Daniel J. W. Chong, Laura-Oana Albulescu, Adam Westhorpe, Rachel H. Clare, Amy E. Marriott, Christopher M. Woodley, Ramachandran Gunasekar, Nada Mosallam, Edouard Crittenden, Emma Stars, Charlotte A. Dawson, Jeroen Kool, Mark C. Wilkinson, Suet C. Leung, Neil G. Berry, Nicholas R. Casewell, P. O’Neill
High Resolution Image Download MS PowerPoint Slide Snakebite envenoming is a neglected tropical disease that causes high mortality and morbidity. The current treatment, intravenous antivenom, comes with numerous disadvantages, making new therapeutics important. Optimized small molecules offer the possibility for oral use at the onset of envenoming, and the highly pathogenic, zinc-dependent snake venom metalloproteinase toxin family represents an attractive target for drug discovery. Through systematic chemical modification guided by molecular modeling, we describe the development of hydroxamic acid 23 (DC-174), a molecule that displays potent broad-spectrum metalloproteinase inhibition (IC50s < 10 nM) and neutralizes the procoagulant activities of multiple snake venoms. In oral dosing studies, 23 showed preclinical efficacy in a mouse model of severe envenoming, with efficacy boosted by a pharmacokinetically informed multiple dosing regimen. This rationally designed, orally bioavailable metalloproteinase inhibitor represents an excellent lead compound for the development of a small-molecule drug treatment for snakebite.