A Decoy-Receptor Approach Using Nicotinic Acetylcholine Receptor Mimics Reveals Their Potential as Novel Therapeutics Against Neurotoxic Snakebite

Abstract

Snakebite is a neglected tropical disease that causes 138,000 deaths each year. Neurotoxic snake venoms contain small neurotoxins, including three-finger toxins (3FTxs), which can cause rapid paralysis in snakebite victims by blocking postsynaptic transmission via nicotinic acetylcholine receptors (nAChRs). These toxins are typically weakly immunogenic and thus are often not effectively targeted by current polyclonal antivenom therapies. We investigated whether nAChR mimics, also known as acetylcholine binding proteins (AChBPs), could effectively capture 3FTxs and therefore be developed as a novel class of snake-generic therapeutics for combatting neurotoxic envenoming. First, we identified the binding specificities of 3FTx from various medically important elapid snake venoms to nAChR using two recombinant nAChR mimics: the AChBP from Lymnaea stagnalis and a humanized neuronal α7 version (α7-AChBP). We next characterized these AChBP-bound and unbound fractions using SDS-PAGE and mass spectrometry. Interestingly, both mimics effectively captured long-chain 3FTxs from multiple snake species but largely failed to capture the highly related short-chain 3FTxs, suggesting a high level of binding specificity. We next investigated whether nAChR mimics could be used as snakebite therapeutics. We showed that while α7-AChBP alone did not protect against Naja haje (Egyptian cobra) venom lethality in vivo , it significantly prolonged survival times when coadministered with a nonprotective dose of antivenom. Thus, nAChR mimics are capable of neutralizing specific venom toxins and may be useful adjunct therapeutics for improving the safety and affordability of existing snakebite treatments by reducing therapeutic doses. Our findings justify exploring the future development of AChBPs as potential snakebite treatments.

Identification of a prognostic immune signature for cervical cancer to predict survival and response to immune checkpoint inhibitors

“…Evidence has accumulated demonstrating the potential of ICI in CC treatment. 33 However, only a small portion of CC patients obtain therapeutic effect from ICI. It is critical to identify and develop predictive biomarkers for ICI response.…”

Varespladib (LY315920) and Methyl Varespladib (LY333013) Abrogate or Delay Lethality Induced by Presynaptically Acting Neurotoxic Snake Venoms

“…An unmet need is for the development of novel therapies that could be administered in the field rapidly after the onset of envenoming [4], as well as to augment antivenom performance where specific toxins have become inaccessible to antivenom upon distribution into the tissues, but might be amenable to inhibition or dislodgement by smaller molecules. Promising developments in this area have emerged, including natural and synthetic inhibitors of snake venom metalloproteinases (SVMPs) [5,6], phospholipases A 2 (PLA 2 s) [7], cytotoxins of the three finger toxin family [8,9], and α-neurotoxins [10], among others.…”

Complex approach for analysis of snake venom α-neurotoxins binding to HAP, the high-affinity peptide

“…Such high affinity stimulated the idea that HAP might be used as a remedy against snake bites. The principle possibility of such an approach against poisoning was recently shown by application of AChBP which could bind long, but not short α-neurotoxins 19,20 . This line of research is still of interest.…”