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

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 Zn 2þ 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.

Threats to adhesive/dentin interfacial integrity and next generation bio‐enabled multifunctional adhesives

“…The binding interaction was reduced by blocking the metal‐binding site in the tether‐MAP. The results suggest that the mechanism for MMP‐8 inhibition by the tether‐MAP peptide occurred through the interaction between the MAP tag and the Zn 2+ active site in MMP‐8 …”

“…The mechanism of MMP‐8 inhibition by the tether‐MAP peptide was investigated in a subsequent study using ellipsometry. Based on the MAP chemistry, it was postulated that MMP‐8 inhibition could involve: (1) shared binding of the zinc ion at the active site of MMP‐8 by the MAP sequence or (2) abstracting the zinc ion from the catalytic portion of the MMP‐8 by the MAP tag . Tether‐MAP was attached to hydroxyl‐ and amine‐terminated self‐assembled monolayers.…”