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Angew Chem Int Ed Engl. 2018 Sep 3;57(36):11640-11643. doi: 10.1002/anie.201805208. Epub 2018 Aug 6.

Solid-Phase Thiol-Ene Lipidation of Peptides for the Synthesis of a Potent CGRP Receptor Antagonist.

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School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland, 1142, New Zealand.
Maurice Wilkins Centre for Molecular Biodiscovery, School of Biological Sciences, The University of Auckland, Auckland, 1142, New Zealand.
School of Biological Sciences, The University of Auckland, 3A Symonds Street, Auckland, 1142, New Zealand.


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 CGRP8-37 and CGRP7-37 , has potential for the treatment of migraine.


conjugation; lipidation; peptides; solid-phase synthesis; synthetic methods

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