In Silico Identification and Multi-Property Prediction of Snake Venom-Derived PLA2 C-Terminal Peptides as Potential CNS Shuttle Platforms for Brain-Targeted Delivery

Targeted drug delivery to the central nervous system (CNS) remains a formidable challenge due to the restrictive nature of the blood-brain barrier (BBB). Snake venom-derived Phospholipase A2 (PLA2) complexes possess evolved, highly optimized molecular architectures capable of intense membrane interactions. This study proposes a novel conceptual framework utilizing specific C-terminal derived peptides from snake venom Y, specifically focusing on the cationic residues within the amino acid 115-129 region.

We highlight specific sequence patterns, such as the RRWFK motif, where localized concentrations of Lysine (Lys), Arginine (Arg), and Tyrosine (Tyr) facilitate cell-binding and lipid bilayer insertion via adsorptive-mediated transcytosis (AMT). To circumvent the inherent functional bottlenecks of venom-derived biomolecules—namely systemic toxicity, hemolysis, tissue accumulation, and microglia activation—we propose an advanced AI-driven workflow. By constructing an in silico Multi-property Prediction Model, the structural variants, isoforms, and minimal active fragments can be systematically screened and optimized.

This dual platform approach provides a powerful, pre-validated pipeline for the discovery of non-toxic, highly efficient CNS shuttle peptides, showing massive potential for the targeted delivery of next-generation therapeutics, including RNA-based drugs and surface-modified exosomes.