The Journal of pharmacy and pharmacology · 2023
Novel peptide calcitonin gene-related peptide antagonists for migraine therapy.
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Killoran Patrick M, Capel Vicky, D'Aloisio Vera, Schofield Adam, Aczél Tímea, Bölcskei Kata, Helyes Zsuzsanna, von Mentzer Bengt, Kendall David A, Coxon Chris R, Hutcheon Gillian A
Аннотация
OBJECTIVES: It has previously been shown that the peptide (34Pro,35Phe)CGRP27-37 is a potent calcitonin gene-related peptide, CGRP receptor antagonist, and in this project we aimed to improve the antagonist potency through the structural modification of truncated C-terminal CGRP peptides.
METHODS: Six peptide analogues were synthesized and the anti-CGRP activity confirmed using both in vitro and in vivo studies.
KEY FINDINGS: A 10 amino acid-containing peptide VPTDVGPFAF-NH2 (P006) was identified as a key candidate to take forward for in vivo evaluation, where it was shown to be an effective antagonist after intraperitoneal injection into mice. P006 was formulated as a preparation suitable for nasal administration by spray drying with chitosan to form mucoadhesive microcarriers (9.55 ± 0.91 mm diameter) and a loading of 0.2 mg peptide per 20 mg dose.
CONCLUSIONS: The project has demonstrated the potential of these novel small peptide CGRP antagonists, to undergo future preclinical evaluation as anti-migraine therapeutics.
METHODS: Six peptide analogues were synthesized and the anti-CGRP activity confirmed using both in vitro and in vivo studies.
KEY FINDINGS: A 10 amino acid-containing peptide VPTDVGPFAF-NH2 (P006) was identified as a key candidate to take forward for in vivo evaluation, where it was shown to be an effective antagonist after intraperitoneal injection into mice. P006 was formulated as a preparation suitable for nasal administration by spray drying with chitosan to form mucoadhesive microcarriers (9.55 ± 0.91 mm diameter) and a loading of 0.2 mg peptide per 20 mg dose.
CONCLUSIONS: The project has demonstrated the potential of these novel small peptide CGRP antagonists, to undergo future preclinical evaluation as anti-migraine therapeutics.