Citation:
J Am Chem Soc. 2013 Jun 19;135(24):9139-48. doi: 10.1021/ja403523p. Epub 2013 Jun 6.
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 modifi-cation 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 (MMP-14).
Epub:
Not Epub
Link to Publication:
http://pubs.acs.org/doi/abs/10.1021/ja403523p
Organism or Cell Type:
zebrafish
Delivery Method:
Microinjection