Identification of DC-174 as a Novel Hydroxamic Precandidate for the Development of an Oral Snakebite Treatment

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.