Wade John D, Lin Feng, Hossain M Akhter, Shabanpoor Fazel, Zhang Suode, Tregear Geoffrey W
Howard Florey Institute, School of Chemistry, University of Melbourne, Victoria, Australia.
Ann N Y Acad Sci. 2009 Apr;1160:11-5. doi: 10.1111/j.1749-6632.2009.03951.x.
Successful methods for the chemical assembly of insulin-like peptides allow the detailed study of their structure and function relationships. However, the two-chain, three-disulfide bond structure of this family of peptides, which includes relaxin, has long represented a significant challenge with respect to their chemical synthesis. Early efforts involved the random combination of the two synthetic S-reduced chains under oxidizing conditions to spontaneously form the three disulfide bonds. Such an approach, while generally effective for native sequences, is critically dependent upon the presence of intact secondary structures within the individual chains which guide the subsequent folding and oxidation pathway. This limitation prevents the use of this approach for the preparation of analogs in which these secondary elements are either absent or modified. Nowadays, the use of highly efficient solid-phase peptide synthesis methodologies together with selective S-thiol-protecting groups allows the acquisition of individual chains that can be combined by effective sequential chemically directed formation of each of the three disulfide bonds. These approaches have allowed the high-yield assembly of an array of insulin-like peptides which, in turn, has provided considerable and valuable structural and biological information.
胰岛素样肽化学组装的成功方法有助于详细研究其结构与功能的关系。然而，包括松弛素在内的这类肽的双链、三二硫键结构，长期以来在其化学合成方面构成了重大挑战。早期的努力包括在氧化条件下将两条合成的S-还原链随机组合，以自发形成三个二硫键。这种方法虽然对天然序列通常有效，但严重依赖于各链中完整二级结构的存在，这些二级结构指导后续的折叠和氧化途径。这一局限性使得该方法无法用于制备这些二级结构缺失或被修饰的类似物。如今，高效的固相肽合成方法与选择性S-硫醇保护基团的使用，使得能够获得可通过有效顺序化学定向形成三个二硫键中的每一个而进行组合的单个链。这些方法实现了一系列胰岛素样肽的高产率组装，进而提供了大量有价值的结构和生物学信息。
