Avaliação toxicológica integrada - in vivo e in silico - de NXH8, uma α-neurotoxina não convencional da cobra coral brasileira, Micrurus corallinus

Abstract

The study aimed to evaluate the in vivo toxicity of NXH8, a non-conventional α-neurotoxin from Micrurus corallinus, and investigate its interaction with the nicotinic acetylcholine receptor (nAChR) from Tetronarce californica (formerly known as Torpedo californica). To achieve this, lethality experiments were conducted to determine the toxicity of NXH8 and the efficacy of anti-NXH8 antibodies in neutralising the lethality of M. corallinus venom. Additionally, the effect of Varespladib, a phospholipase A2 (PLA2) inhibitor, on the survival of mice exposed to M. corallinus venom was assessed. In silico analyses were performed to understand the molecular interactions between NXH8 and the nAChR of T. californica, comparing them with the interactions of α-bungarotoxin (α-BgTx), a neurotoxin from Bungarus multicinctus with high affinity for the same receptor. The results showed that NXH8 exhibits low in vivo toxicity and that anti-NXH8 antibodies were ineffective in neutralising M. corallinus venom. Conversely, the administration of Varespladib significantly increased animal survival, suggesting the critical role of PLA2 activity in the venom’s lethality. In silico analyses, including molecular modelling, molecular docking, and molecular dynamics, revealed that NXH8 binds to the same nAChR interfaces as α-BgTx (αδ and αγ) but displays less favourable interactions due to the absence of critical residues required for effective binding. While α-BgTx induces significant structural alterations in the nAChR, NXH8 preserves the receptor’s structure nearly unchanged, explaining its lower toxicity. These findings contribute to a better understanding of NXH8’s mechanisms of action and its differences compared to other neurotoxins, such as α-BgTx.