Zinc-Chelating Compounds as Inhibitors of Human and Bacterial Zinc Metalloproteases
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 virulenc...
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MDPI AG
2021-12-01
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| Online Access: | https://www.mdpi.com/1420-3049/27/1/56 |
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| author | Fatema Rahman Imin Wushur Nabin Malla Ove Alexander Høgmoen Åstrand Pål Rongved Jan-Olof Winberg Ingebrigt Sylte |
| author_facet | Fatema Rahman Imin Wushur Nabin Malla Ove Alexander Høgmoen Åstrand Pål Rongved Jan-Olof Winberg Ingebrigt Sylte |
| author_sort | Fatema Rahman |
| collection | DOAJ |
| description | 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 <i>K</i><sub>i</sub> 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 <i>K</i><sub>i</sub> 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. |
| first_indexed | 2024-03-10T03:30:57Z |
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| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T03:30:57Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-82d8428881e047cba6314decdca3320b2023-11-23T11:56:03ZengMDPI AGMolecules1420-30492021-12-012715610.3390/molecules27010056Zinc-Chelating Compounds as Inhibitors of Human and Bacterial Zinc MetalloproteasesFatema Rahman0Imin Wushur1Nabin Malla2Ove Alexander Høgmoen Åstrand3Pål Rongved4Jan-Olof Winberg5Ingebrigt Sylte6Molecular Pharmacology and Toxicology, Department of Medical Biology, Faculty of Health Sciences, UiT—The Arctic University of Norway, NO-9037 Tromsø, NorwayMolecular Pharmacology and Toxicology, Department of Medical Biology, Faculty of Health Sciences, UiT—The Arctic University of Norway, NO-9037 Tromsø, NorwayMolecular Pharmacology and Toxicology, Department of Medical Biology, Faculty of Health Sciences, UiT—The Arctic University of Norway, NO-9037 Tromsø, NorwayDepartment of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, NO-0316 Oslo, NorwayDepartment of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, NO-0316 Oslo, NorwayMolecular Pharmacology and Toxicology, Department of Medical Biology, Faculty of Health Sciences, UiT—The Arctic University of Norway, NO-9037 Tromsø, NorwayMolecular Pharmacology and Toxicology, Department of Medical Biology, Faculty of Health Sciences, UiT—The Arctic University of Norway, NO-9037 Tromsø, NorwayInhibition 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 <i>K</i><sub>i</sub> 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 <i>K</i><sub>i</sub> 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.https://www.mdpi.com/1420-3049/27/1/56bacterial virulence factorsmatrix metalloproteaseszinc chelatorsenzyme inhibitiondockingmolecular interactions |
| spellingShingle | Fatema Rahman Imin Wushur Nabin Malla Ove Alexander Høgmoen Åstrand Pål Rongved Jan-Olof Winberg Ingebrigt Sylte Zinc-Chelating Compounds as Inhibitors of Human and Bacterial Zinc Metalloproteases Molecules bacterial virulence factors matrix metalloproteases zinc chelators enzyme inhibition docking molecular interactions |
| title | Zinc-Chelating Compounds as Inhibitors of Human and Bacterial Zinc Metalloproteases |
| title_full | Zinc-Chelating Compounds as Inhibitors of Human and Bacterial Zinc Metalloproteases |
| title_fullStr | Zinc-Chelating Compounds as Inhibitors of Human and Bacterial Zinc Metalloproteases |
| title_full_unstemmed | Zinc-Chelating Compounds as Inhibitors of Human and Bacterial Zinc Metalloproteases |
| title_short | Zinc-Chelating Compounds as Inhibitors of Human and Bacterial Zinc Metalloproteases |
| title_sort | zinc chelating compounds as inhibitors of human and bacterial zinc metalloproteases |
| topic | bacterial virulence factors matrix metalloproteases zinc chelators enzyme inhibition docking molecular interactions |
| url | https://www.mdpi.com/1420-3049/27/1/56 |
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