Neurobiological and Chemical Characterization of the Cyanobacterial Metabolite Veraguamide E

Ver Es structure was validated by {superscript 1}H NMR, HRMS, and molecular networking analyses. Computational docking and NMR titration confirmed direct, saturable, and tight binding of Ver E to the human Sigma-2 receptor/transmembrane protein 97 ({sigma}2R/TMEM97). Functional calcium imaging in primary mouse sensory neurons revealed that Ver E increases intracellular Ca{superscript 2} levels without modulating store-operated calcium entry (SOCE). Multi-well microelectrode array experiments using human induced pluripotent stem cell (hiPSC) derived nociceptors showed that Ver E significantly reduced neuronal activity at physiological temperatures, but not under heat-stress conditions. Ver E exhibited no cytotoxicity at concentrations up to 30 {micro}M in HEK293 cells, and immunocytochemistry confirmed that it does not alter phosphorylated eIF2 (p-eIF2) expression, indicating a mechanism distinct from integrated stress response modulators. Collectively, these findings position Ver E as a non-toxic compound capable of selectively modulating neuronal excitability, thereby advancing the development of novel therapeutics for pain management. SignificanceNatural products have long been recognized as a rich source of therapeutics, accounting for over 60% of currently approved small-molecule drugs and underscoring their pivotal role in drug discovery. Marine cyanobacteria produce structurally diverse secondary metabolites with a wide array of biological activities. Among these are the veraguamides, a family of depsipeptides that have shown promise as future therapeutics in our recent studies. This work presents a detailed biological and chemical characterization of veraguamide E (Ver E), isolated from a Panamanian marine cyanobacterial collection. The {sigma}2R/TMEM97 system has been identified as a promising target to address unmet need for non-opioid therapeutics which can modulate neuronal excitability in the context of chronic pain. Discovery and identification of novel compounds which modulate this system can help us better understand its function as well as allow us to develop future therapeutics targeting this pathway. HighlightsO_LIVeraguamide E specifically binds {sigma}2R/TMEM97 receptor with high affinity. C_LIO_LIComputational docking and NMR confirm a distinct binding mechanism. C_LIO_LIVer E modulates calcium signaling in mouse DRG neurons and human iPSC-derived nociceptors. C_LIO_LIVer E demonstrates no detectable cytotoxicity in human cell lines. C_LI