Venomous snakebites cause >100 000 deaths every year, in many cases via potent depression of human neuromuscular signaling by snake α-neurotoxins. Emergency therapy still relies on antibody-based antivenom, hampered by poor access, frequent adverse reactions, and cumbersome production/purification. Combining high-throughput discovery and subsequent structure–function characterization, we present simple peptides that bind α-cobratoxin (α-Cbtx) and prevent its inhibition of nicotinic acetylcholine receptors (nAChRs) as a lead for the development of alternative antivenoms. Candidate peptides were identified by phage display and deep sequencing, and hits were characterized by electrophysiological recordings, leading to an 8-mer peptide that prevented α-Cbtx inhibition of nAChRs. We also solved the peptide:α-Cbtx cocrystal structure, revealing that the peptide, although of unique primary sequence, binds to α-Cbtx by mimicking structural features of the nAChR binding pocket. This demonstrates the potential of small peptides to neutralize lethal snake toxins in vitro, establishing a potential route to simple, synthetic, low-cost antivenoms.

Many snake venom toxins cause local tissue damage in prey and victims, which constitutes an important pathology that is challenging to treat with existing antivenoms. One of the notorious toxins that causes such effects is myotoxin II present in the venom of the Central and Northern South American viper, Bothrops asper . This Lys49 PLA 2 homologue is devoid of enzymatic activity and causes myotoxicity by disrupting the cell membranes of muscle tissue. To improve envenoming therapy, novel approaches are needed, warranting the discovery and development of inhibitors that target key toxins that are currently difficult to neutralize. Here, we report the identification of a new peptide (JB006), discovered using phage display technology, that is capable of binding to and neutralizing the toxic effects of myotoxin II in vitro and in vivo . Through computational modeling, we further identify hypothetical binding interactions between the toxin and the peptide to enable further development of inhibitors that can neutralize myotoxin II.

Obesity is associated with low grade inflammation, which may adversely impact the biological functions of adipose tissue and consequently of adipose-derived stem cells (ASCs). Studies in humans and rodents have described that obesity alters ASC properties and functionality, compromising their therapeutic prospects. The Gottingen Minipig (GM) is a commonly used obesity model. Nevertheless, there are no studies investigating the effect of obesity on ASCs from GM, which could constitute a valuable addition to both obesity modelling and adult stem cells investigations. In this study, we isolated subcutaneous ASCs from lean and obese GM to investigate the effect of obesity on cell behavior and differentiation capacity. During culturing, we observed an inherent difference in cell morphology between lean and obese ASCs. Upon adipogenic induction, obese-ASCs readily differentiated, developing significantly larger amounts of adipocytes than corresponding lean-ASCs, hinting at a predisposition towards adipogenic differentiation. Expression profiling of obesity-related genes in cell cultures, before and after adipogenic differentiation, revealed a tendency towards up-regulation in differentiated obese-cultures. Altogether, our results indicate that stem cells from obese donors could display different therapeutic properties. In summary, our results point towards GM as a valuable model for future ASCs investigations in healthy and obese states.