Optimized Fmoc Solid-Phase Synthesis of the Cysteine-Rich Peptide Linaclotide

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. (C) 2010 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 96: 69-80, 2011.