Molecular design, chemical synthesis and structural characterisation of novel peptides and peptidomimetics

衍生自天然来源的肽是用于开发治疗剂的有用的先导化合物。天然存在的肽的结构多样性涵盖了位于更传统的小分子（<500道尔顿）和生物制剂（通常是蛋白质）之间的大部分化学空间。肽通常对其靶标具有优异的选择性和结合亲和力。然而，它们具有物理化学问题，限制了它们作为药物的发展。这些包括由于蛋白水解降解导致的血浆稳定性差和由于它们固有的极性而不能穿过膜结构导致的有限的生物利用度。Jamieson集团正在进行的研究计划（Chem. Sci.，2019，10，1671）专注于开发新的拟肽化学物质，可用于克服肽的物理化学限制并促进肽药物的发现。这是通过化学修饰肽结构来实现的;去除脆弱的功能并引入化学模拟结构以保留肽的整体三维结构。假设：该项目的中心假设是研究合成模拟物是否可以用来取代芋螺毒素肽中发现的二硫键和复杂的二硫键网络，并产生更稳定的类似物，天然肽可用于探测与其蛋白质配偶体的分子识别的性质。具体目标：i）芋螺毒素肽和肽模拟物的自动化固相合成。ii）利用NMR光谱来解析这些芋螺毒素模拟物的3D NMR结构，并且这些使用该信息来开发结构-活性-关系。iii）建立模拟物的生物活性，并且重要的是，研究模拟物的受体亚型选择性。

Peptides derived from natural sources are useful lead compounds to develop therapeutics. The structural diversity of naturally occurring peptides covers a large section of chemical space that sits between more traditional small molecules (<500 daltons) and biologics (typically proteins). Peptides typically have excellent selectivity and binding affinity for their targets. However, they have physicochemical issues that limit their development as drugs. These include poor blood plasma stability due to proteolytic degradation and limited bioavailability because they are unable to cross membrane structures, due to their inherent polarity. The Jamieson Group's ongoing research program (Chem. Sci., 2019, 10, 1671) is focused on the development of new peptidomimetic chemistries that can be used to overcome the physicochemical limitations of peptides and facilitate peptide drug discovery. This is achieved by chemically modifying the peptide structure; removing the vulnerable functionality and introducing chemical mimic structures to retain the overall 3-dimensional structure of the peptide.Hypothesis: The central hypothesis of this project is to investigate whether synthetic mimics can be used to replace the disulfide bonds and complex disulfide bond networks found in conotoxin peptides and produce more stable analogues that retain the activity of the native peptides and can be used to probe the nature of molecular recognition with their protein partners. Specific objectives:i) Automated solid phase synthesis of conotoxin peptides and peptidomimetics.ii) Utilise NMR spectroscopy to solve the 3D NMR structure of these conotoxin mimetics and these use this information to develop a structure-activity-relationship.iii) Establish the bioactivity of the mimetics and importantly, investigate the receptor subtype selectivity of the mimetics.