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Optimized Fmoc solid‐phase synthesis of the cysteine‐rich peptide linaclotide
Author(s) -
GóngoraBenítez Miriam,
TullaPuche Judit,
ParadísBas Marta,
Werbitzky Oleg,
Giraud Matthieu,
Albericio Fernando
Publication year - 2010
Publication title -
peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.21480
Subject(s) - chemistry , peptide , cysteine , combinatorial chemistry , peptide synthesis , solid phase synthesis , oxidative folding , folding (dsp implementation) , disulfide bond , biochemistry , electrical engineering , enzyme , engineering
Abstract 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. © 2010 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 96: 69–80, 2011.