1. Quinolinonyl Non-Diketo Acid Derivatives as Inhibitors of HIV-1 Ribonuclease H and Polymerase Functions of Reverse Transcriptase
- Author
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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, 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., and Di Santo, R.
- Subjects
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 - Abstract
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.
- Published
- 2021