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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Calcitonin Gene-Related Peptide Receptor Antagonists / chemical synthesis*
  • Calcitonin Gene-Related Peptide Receptor Antagonists / chemistry
  • Cysteine / chemical synthesis
  • Cysteine / chemistry*
  • Lipids / chemical synthesis
  • Lipids / chemistry*
  • Peptides / chemical synthesis*
  • Peptides / chemistry
  • Solid-Phase Synthesis Techniques / methods*
  • Stereoisomerism

Substances

  • Calcitonin Gene-Related Peptide Receptor Antagonists
  • Lipids
  • Peptides
  • Cysteine