Calcitonin gene-related peptide receptor and Synaptosomal-associated protein 25 (CGRP-R/SNAP-25)

The trigeminovascular system is a critical sensory pathway involved in the pathophysiology of migraine, consisting of trigeminal neurons that innervate cranial blood vessels (Goadsby et al., 2017, PMID: 28614607). This therapeutic target concept represents a dual-mechanism approach that combines the blockade of the Calcitonin Gene-Related Peptide (CGRP) receptor with the enzymatic cleavage of Synaptosomal-Associated Protein 25 (SNAP-25). CGRP is a potent vasodilator and pain-signaling neuropeptide, while SNAP-25 is a core component of the SNARE complex required for the vesicular release of CGRP from trigeminal nerve endings (Durham, 2006, PMID: 16732134). Targeted secretion inhibitors (TSIs), such as the fusion protein AGN-241686, utilize a CGRP receptor-binding domain to deliver a botulinum-derived protease into the neuron, where it cleaves SNAP-25 to provide a prolonged inhibition of neuropeptide secretion (Foster et al., 2018, PMID: 29438654). This strategy is designed to offer superior efficacy and duration of action for patients with chronic or refractory migraine by simultaneously inhibiting both the release and the signaling of CGRP within the trigeminovascular system.

Other names

Trigeminovascular system dual targetCGRP-R/SNAP-25 dual inhibitionCGRP-BoNT fusion targetTargeted Secretion Inhibitor (TSI) target

Dual-action inhibition involving the blockade of the CGRP receptor and the proteolytic cleavage of SNAP-25 to prevent the release of pro-inflammatory neuropeptides from trigeminal nerves (Foster et al., 2018, PMID: 29438654).