Novel Somatostatin Receptor-4 Agonist SM-I-26 Mitigates Lipopolysaccharide-Induced Inflammatory Gene Expression in Microglia

Silwal, Ashok; House, Austin; Sandoval, Karin E.; Vijeth, Shaluah; Umbaugh, David S.; Crider, A. Michael; Mobayen, Shirin; Neumann, William L.; Witt, K.

doi:10.1007/s11064-021-03482-z

Cited by 2 publications

(1 citation statement)

References 47 publications

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“…The expression pattern of the SSTR 4 in C- and Aδ-fibers is not well established, but differences here, along with the central effects of opioids, could help explain the difference in the maximal response observed between Fj1 and morphine. The expression of SSTR 4 is upregulated in inflammatory models ( 53 ), and activation can inhibit inflammation induced by either mustard oil or lipopolysaccharide ( 10, 54, 55 ). In response to injury, inflammatory responses are generally observed within 2 h ( 56, 57 ).…”

Section: Discussionmentioning

confidence: 99%

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

Bjørn-Yoshimoto,

Ramiro,

Koch

et al. 2024

Preprint

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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 (SSTR4), 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 SSTR4< 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 SSTR4-selective pain therapeutics.

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