Repozytorium
Wyszukaj
Kolekcje
Inne
Comparative coordination chemistry of MMP-14 peptide inhibitors: histamine-like coordination and poly-glycine effect in Cu(II) complexes
Autorzy
Rok wydania
2026
Czasopismo
Numer woluminu
55
Strony
11644-11659
DOI
10.1039/d6dt01088a
Kolekcja
Język
Angielski
Typ publikacji
Artykuł
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.
Licencja otwartego dostępu
Licencja na prawach której można swobodnie kopiować, rozprowadzać, zmieniać i remiksować objęty prawem autorskim utwór (Utwór-przedmiot prawa autorskiego) pod warunkiem podania imienia i nazwiska autora utworu pierwotnego oraz źródła pochodzenia utworu.
Pełny tekst licencji: https://creativecommons.org/licenses/by/3.0/pl/legalcode
Adres publiczny
http://dx.doi.org/10.1039/d6dt01088a
Strona internetowa wydawcy
Podobne publikacje
Competition between histamine-like and poly-imidazole coordination sites for Cu2+ and Zn2+ ions in zebra-fish peptide of prion-like protein.
Migliorini Caterina, Witkowska Danuta, Valensin Daniela, Kamysz Wojciech, Kozłowski Henryk