Chem Rev. 2021 Apr 28;121(8):4531-4560. doi: 10.1021/acs.chemrev.0c01251. Epub 2021 Mar 9.
The pancreatic peptide hormone insulin, first discovered exactly 100 years ago, is essential for glycemic control and is used as a therapeutic for the treatment of type 1 and, increasingly, type 2 diabetes. With a worsening global diabetes epidemic and its significant health budget imposition, there is a great demand for new analogues possessing improved physical and functional properties. However, the chemical synthesis of insulin's intricate 51-amino acid, two-chain, three-disulfide bond structure, together with the poor physicochemical properties of both the individual chains and the hormone itself, has long represented a major challenge to organic chemists. This review provides a timely overview of the past efforts to chemically assemble this fascinating hormone using an array of strategies to enable both correct folding of the two chains and selective formation of disulfide bonds. These methods not only have contributed to general peptide synthesis chemistry and enabled access to the greatly growing numbers of insulin-like and cystine-rich peptides but also, today, enable the production of insulin at the synthetic efficiency levels of recombinant DNA expression methods. They have led to the production of a myriad of novel analogues with optimized structural and functional features and of the feasibility for their industrial manufacture.
胰腺肽激素胰岛素，早在 100 年前就被首次发现，对血糖控制至关重要，被用作治疗 1 型糖尿病的药物，而且越来越多地用于治疗 2 型糖尿病。随着全球糖尿病流行情况的恶化及其对卫生预算的重大影响，人们对具有改善的物理和功能特性的新型类似物有巨大需求。然而，胰岛素复杂的 51 个氨基酸、双链、三硫键结构的化学合成，以及两条链和激素本身的较差理化性质，长期以来一直是有机化学家面临的重大挑战。这篇综述及时概述了过去使用各种策略来化学组装这种迷人激素的努力，这些策略可实现两条链的正确折叠和二硫键的选择性形成。这些方法不仅促进了一般肽合成化学的发展，并使越来越多的胰岛素样和富含半胱氨酸的肽得以获得，而且还使胰岛素能够以重组 DNA 表达方法的合成效率水平进行生产。它们已经产生了具有优化结构和功能特性的无数新型类似物，并使其具有工业化生产的可行性。
