Discovery, Structural Optimization, and Analgesic Mechanism of A Novel Conopeptide Targeting Somatostatin Receptor SSTR4

摘要

Objective: To discover novel analgesic conopeptides selectively targeting the somatostatin receptor SSTR4 and enhance their potency and selectivity through structural optimization, providing candidate molecules for the development of effective and low-toxicity nonopioid analgesics. Methods: Based on a previously constructed peptide resource library of Conus terebra using multi-omics technologies, candidate peptides were selected through bioinformatic screening and synthesized by solid-phase chemical synthesis. The in vivo analgesic activities were evaluated using multiple pain models in zebrafish and mice（acute thermal pain, chronic inflammatory pain, and neuropathic pain）. Site-directed mutagenesis was performed on the lead peptide based on virtual amino acid mutation and conserved domain analysis. The agonist activity(EC₅₀) and selectivity of the peptides toward SSTR4 were measured using a cAMP functional assay. The interaction mode between the peptides and SSTR4 was analyzed by molecular docking simulation. Results: Four peptide sequences were screened and predicted from the Conus terebra peptide resource library. Among them, peptide T2（Consomatin family） showed significant analgesic effects in pain models. Its mutant [I8F]T2 exhibited the best efficacy in acute thermal pain and chronic inflammatory pain models, while [S15H]T2 showed the strongest activity in neuropathic pain models. Functional assays confirmed that these peptides are selective agonists of SSTR4, with EC₅₀ values of 223.3 nM for [I8F]T2 and 770.3 nM for [S15H]T2. Molecular docking revealed key binding sites between the peptides and SSTR4. Conclusion: This study successfully identified and optimized novel conopeptides targeting SSTR4 with potent analgesic efficacy, high selectivity, and low toxicity. The results clarify their mechanism of action via SSTR4 activation, highlighting their promise as lead compounds for non-opioid analgesic development.

关键词

conotoxin / analgesia / somatostatin receptor subtype 4(SSTR4) / structural optimization / molecular docking