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Updated: Aug 6, 2026
Structure and Coordination Determination of Peptide-metal Complexes Using 1D and 2D 1H NMR
Published on: December 16, 2013
Comparative coordination chemistry of MMP-14 peptide inhibitors: histamine-like coordination and poly-glycine effect
Martyna Zawada1, Paulina Potok1, Robert Wieczorek1
1Faculty of Chemistry, University of Wroclaw, 14 Joliot-Curie St., 50-383 Wroclaw, Poland. slawomir.potocki@uwr.edu.pl.
Abstract:
The rational design of matrix metalloproteinase (MMP) inhibitors, such as those targeted for MMP-14, prioritizes the native Zn(II) cofactor. The elevated levels of Cu(II), which are characteristic of the tumor microenvironment, are often overlooked. In this study, we investigated the Cu(II) coordination chemistry of selected MMP-14 inhibitors using potentiometric titrations, UV-Vis spectroscopy, circular dichroism, and density functional theory. Our findings reveal a striking inversion of metal selectivity in comparison with previously studied Zn(II) complexes. While Inhibitor 1 (Inh1) retains high specificity for the native Zn(II) active site, Inhibitor 4 (Inh4) exhibits exceptional thermodynamic stability with Cu(II) (pKd = 11.87). Inh4 favors copper over zinc by more than six orders of magnitude. This remarkable stability comes from a highly pre-organized, histamine-like mixed N/O donor environment and an extended poly-glycine tail. This tail adopts a 310-helical conformation that additionally stabilizes the coordination site and minimizes the entropic penalty of complexation. These results demonstrate that while Inh1 remains a highly specific candidate for targeted MMP-14 inhibition, the pronounced selectivity gap of Inh4 transforms it into a highly specific Cu(II) scavenger. This study highlights the critical risk of off-target metal sequestration in the tumor microenvironment while simultaneously opening the door to the potential repurposing of Inh4 as a targeted, copper-depleting agent in anti-angiogenic therapies.
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