(Bio)Syntheses of chondramides and related cyclodepsipeptides

软骨酰胺和相关环缩肽的（生物）合成

• 批准号: 187752720
• 负责人: Professor Dr. Uli Kazmaier
• 金额: --
• 依托单位: Helmholtz-Institut für Pharmazeutische Forschung Saarland
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/187752720?language=en
• 关键词: Bio; Syntheses; chondramides; related; cyclodepsipeptides

Myxobacteria produce a wealth of bioactive natural products including cyclic peptides and depsipeptides such as the chondramides and miuraenamides. The chondramides mainly interact with the actin cytoskeleton, but only sporadic experiments have been carried out with the miuraenamides and related peptides, probably because not enough material is available for biological testing. Therefore, our aim is to develop a highly flexible protocol for the synthesis of miuraenamides and related peptides, based on peptide modification. This concept would allow us to generate libraries of similar compounds easily by introducing relevant side chains in the last step of the synthesis. Compound libraries of these cyclic depsipeptides and related compounds shall be screened in various cell-based and in vitro biological assays in order to establish structure-activity relationships. Furthermore, targeted approaches shall be developed and applied to elucidate putative molecular targets and to characterize protein-ligand interactions. A further aim of the project is the production and biological evaluation of novel chondramide variants, which exhibit, based on structural variations, a more cancer cell specific mode of action than the original analogs. In initial studies with novel natural derivatives of this compound class, found in an alternative producer strain during the first funding period, it has already been shown that specific derivatizations of the core structure lead to higher cytotoxicity towards cancer cell lines. Overall, these studies implied a putative cellular target other than actin (off-target), which shall be identified and investigated in further studies. To ensure sufficient supply of test substances synthetic approaches which should be accomplished by biotechnological onsets are planned. To guarantee for a sustainable supply the original chondramide producer strain will be genetically engineered, thereby allowing fermentative production of the novel chondramides plus further derivatives. The targeted manipulation of the biosynthesis gene cluster shall furthermore allow the incorporation of synthesized precursors to enable mutasynthetic onsets to produce desired structural variants. Also the fermentative biotechnological production process will be optimized and adapted to the specific requirements.

粘细菌产生丰富的生物活性天然产物，包括环肽和缩肽，如软骨酰胺和miuraenamides。软骨酰胺主要与肌动蛋白细胞骨架相互作用，但只有零星的实验已经进行了miuraenamides和相关肽，可能是因为没有足够的材料可用于生物测试。因此，我们的目标是开发一个高度灵活的协议的miuraenamides和相关肽的合成，肽修饰的基础上。这一概念将使我们能够通过在合成的最后一步引入相关的侧链来容易地生成类似化合物的文库。这些环状缩酚肽和相关化合物的化合物库应在各种基于细胞的和体外生物测定中进行筛选，以建立结构-活性关系。此外，有针对性的方法应开发和应用，以阐明推定的分子靶点，并表征蛋白质-配体相互作用。该项目的另一个目的是生产和生物学评价新的软骨酰胺变体，其基于结构变异，比原始类似物表现出更具有癌细胞特异性的作用模式。在第一个资助期内在替代生产菌株中发现的该化合物类别的新型天然衍生物的初步研究中，已经表明核心结构的特定衍生化导致对癌细胞系的更高细胞毒性。总的来说，这些研究暗示了除肌动蛋白（脱靶）以外的假定细胞靶点，这将在进一步的研究中进行鉴定和研究。为确保供试品的充足供应，计划采用生物技术合成方法。为了保证可持续的供应，将对原始的软骨酰胺生产菌株进行基因工程改造，从而允许发酵生产新型软骨酰胺和其他衍生物。生物合成基因簇的靶向操作还应允许掺入合成的前体，以使突变合成起始能够产生所需的结构变体。此外，发酵生物技术生产工艺将进行优化，并适应具体要求。