A broad-spectrum antidote against venomous snakebites based on engineering of nicotinic acetylcholine receptors and derivatives.

Snakebite envenoming affects up to 2.7 million people each year, resulting in 138,000 deaths annually. Consequently, the World Health Organization recently recognized snakebite as a priority Neglected Tropical Disease. Snake venoms are composed of a lethal cocktail of several toxins, including α-neurotoxins that target nicotinic acetylcholine receptors (nAChRs) at the neuromuscular synapse, causing paralysis. Existing snakebite antivenom treatments are usually antibody-based, but lack efficacy and cause severe side effects, including acute immune reactions because of the foreign origin. We recently engaged in a study (Albulescu et al., 2019) investigating whether acetylcholine binding proteins (AChBPs), homologues of the ligand-binding domain of nAChRs, can be lead compounds for new antidotes by binding α-neurotoxins. Our proof of principle data demonstrate that AChBP indeed prolongs survival times in animals, but the AChBP activity is currently limited due to its capacity to capture only one important venom component, namely the long-chain α-neurotoxins, but not the related short-chain α-neurotoxins. The goal of this study is to further develop AChBP as an antivenom with broad-spectrum binding capacities for α-neurotoxins from a wide range of different snakes. We will accomplish this goal through structure-guided protein engineering of humanized AChBPs, as well as engineered LBDs from human receptors and their mimotope peptides.