ja403523p_si_001.pdf (3.16 MB)
Coupling Protein Engineering with Probe Design To Inhibit and Image Matrix Metalloproteinases with Controlled Specificity
journal contributionposted on 2013-06-19, 00:00 authored by Montse Morell, Thinh Nguyen Duc, Amanda L. Willis, Salahuddin Syed, Jiyoun Lee, Edgar Deu, Yang Deng, Junpeng Xiao, Benjamin E. Turk, Jason R. Jessen, Stephen J. Weiss, Matthew Bogyo
Matrix metalloproteinases (MMPs) are zinc endopeptidases that play roles in numerous pathophysiological processes and therefore are promising drug targets. However, the large size of this family and a lack of highly selective compounds that can be used for imaging or inhibition of specific MMPs members has limited efforts to better define their biological function. Here we describe a protein engineering strategy coupled with small-molecule probe design to selectively target individual members of the MMP family. Specifically, we introduce a cysteine residue near the active-site of a selected protease that does not alter its overall activity or function but allows direct covalent modification by a small-molecule probe containing a reactive electrophile. This specific engineered interaction between the probe and the target protease provides a means to both image and inhibit the modified protease with absolute specificity. Here we demonstrate the feasibility of the approach for two distinct MMP proteases, MMP-12 and MT1-MMP (or MMP-14).
pathophysiological processesProtein Engineeringdrug targetstarget proteaseMMP proteasesImage Matrix Metalloproteinaseszinc endopeptidasescysteine residueMMP familyreactive electrophileprotein engineering strategyProbe DesignMMPs membersControlled SpecificityMatrix metalloproteinasescovalent modificationprobeMT