Beyond Making Thiazolines and Oxazolines: Expanding the Enzymatic Repertoire to incorporate other 5- and 6-membered heterocyclic rings in peptides

超越制造噻唑啉和恶唑啉：扩展酶库以将其他 5 元和 6 元杂环纳入肽中

• 批准号: 2466630
• 金额: --
• 依托单位: University of Aberdeen
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2466630
• 关键词: Beyond; Making; Thiazolines; Oxazolines; Expanding

his project aims at developing a novel, efficient and eco-friendly enzymatic approach to incorporate a range of heterocyclic rings in cyclic peptides at a commercially viable cost. These modifications will: 1) improve activity, receptor binding affinity and selectivity by stabilizing the peptide secondary structure; 2) enhance the stability against metabolic and digestive enzymes thus improve oral bioavailability and 3) improve cellular permeability by decreasing the number of hydrogen bond donors (HBDs). We previously reported the use of enzymes to incorporate thiazolines and oxazolines in cyclic peptides by dehydrative cyclization of cysteine, serine and threonine. These enzymes were derived from the biosynthetic pathways of the ribosomally synthesized and posttranslationally modified peptides (RiPPs) in which a precursor peptide is ribosomally-synthesised and tailored by a set of processing enzymes to give the modified cyclic peptide. The precursor peptide contains a sequence recognised by the heterocyclase called "leader", typically followed by a protease cleavage signal and the sequence to be processed to a final product (the core peptide). The distant separation of the recognition and processing sites makes these enzymes highly tolerant to variations in substrate sequence and appealing for biotechnological applications. We have studied the structure and mechanism of some of these enzymes and engineered an enzyme which is fused with its substrate recognition sequence so it can process stand-alone core sequences. We aim to apply our expertise to add new enzymes to our toolbox and to explore the chemical flexibility of the nucleophilic side chain to enable the incorporation of other 5 and 6 membered heterocycles in cyclic peptides.

他的项目旨在开发一种新颖，高效且环保的酶促方法，以将一系列的杂环环以市值可行的成本融合到环状肽中。这些修饰将：1）通过稳定肽二级结构来改善活性，受体结合亲和力和选择性； 2）从而提高对代谢和消化酶的稳定性，从而改善了口服生物利用度，3）通过减少氢键供体（HBD）的数量来改善细胞渗透性。我们先前报道了使用酶通过半胱氨酸，丝氨酸和苏氨酸的脱水环化在环状肽中掺入噻唑啉和恶作剂。这些酶源自核糖体合成和翻译后修饰的肽（RIPP）的生物合成途径，其中前体肽是核糖体合成的，并由一组加工酶量身定制的酶，以使酶获得修饰的环状肽。前体肽包含由称为“ Leader”的杂环识别的序列，通常是蛋白酶裂解信号和要处理到​​最终产物（核心肽）的序列。识别和加工位点的遥远分离使这些酶高度耐受底物序列的变化，并吸引了对生物技术应用的吸引力。我们已经研究了其中一些酶的结构和机制，并设计了一种与其底物识别序列融合的酶，因此它可以处理独立的核心序列。我们旨在应用我们的专业知识，以在我们的工具箱中添加新酶，并探索亲核侧链的化学柔韧性，以使其他5和6个成员的杂环在环状肽中掺入。