Mechanistic investigations of matrix metalloproteinase-8 inhibition by metal abstraction peptide

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Abstract
The mechanism of matrix metalloproteinase-8 (MMP-8) inhibition was investigated using ellipsometric measurements of the interaction of MMP-8 with a surface bound peptide inhibitor, tether-metal abstraction peptide (MAP), bound to self-assembled monolayer films. MMP-8 is a collagenase whose activity and dysregulation have been implicated in a number of disease states, including cancer metastasis, diabetic neuropathy, and degradation of biomedical reconstructions, including dental restorations. Regulation of activity of MMP-8 and other matrix metalloproteinases is thus a significant, but challenging, therapeutic target. Strong inhibition of MMP-8 activity has recently been achieved via the small metal binding peptide tether-MAP. Here, the authors elucidate the mechanism of this inhibition and demonstrate that it occurs through the direct interaction of the MAP Tag and the Zn2+ binding site in the MMP-8 active site. This enhanced understanding of the mechanism of inhibition will allow the design of more potent inhibitors as well as assays important for monitoring critical MMP levels in disease states.
Funding Information
  • National Institute of Dental and Craniofacial Research (DE022054-03, R01-DE014392)
  • National Institutes of Health (P20 RR017708, T32GM008545)

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