A therapeutic combination of two small molecule toxin inhibitors provides pancontinental preclinical efficacy against viper snakebite
Laura-Oana Albulescu, Chunfang Xie, Stuart Ainsworth, Jaffer Alsolaiss, Edouard Crittenden, Charlotte A. Dawson, Rowan Softley, Keirah E. Bartlett, Robert A. Harrison, Jeroen Kool, Nicholas R. Casewell
Received Date: 16th May 20
Snakebite is a medical emergency causing high mortality and morbidity in rural tropical communities that typically experience delayed access to unaffordable therapeutics. Viperid snakes are responsible for the majority of envenomings, but extensive interspecific variation in venom composition dictates that different antivenom treatments are used in different parts of the world, resulting in clinical and fiscal snakebite management challenges. Here, we show that a number of repurposed Phase 2-approved small molecules are capable of broadly neutralizing distinct viper venom bioactivities in vitro by inhibitingdifferent enzymatic toxin families. Furthermore, using multiple in vivo models of envenoming, we demonstrate that a single dose of a rationally-selected dual inhibitor combination consisting of marimastat and varespladib prevents lethality caused by venom from the most medically-important vipers of Africa, South Asia and Central America. Our findings strongly support the translation of combinations of safe and affordable enzyme inhibitors as novel broad-spectrum therapeutics for snakebite.
Read in full at bioRxiv.
This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.