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Solid‐Phase Thiol–Ene Lipidation of Peptides for the Synthesis of a Potent CGRP Receptor Antagonist
Author(s) -
Williams Elyse T.,
Harris Paul W. R.,
Jamaluddin Muhammad A.,
Loomes Kerry M.,
Hay Debbie L.,
Brimble Margaret A.
Publication year - 2018
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201805208
Subject(s) - calcitonin gene related peptide , peptide , chemistry , cysteine , thiol , peptide synthesis , calcitonin , antagonist , yield (engineering) , combinatorial chemistry , ene reaction , amino acid , receptor , chromatography , biochemistry , stereochemistry , neuropeptide , biology , enzyme , materials science , metallurgy , endocrinology
We report a new method herein coined SP‐CLipPA (solid‐phase cysteine lipidation of a peptide or amino acid) for the synthesis of mono‐S‐lipidated peptides. This technique utilizes thiol–ene chemistry for conjugation of a vinyl ester to a free thiol of a semiprotected, resin‐bound peptide. Advantages of SP‐CLipPA include: ease of handling, conversions of up to 91 %, by‐product removal by simple filtration, and a single purification step. Additionally, the desired lipidated products show high chromatographic separation from impurities, thus facilitating RP‐HPLC purification. To showcase the utility of SP‐CLipPA, we synthesized a potent calcitonin gene‐related peptide (CGRP) receptor antagonist peptide in excellent yield and purity. This peptide, selected from a series of lipidated analogues of CGRP 8–37 and CGRP 7–37 , has potential for the treatment of migraine.