Quinolinonyl Non-Diketo Acid Derivatives as Inhibitors of HIV-1 Ribonuclease H and Polymerase Functions of Reverse Transcriptase
| Autor: | Nicole Grandi, Enzo Tramontano, Francesca Esposito, Davide Ialongo, Alessandro De Leo, Giorgio Amendola, Daniela De Vita, Antonella Messore, Valentina Noemi Madia, Marie-Line Andreola, Ettore Novellino, Mathieu Métifiot, Sandro Cosconati, Roberta Costi, Angela Corona, Roberto Di Santo, Valeria Tudino, Francesco Saccoliti, Luigi Scipione |
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| Přispěvatelé: | Microbiologie Fondamentale et Pathogénicité [Bordeaux] (MFP), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Messore, A., Corona, A., Madia, V. N., Saccoliti, F., Tudino, V., De Leo, A., Ialongo, D., Scipione, L., De Vita, D., Amendola, G., Novellino, E., Cosconati, S., Metifiot, M., Andreola, M. -L., Esposito, F., Grandi, N., Tramontano, E., Costi, R., Di Santo, R. |
| Rok vydání: | 2021 |
| Předmět: |
Quinolone
Anti-HIV Agents Microbial Sensitivity Tests Quinolones HeLa Cell Virus Replication 01 natural sciences Article 03 medical and health sciences Drug Discovery Humans Ribonuclease H Human Immunodeficiency Viru Magnesium AIDS HIV rNase H inhibitors Quinolinonyl non-diketo acid derivatives RNase H ComputingMilieux_MISCELLANEOUS Polymerase 030304 developmental biology chemistry.chemical_classification 0303 health sciences biology Microbial Sensitivity Test [CHIM.ORGA]Chemical Sciences/Organic chemistry Chemistry Anti-HIV Agent Reverse transcriptase Reverse Transcriptase Inhibitor 3. Good health 0104 chemical sciences Amino acid Integrase Molecular Docking Simulation 010404 medicinal & biomolecular chemistry Ribonuclease H Human Immunodeficiency Virus Enzyme Biochemistry Viral replication Docking (molecular) Mutation [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology HIV-1 Mutagenesis Site-Directed biology.protein Reverse Transcriptase Inhibitors Molecular Medicine Human HeLa Cells Protein Binding |
| Zdroj: | Journal of Medicinal Chemistry Journal of Medicinal Chemistry, American Chemical Society, 2021, 64 (12), pp.8579-8598. ⟨10.1021/acs.jmedchem.1c00535⟩ |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.1c00535 |
| Popis: | Novel anti-HIV agents are still needed to overcome resistance issues, in particular inhibitors acting against novel viral targets. The ribonuclease H (RNase H) function of the reverse transcriptase (RT) represents a validated and promising target, and no inhibitor has reached the clinical pipeline yet. Here, we present rationally designed non-diketo acid selective RNase H inhibitors (RHIs) based on the quinolinone scaffold starting from former dual integrase (IN)/RNase H quinolinonyl diketo acids. Several derivatives were synthesized and tested against RNase H and viral replication and found active at micromolar concentrations. Docking studies within the RNase H catalytic site, coupled with site-directed mutagenesis, and Mg2+ titration experiments demonstrated that our compounds coordinate the Mg2+ cofactor and interact with amino acids of the RNase H domain that are highly conserved among naïve and treatment-experienced patients. In general, the new inhibitors influenced also the polymerase activity of RT but were selective against RNase H vs the IN enzyme. |
| Databáze: | OpenAIRE |
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