Venom-inspired somatostatin receptor 4 (SSTR4) agonists as new drug leads for peripheral pain conditions.

Autor: Bjørn-Yoshimoto WE, Ramiro IBL, Koch TL, Engholm E, Yeung HY, Sørensen KK, Goddard CM, Jensen KL, Smith NA, Martin LF, Smith BJ, Madsen KL, Jensen KJ, Patwardhan A, Safavi-Hemami H
Jazyk: angličtina
Zdroj: BioRxiv : the preprint server for biology [bioRxiv] 2024 Apr 30. Date of Electronic Publication: 2024 Apr 30.
DOI: 10.1101/2024.04.29.591104
Abstrakt: Persistent pain affects one in five people worldwide, often with severely debilitating consequences. Current treatment options, which can be effective for mild or acute pain, are ill-suited for moderate-to-severe persistent pain, resulting in an urgent need for new therapeutics. In recent years, the somatostatin receptor 4 (SSTR 4 ), which is expressed in sensory neurons of the peripheral nervous system, has emerged as a promising target for pain relief. However, the presence of several closely related receptors with similar ligand-binding surfaces complicates the design of receptor-specific agonists. In this study, we report the discovery of a potent and selective SSTR 4 peptide, consomatin Fj1, derived from extensive venom gene datasets from marine cone snails. Consomatin Fj1 is a mimetic of the endogenous hormone somatostatin and contains a minimized binding motif that provides stability and drives peptide selectivity. Peripheral administration of synthetic consomatin Fj1 provided analgesia in mouse models of postoperative and neuropathic pain. Using structure-activity studies, we designed and functionally evaluated several Fj1 analogs, resulting in compounds with improved potency and selectivity. Our findings present a novel avenue for addressing persistent pain through the design of venom-inspired SSTR 4 -selective pain therapeutics.
One Sentence Summary: Venom peptides from predatory marine mollusks provide new leads for treating peripheral pain conditions through a non-opioid target.
Databáze: MEDLINE
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