Genome-Guided Discovery of ShK-like Peptides from Sanderia malayensis with Anti-Amyloidogenic and Neuroprotective Activities

While jellyfish venom represents a promising bioresource for biotechnological applications, the extraction of adequate venom amounts and the isolation of pure toxins present significant technical bottlenecks. To overcome these difficulties, a pipeline utilizing bioinformatic analyses was established to identify toxin candidates from genomic datasets, subsequently validating their functions from chemical synthesis. Specifically, a high-quality, 144 Mb genome assembly of the jellyfish Sanderia malayensis was constructed using PacBio CLR long reads (38.2 Gb), Illumina short reads (24.5 Gb), and Hi-C reads (65.8 Gb). The prediction of secreted toxin-associated domains across five cnidarian species indicated that phospholipase A2 (PF00068, PF05826), metalloproteases (PF01421), ShK-like domains (PF01549), and prokineticins (PF06607) were the major venom constituents. Given that ShK-like domains represent a predominant component of cnidarian venom, we focused on this family and identified 35 ShK-like peptides in S. malayensis. Out of ten selected and chemically synthesized candidates, eight peptides significantly inhibited amyloid-β (Aβ) oligomerization and fibrillization in vitro. Moreover, several peptides markedly attenuated Aβ-induced cytotoxicity and reactive oxygen species (ROS) production in SH-SY5Y cells. Taken together, these results demonstrate that S. malayensis ShK-like peptides could be potential anti-amyloidogenic agents and provided a solid foundation for further mechanistic and in vivo studies.