TY - JOUR
T1 - Veraguamide E, a Marine Cyanobacterial Depsipeptide Targeting σ2R/TMEM97
T2 - Chemical and Neurobiological Characterization
AU - Sotelo-Morales, Jesus E.
AU - Mofidi Tabatabaei, Sahar
AU - Fofie, Christian K.
AU - Fosu, Kelvin K.
AU - Dodd-O, Joseph B.
AU - Simcik, Rebekah D.
AU - Tack, See H.
AU - Soto-Reyes, Miguel J.
AU - Yousuf, Muhammad Saad
AU - Caro-Diaz, Eduardo J.E.
AU - Kumar, Vivek A.
AU - Van Horn, Wade D.
AU - Kolber, Benedict
AU - Tidgewell, Kevin J.
PY - 2025/11/28
Y1 - 2025/11/28
N2 - The human sigma-2 receptor/transmembrane protein 97 (σ2R/TMEM97) has been identified as a promising target to modulate neuronal excitability in chronic pain and address the unmet need for nonopioid therapeutics. We report the chemical and biological characterization of the cyclic depsipeptide, veraguamide E (Ver E), isolated from a Panamanian marine cyanobacterial collection, as a novel σ2R/TMEM97 ligand and modulator of calcium in neurons. Ver E's structure was confirmed using 1D and 2D-NMR, HRMS, and MS/MS molecular networking analyses. NMR titration and computational docking confirmed direct, saturable, and tight binding of Ver E to σ2R/TMEM97. Functional calcium imaging in primary mouse sensory neurons revealed that Ver E increases intracellular Ca2+ levels without modulating store-operated calcium entry (SOCE). Multiwell microelectrode array experiments using human induced pluripotent stem cell (hiPSC) nociceptors showed that Ver E reduced neuronal activity at physiological temperatures, but not under heat-stress. Ver E exhibited no cytotoxicity in HEK293 cells, and immunocytochemistry confirmed it does not alter phosphorylated eIF2α (p-eIF2α) expression, indicating a mechanism distinct from integrated stress response modulators. Collectively, these findings position Ver E as a nontoxic σ2R/TMEM97 ligand capable of selectively modulating neuronal excitability, creating a starting point for developing novel pain therapeutics.
AB - The human sigma-2 receptor/transmembrane protein 97 (σ2R/TMEM97) has been identified as a promising target to modulate neuronal excitability in chronic pain and address the unmet need for nonopioid therapeutics. We report the chemical and biological characterization of the cyclic depsipeptide, veraguamide E (Ver E), isolated from a Panamanian marine cyanobacterial collection, as a novel σ2R/TMEM97 ligand and modulator of calcium in neurons. Ver E's structure was confirmed using 1D and 2D-NMR, HRMS, and MS/MS molecular networking analyses. NMR titration and computational docking confirmed direct, saturable, and tight binding of Ver E to σ2R/TMEM97. Functional calcium imaging in primary mouse sensory neurons revealed that Ver E increases intracellular Ca2+ levels without modulating store-operated calcium entry (SOCE). Multiwell microelectrode array experiments using human induced pluripotent stem cell (hiPSC) nociceptors showed that Ver E reduced neuronal activity at physiological temperatures, but not under heat-stress. Ver E exhibited no cytotoxicity in HEK293 cells, and immunocytochemistry confirmed it does not alter phosphorylated eIF2α (p-eIF2α) expression, indicating a mechanism distinct from integrated stress response modulators. Collectively, these findings position Ver E as a nontoxic σ2R/TMEM97 ligand capable of selectively modulating neuronal excitability, creating a starting point for developing novel pain therapeutics.
UR - https://www.scopus.com/pages/publications/105023303997
UR - https://www.scopus.com/pages/publications/105023303997#tab=citedBy
U2 - 10.1021/acs.jnatprod.5c01092
DO - 10.1021/acs.jnatprod.5c01092
M3 - Article
C2 - 41195793
AN - SCOPUS:105023303997
SN - 0163-3864
VL - 88
SP - 2736
EP - 2749
JO - Journal of Natural Products
JF - Journal of Natural Products
IS - 11
ER -