Lipidated Calcitonin Gene-Related Peptide (CGRP) Peptide Antagonists Retain CGRP Receptor Activity and Attenuate CGRP Action In Vivo .

Autor: Jamaluddin A; School of Biological Sciences, University of Auckland, Auckland, New Zealand., Chuang CL; School of Biological Sciences, University of Auckland, Auckland, New Zealand., Williams ET; School of Chemical Sciences, University of Auckland, Auckland, New Zealand., Siow A; School of Chemical Sciences, University of Auckland, Auckland, New Zealand., Yang SH; School of Chemical Sciences, University of Auckland, Auckland, New Zealand., Harris PWR; School of Chemical Sciences, University of Auckland, Auckland, New Zealand., Petersen JSSM; School of Biological Sciences, University of Auckland, Auckland, New Zealand., Bower RL; School of Biological Sciences, University of Auckland, Auckland, New Zealand., Chand S; School of Biological Sciences, University of Auckland, Auckland, New Zealand., Brimble MA; School of Chemical Sciences, University of Auckland, Auckland, New Zealand., Walker CS; School of Biological Sciences, University of Auckland, Auckland, New Zealand., Hay DL; School of Biological Sciences, University of Auckland, Auckland, New Zealand.; Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand., Loomes KM; School of Biological Sciences, University of Auckland, Auckland, New Zealand.
Jazyk: angličtina
Zdroj: Frontiers in pharmacology [Front Pharmacol] 2022 Mar 07; Vol. 13, pp. 832589. Date of Electronic Publication: 2022 Mar 07 (Print Publication: 2022).
DOI: 10.3389/fphar.2022.832589
Abstrakt: Signaling through calcitonin gene-related peptide (CGRP) receptors is associated with pain, migraine, and energy expenditure. Small molecule and monoclonal antibody CGRP receptor antagonists that block endogenous CGRP action are in clinical use as anti-migraine therapies. By comparison, the potential utility of peptide antagonists has received less attention due to suboptimal pharmacokinetic properties. Lipidation is an established strategy to increase peptide half-life in vivo . This study aimed to explore the feasibility of developing lipidated CGRP peptide antagonists that retain receptor antagonist activity in vitro and attenuate endogenous CGRP action in vivo . CGRP peptide analogues based on the archetypal CGRP receptor antagonist, CGRP 8-37 , were palmitoylated at the N-terminus, position 24, and near the C-terminus at position 35. The antagonist activities of the lipidated peptide analogues were tested in vitro using transfected Cos-7 cells expressing either the human or mouse CGRP receptor, amylin subtype 1 (AMY 1 ) receptor, adrenomedullin (AM) receptors, or calcitonin receptor. Antagonist activities were also evaluated in SK-N-MC cells that endogenously express the human CGRP receptor. Lipidated peptides were then tested for their ability to antagonize endogenous CGRP action in vivo using a capsaicin-induced dermal vasodilation (CIDV) model in C57/BL6J mice. All lipidated peptides except for the C-terminally modified analogue retained potent antagonist activity compared to CGRP 8-37 towards the CGRP receptor. The lipidated peptides also retained, and sometimes gained, antagonist activities at AMY 1 , AM 1 and AM 2 receptors. Several lipidated peptides produced robust inhibition of CIDV in mice. This study demonstrates that selected lipidated peptide antagonists based on αCGRP 8-37 retain potent antagonist activity at the CGRP receptor and are capable of inhibition of endogenous CGRP action in vivo . These findings suggest that lipidation can be applied to peptide antagonists, such as αCGRP 8-37 and are a potential strategy for antagonizing CGRP action.
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer DP declared a past co-authorship with several of the authors CSW, DLH to the handling editor.
(Copyright © 2022 Jamaluddin, Chuang, Williams, Siow, Yang, Harris, Petersen, Bower, Chand, Brimble, Walker, Hay and Loomes.)
Databáze: MEDLINE
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