Chemical synthesis and biological evaluation of conotoxin peptides

天然多肽是开发治疗药物的有用先导化合物。天然多肽的结构多样性覆盖了传统小分子（<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。多肽通常对其靶标具有极好的选择性和结合亲和力。然而，它们有物理化学问题，限制了它们作为药物的发展。其中包括由于蛋白质水解降解导致血浆稳定性差，以及由于其固有极性而无法穿过膜结构而限制生物利用度。贾米森集团正在进行的研究项目(化学。科学。（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，促进肽药物的发现。这是通过化学修饰肽结构实现的；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。利用这些合成分子，我们正在研究conotoxins和烟碱乙酰胆碱受体（nAChR）之间分子识别的性质。

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. Using these synthetic molecules we are investigating the nature of molecular recognition between conotoxins and the nicotinic acetylcholine receptor (nAChR).