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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.

Author information

1
School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland, 1142, New Zealand.
2
Maurice Wilkins Centre for Molecular Biodiscovery, School of Biological Sciences, The University of Auckland, Auckland, 1142, New Zealand.
3
School of Biological Sciences, The University of Auckland, 3A Symonds Street, Auckland, 1142, New Zealand.

Abstract

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.

KEYWORDS:

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

PMID:
29978532
DOI:
10.1002/anie.201805208
[Indexed for MEDLINE]

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