Institute for Research in Biomedicine, Barcelona Science Park, Baldiri Reixac 10, 08028 Barcelona, Spain.
Biopolymers. 2011;96(1):69-80. doi: 10.1002/bip.21480. Epub 2010 Aug 21.
Linaclotide, a small 14-mer peptide highly rich in cysteines, is currently in phase III clinical trials for the treatment of gastrointestinal disorders. The challenge in the assembly of linaclotide consists of achieving the correct and clean folding of its three disulfide bridges. For this purpose, a number of regioselective, semiregioselective, and random strategies have been studied. In addition to selecting distinct protecting groups for the thiol function, their position in the sequence, the influence of the neighboring protecting groups, as well as the order in which the disulfides fold were studied. Here we describe an optimized solid-phase synthesis of linaclotide that should allow the production of this peptide in multigram amounts.
利那洛肽是一种富含半胱氨酸的 14 肽小分子，目前正处于治疗胃肠疾病的 III 期临床试验阶段。该药物的装配难点在于实现其 3 个二硫键的正确和清洁折叠。为此，人们研究了多种区域选择性、半区域选择性和随机策略。除了选择不同的巯基保护基外，还研究了其在序列中的位置、相邻保护基的影响以及二硫键折叠的顺序。本文描述了一种优化的利那洛肽固相合成方法，有望实现该肽的多克级生产。
