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

Fatema Rahman,Imin Wushur,Jan-Olof Winberg,Ingebrigt Sylte,Pål Rongved,Nabin Malla,Ove Alexander Høgmoen Åstrand

doi:10.3390/molecules27010056

Fatema Rahman, Imin Wushur + Show 5 more

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https://doi.org/10.3390/molecules27010056

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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.

Highlights

IntroductionProteases (proteinases, peptidases, proteolytic enzymes) are involved in a variety of biological processes and comprise many enzymes in different families with structural and catalytic diversity
Received: 24 November 2021Proteases are involved in a variety of biological processes and comprise many enzymes in different families with structural and catalytic diversity
We decided to test if the 20 compounds are time-dependent inhibitors of the bacterial virulence factors TLN, PLN and ALN and two human zinc metalloproteases, matrix metalloprotease-9 (MMP-9) and matrix metalloprotease-14 (MMP-14)

Summary

Introduction

Proteases (proteinases, peptidases, proteolytic enzymes) are involved in a variety of biological processes and comprise many enzymes in different families with structural and catalytic diversity. Proteases are involved in processes such as generation of nutrition, growth, survival, virulence, and formation of biofilm [8,9]. Metalloproteases are a heterogeneous group of proteases using a metal ion to bind the substrate and polarize a water molecule to perform the hydrolytic reaction. One of the human enzyme families that utilize a zinc-ion in the hydrolytic reactions is the matrix metalloproteases (MMPs). They belong to the M10 family of proteases [15], are calciumdependent, and contain both a catalytic and a structural zinc ion [16]. The catalytic zinc is coordinated by three histidine residues and a water molecule in activated MMPs [17,18], and Accepted: 20 December 2021

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