特性的类似物的生物。该建议包含两个目的：（i） 研究两个LNM的关键生物合成步骤和（ii）访问合理设计的类似物的机制 和LNM E1回答有关化合物生物学活动的具体问题。中心假设 该建议是，LNM化合物可以通过理性调整和改善稳定性和效力 设计。这一假设是由大自然产生一系列LNM型化合物的能力合理化的，该化合物的能力 已成为此处提出的结构变化的灵感。此应用程序的结果将 成为对LNM生物合成的关键步骤之一的机械理解，并获得新的LNM类似物 可以用来回答有关LNM DNA破坏和抗癌活性的关键问题。这些发现 可以应用于有理生物合成操作以产生有针对性的结构LNM的长期目标 用于进一步抗癌的类似物。