Enzyme inhibition is a therapeutically important approach to regulate many biological processes. Enzyme inhibitors may be based on small molecules, biomacromolecules and/or synthetic polymers. In this study, we hypothesized that synthetic polymer nanoparticles (NPs) displaying both inhibitor-bearing groups and hydrophobic functional groups can achieve high inhibition for a target enzyme. We describe efforts to synthesize polymer NP inhibitors against snake venom metalloproteinases (SVMPs), one of the major families of toxic proteins found in venomous snakes. Traditional antivenom, comprised of antibodies isolated from the blood of large mammals inoculated with venom, is utilized as an antidote for snake bite. However, SVMPs, major contributors to tissue necrosis, are fast acting and even in the event that traditional immunological therapy can be administered in a timely manor, it does little to mitigate morbid injuries at the site of envenomation. Further complicating an effective therapeutic intervention is the fact that SVMPs are not pure substances, they consist of many isoforms, which can moderate the therapeutic efficacy. Our goal is to develop a stable and inexpensive abiotic NP therapeutic intervention with broad spectrum efficacy against SVMPs. We selected whole venom from Crotalus atrox, a typical SVMP rich venom as a target for our studies. SVMPs are zinc ion dependent enzymes and their catalytic domains are highly conserved. Lead NP candidates were identified by directed chemical evolution, a process involving synthesizing and screening synthetic polymer libraries of poly-N-isopropylacrylamide based NPs with various functional groups. Promising candidates were found to require both inhibitor and hydrophobic groups. The talk will describe progress towards developing an effective, broad-spectrum abiotic inhibitor for SVMP.

Design of synthetic polymer nanoparticles for metalloproteinase inhibition

2019 Fall National Meeting

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