Results: The bifunctional antagonists generally displayed similar antagonist activity to CGRP 8-37 and PACAP 6-38 in receptor transfected Cos7 cells and spinal cord cultures. Translational relevance was assessed by measuring antagonism of agonist-stimulated cAMP production in primary rat spinal cord cultures. We tested antagonism against CGRP at the human CGRP and AMY 1 receptors and against PACAP-27, PACAP-38 and VIP at the human PAC 1, VPAC 1 and VPAC 2 receptors in Cos7 cells (cAMP production). The potency of these peptides as bifunctional antagonists was then tested, and compared to the parent fragments. Methods: Peptides were synthesized in-house and CGRP 8-37 was linked to PACAP 6-38 using 1,3-dipolar cycloaddition at amino acid positions 21, 34 and 38. From this, we selected CGRP 8-37 and PACAP 6-38 to attach together and assessed these molecules as bifunctional antagonists. As a starting point we utilized the known antagonism imparted by CGRP and PACAP peptide fragments, exploring different lengths of PACAP. One strategy is to develop a bifunctional ligand, capable of antagonizing both systems at once. Blocking the activity of these peptides simultaneously may provide a clinical advantage over individual blockade. Question: The neuropeptides calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating peptide (PACAP) are both implicated in migraine. Walker 2 1University of Otago, Dunedin, New Zealand 2University of Auckland, Auckland, New Zealand Correspondence: D.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |