1. Coupling Protein Engineering with Probe Design To Inhibit and Image Matrix Metalloproteinases with Controlled Specificity.
- Author
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Morell, Montse, Nguyen Duc, Thinh, Willis, Amanda L., Syed, Salahuddin, Jiyoun Lee, Edgar Deu, Yang Deng, Junpeng Xiao, Turk, Benjamin E., Jessen, Jason R., Weiss, Stephen J., and Bogyo, Matthew
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MATRIX metalloproteinases , *PATHOLOGICAL physiology , *PROTEIN engineering , *CYSTEINE , *PROTEOLYTIC enzymes , *ELECTROPHILES , *TISSUE inhibitors of metalloproteinases , *CROSSLINKING (Polymerization) - Abstract
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). [ABSTRACT FROM AUTHOR]
- Published
- 2013
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