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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2019.00848

A decoy-receptor approach using nicotinic acetylcholine receptor mimics reveals their potential as novel therapeutics against neurotoxic snakebite

 Laura-Oana Albulescu1, Taline Kazandjian1, Julien Slagboom1, Ben Bruyneel2,  Stuart Ainsworth1, Jaffer AlSolaiss1, Simon C. Wagstaff1, Gareth Whiteley1,  Robert A. Harrison1, Chris Ulens3, Jeroen Kool2 and  Nicholas R. Casewell1*
  • 1Liverpool School of Tropical Medicine, United Kingdom
  • 2Vrije Universiteit Amsterdam, Netherlands
  • 3KU Leuven, Belgium

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 (nAChR). 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 by 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.

Keywords: nicotinic acetylcholine receptor (nAChR), Acetylcholine binding protein, snake venom neurotoxins, Envenoming, long chain three finger toxins, Therapeutics

Received: 24 Jan 2019; Accepted: 02 Jul 2019.

Edited by:

Victor I. Tsetlin, Institute of Bioorganic Chemistry (RAS), Russia

Reviewed by:

Richard J. Lewis, University of Queensland, Australia
Choo Hock Tan, Department of Pharmacology, Faculty of Medicine, University of Malaya, Malaysia  

Copyright: © 2019 Albulescu, Kazandjian, Slagboom, Bruyneel, Ainsworth, AlSolaiss, Wagstaff, Whiteley, Harrison, Ulens, Kool and Casewell. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Nicholas R. Casewell, Liverpool School of Tropical Medicine, Liverpool, United Kingdom, nicholas.casewell@lstmed.ac.uk