Zinc-Chelating Compounds as Inhibitors of Human and Bacterial Zinc Metalloproteases

Abstract

Inhibition of bacterial virulence is believed to be a new treatment option for bacterial infections. In the present study, we tested dipicolylamine (DPA), tripicolylamine (TPA), tris pyridine ethylene diamine (TPED), pyridine and thiophene derivatives as putative inhibitors of the bacterial virulence factors thermolysin (TLN), pseudolysin (PLN) and aureolysin (ALN) and the human zinc metalloproteases, matrix metalloprotease-9 (MMP-9) and matrix metalloprotease-14 (MMP-14). These compounds have nitrogen or sulfur as putative donor atoms for zinc chelation. In general, the compounds showed stronger inhibition of MMP-14 and PLN than of the other enzymes, with Ki values in the lower μM range. Except for DPA, none of the compounds showed significantly stronger inhibition of the virulence factors than of the human zinc metalloproteases. TPA and Zn230 were the only compounds that inhibited all five zinc metalloproteinases with a Ki value in the lower μM range. The thiophene compounds gave weak or no inhibition. Docking indicated that some of the compounds coordinated zinc by one oxygen atom from a hydroxyl or carbonyl group, or by oxygen atoms both from a hydroxyl group and a carbonyl group, and not by pyridine nitrogen as in DPA and TPA.

Bacterial Zinc Metalloenzyme Inhibitors: Recent Advances and Future Perspectives

“…Moreover, Rahman et al noticed that the substitution of one of the 2-methylpyridine groups of 50 led to a decreasing activity against PLN and MMP-14. Compounds of this series turned out to be reversible inhibitors, in contrast with what is observed for MBLs [37].…”

“…Proteases of the M10 family have a Zn 2+ in the catalytic site coordinated by three histidine residues and one water molecule. Moreover, in the binding pocket the MMPs present the same subsites of the M4 enzymes [37]. However, the particular depth of the S1 subsite might represent a selectivity factor between the M4 and M10 enzymes [38].…”

Molecular strategies to enhance the keratinase gene expression and its potential implications in poultry feed industry

“…Additionally, proteinase itself has the potential to hydrolyze ( Yahaya et al, 2021b ). Proteases are typically released as proenzymes, transmembrane under the direction of signal peptides, and then folded in the periplasmic space to prevent such uncontrolled proteolysis ( Rahman 2023 ). This mechanism involves the propeptide, which contains the inhibitory N-terminal propeptide, and is crucial in directing its proper folding ( Song et al, 2023 ).…”