Development of Potent Inhibitors of the Mycobacterium tuberculosis Virulence Factor Zmp1 and Evaluation of Their Effect on Mycobacterial Survival inside Macrophages
| Autor: | Stefania Butini, Delia Goletti, Ilaria Pepponi, Maurizio Anzini, Giovanni Delogu, Marco Paolino, Andrea Cappelli, Stefania Lamponi, Germano Giuliani, Davide M. Ferraris, Simone Brogi, Chiara Nannicini, Sandra Gemma, Ivana Palucci, Massimo Coletta, Mariachiara Minerva, Alessandra Vallone, Giuseppe Campiani, Diego Sbardella, Gianluca Giorgi, Stefano Marini, Margherita Brindisi |
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| Přispěvatelé: | Paolino, Marco, Brindisi, Margherita, Vallone, Alessandra, Butini, Stefania, Campiani, Giuseppe, Nannicini, Chiara, Giuliani, Germano, Anzini, Maurizio, Lamponi, Stefania, Giorgi, Gianluca, Sbardella, Diego, Ferraris, Davide M, Marini, Stefano, Coletta, Massimo, Palucci, Ivana, Minerva, Mariachiara, Delogu, Giovanni, Pepponi, Ilaria, Goletti, Delia, Cappelli, Andrea, Gemma, Sandra, Brogi, Simone |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Models Molecular Mycobacterium tuberculosi 8-hydroxyquinoline-2-hydroxamate Mycobacterium tuberculosis QPLD Zmp1 metalloprotease inhibitors Animals Anti-Bacterial Agents Bacterial Proteins Humans Hydroxamic Acids Hydroxyquinolines Kinetics Macrophages Metalloproteases Mice Microbial Sensitivity Tests Molecular Structure 01 natural sciences Biochemistry Virulence factor Models Drug Discovery General Pharmacology Toxicology and Pharmaceutics Cytotoxicity chemistry.chemical_classification Metalloproteinase biology Molecular Medicine Intracellular Toxicology and Pharmaceutics (all) Settore MED/07 - MICROBIOLOGIA E MICROBIOLOGIA CLINICA Microbiology 03 medical and health sciences Settore BIO/10 Pharmacology Pharmacology Toxicology and Pharmaceutics (all) Organic Chemistry 010405 organic chemistry Active site Molecular biology.organism_classification 0104 chemical sciences 030104 developmental biology Enzyme chemistry biology.protein Mycobacterium |
| Popis: | The enzyme Zmp1 is a zinc-containing peptidase that plays a critical role in the pathogenicity of Mycobacterium tuberculosis. Herein we describe the identification of a small set of Zmp1 inhibitors based on a novel 8-hydroxyquinoline-2-hydroxamate scaffold. Among the synthesized compounds, N-(benzyloxy)-8-hydroxyquinoline-2-carboxamide (1 c) was found to be the most potent Zmp1 inhibitor known to date, and its binding mode was analyzed both by kinetics studies and molecular modeling, identifying critical interactions of 1 c with the zinc ion and residues in the active site. The effect of 1 c on intracellular Mycobacterium survival was assayed in J774 murine macrophages infected with M. tuberculosis H37Rv or M. bovis BCG and human monocyte-derived macrophages infected with M. tuberculosis H37Rv. Cytotoxicity and genotoxicity were also assessed. Overall, inhibitor 1 c displays interesting in vitro antitubercular properties worthy of further investigation. |
| Databáze: | OpenAIRE |
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