<i>α</i> ‐Conopeptide From <i>Conus planorbis</i> Inhibits Glioblastoma Stem Cells and Angiogenesis via Sonic Hedgehog and ADAMDEC1–FGF2–FGFR1 Loop Signaling Pathway

Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor with limited effective treatments. This study explores the anti-GBM potential of an α-conopeptide isolated from the venom of Conus planorbis, a marine cone snail from Rameswaram, India. Peptide extraction and BCA assay quantified an average concentration of 473.34 ± 70.07 µg/mL. Structural analysis via ¹H nuclear magnetic resonance (NMR) revealed a stable tertiary structure with aromatic, aliphatic, sulfur-containing, and basic amino acids, stabilized by hydrogen bonds and disulfide bridges. Molecular docking showed strong interactions between the α-conopeptide and GBM-related proteins PTCH1, FGFR1, and fibroblast growth factor 2 (FGF2), suggesting inhibition of sonic hedgehog (SHH) and ADAM-like Decysin 1 (ADAMDEC1)-FGF2-FGFR1 loop signaling pathway. Molecular dynamics simulations confirmed stable binding with FGFR1. In vitro assays using U87 GBM cells demonstrated that the α-conopeptide had greater cytotoxicity (IC₅₀ ≈ 250 µg/mL) than temozolomide (IC₅₀ ≈ 320 µg/mL). Additional chorioallantoic membrane (CAM) and brine shrimp lethality tests supported its potent bioactivity, with a lower LD₅₀ (50.24 µg/mL) compared to temozolomide (125.82 µg/mL). These findings indicate that the α-conopeptide from C. planorbis possesses multi-target anticancer activity targeting via SHH and FGFR1 loop signaling pathway, structural stability, and superior cytotoxic potency against GBM, highlighting its potential as a novel marine-derived therapeutic agent.