Zinc-Chelating Compounds as Inhibitors of Human and Bacterial Zinc Metalloproteases |
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| Authors: | Fatema Rahman Imin Wushur Nabin Malla Ove Alexander Hgmoen strand Pl Rongved Jan-Olof Winberg Ingebrigt Sylte |
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| Institution: | 1.Molecular Pharmacology and Toxicology, Department of Medical Biology, Faculty of Health Sciences, UiT—The Arctic University of Norway, NO-9037 Tromsø, Norway; (F.R.); (I.W.); (N.M.); (J.-O.W.);2.Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, NO-0316 Oslo, Norway; (O.A.H.Å.); (P.R.) |
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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. |
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| Keywords: | bacterial virulence factors matrix metalloproteases zinc chelators enzyme inhibition docking molecular interactions |
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