Coupling Protein Engineering with Probe Design To Inhibit and Image Matrix Metalloproteinases with Controlled Specificity

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• 作者：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
• 刊名：The Journal of the American Chemical Society
• 出版年：2013
• 出版时间：June 19, 2013
• 年：2013
• 卷：135
• 期：24
• 页码：9139-9148
• 全文大小：440K
• 年卷期：v.135,no.24(June 19, 2013)
• ISSN：1520-5126

文摘

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).