An Abiotic Mimic of Endogenous Tissue Inhibitors of Metalloproteinases. Engineering Synthetic Polymer Nanoparticles for use as a Broad-Spectrum Metalloproteinase Inhibitor

We describe a process for engineering a synthetic polymer nanoparticle (NP) that functions as an effective, broad-spectrum metalloproteinase inhibitor. Inhibition is achieved by incorporating three functional elements in the NP; a group that interacts with the catalytic zinc ion, functionality that enhances affinity to the substrate-binding pocket and by fine-tuning the chemical composition of the polymer to strengthen NP affinity for the enzyme surface. The approach is validated by synthesis of a NP that sequesters and inhibits the proteolytic activity of snake venom metalloproteinases from five clinically relevant species of snakes. The mechanism of action of the NP mimics that of endog-enous tissue inhibitors of metalloproteinases. The strategy pro-vides a general design principle for synthesizing abiotic polymer inhibitors of enzymes.