An immunoinformatic approach to assessing the immunogenic capacity of alpha-neurotoxins in elapid snake venoms

Abstract

Introduction: Most elapid snakes produce venoms that contain alpha-neurotoxins (α-NTXs), which are proteins that cause post-synaptic blockade and paralysis in snakebite envenoming. However, existing elapid antivenoms are known for their low potency in neutralizing the neurotoxic activity of α-NTXs, while the immunological basis has not been elucidated.Methods: In this study, a structure-based major histocompatibility complex II (MHCII) epitope predictor of horse (Equus caballus), complemented with DM-editing determinant screening algorithm was adopted to assess the immunogenicity of α-NTXs in the venoms of major Asiatic elapids (Naja kaouthia, Ophiophagus hannah, Laticauda colubrina, Hydrophis schistosus, Hydrophis curtus).Results: The scoring metric M2R, representing the relative immunogenic performance of respective α-NTXs, showed all α-NTXs have an overall low M2R of <0.3, and most of the predicted binders feature non-optimal P1 anchor residues. The M2R scores correlate strongly (R2 = 0.82) with the potency score (p-score) generated based on the relative abundances of α-NTXs and the neutralization potency of commercial antivenoms.Discussion: The immunoinformatic analysis indicates that the inferior antigenicity of α-NTXs is not only due to their small molecular size but also the subpar immunogenicity affected by their amino acid composition. Structural modification with conjugation and synthetic epitope as immunogen may potentially enhance the immunogenicity for improved antivenom potency against α-NTXs of elapid snakes.

Unveiling the functional epitopes of cobra venom cytotoxin by immunoinformatics and epitope-omic analyses

“…Several factors affecting the immunogenic capability of CTXs including the molecular structure, and sequence variations 5 , 24 . Small molecular size of the toxins may contribute to the sparse antigenicity 25 . Moreover, CTXs exhibit low immunogenicity due to their three-finger folded structures that limit its surface exposure for epitope recognition.…”

“…By characterizing the epitopes of venom toxins, the possible immunogenic sites of toxins can be identified to aids in developing appropriate antivenoms specifically targeting the respective toxins. Computational analysis has been reported to examine the immunogenicity of toxins, such as three-finger toxins (3FTX), phospholipase A 2 s (PLA 2s ), cysteine-rich secretory proteins (CRISP), disintegrins (DIS), Kunitz peptides (KUN), L-amino acid oxidases (LAAO), natriuretic peptides (NP), snake C-type lectins (SNACLEC), snake venom metalloproteinases (SVMP) and snake venom serine proteases (SVSP) 25 , 29 , 30 . Furthermore, high-throughput approaches such as peptide microarray, mass spectrometry (MS) epitope mapping, and phage display methods have also been developed to characterize the toxin-antivenom interaction 29 – 33 .…”