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.

Quinolinonyl non-diketo acid derivatives as Inhibitors of HIV-1 ribonuclease H and polymerase functions of reverse transcriptase / Messore, Antonella; Corona, Angela; Madia, Valentina Noemi; Saccoliti, Francesco; Tudino, Valeria; De Leo, Alessandro; Ialongo, Davide; Scipione, Luigi; De Vita, Daniela; Amendola, Giorgio; Novellino, Ettore; Cosconati, Sandro; Métifiot, Mathieu; Andreola, Marie-Line; Esposito, Francesca; Grandi, Nicole; Tramontano, Enzo; Costi, Roberta; Di Santo, Roberto. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 64:12(2021), pp. 8579-8598. [10.1021/acs.jmedchem.1c00535]

Quinolinonyl non-diketo acid derivatives as Inhibitors of HIV-1 ribonuclease H and polymerase functions of reverse transcriptase

Messore, Antonella;Madia, Valentina Noemi;Saccoliti, Francesco;Tudino, Valeria;De Leo, Alessandro;Ialongo, Davide;Scipione, Luigi;De Vita, Daniela;Esposito, Francesca;Costi, Roberta
;
Di Santo, Roberto
2021

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.
2021
AIDS;HIV; rNase H inhibitors; Quinolinonyl non-diketo acid derivatives
01 Pubblicazione su rivista::01a Articolo in rivista
Quinolinonyl non-diketo acid derivatives as Inhibitors of HIV-1 ribonuclease H and polymerase functions of reverse transcriptase / Messore, Antonella; Corona, Angela; Madia, Valentina Noemi; Saccoliti, Francesco; Tudino, Valeria; De Leo, Alessandro; Ialongo, Davide; Scipione, Luigi; De Vita, Daniela; Amendola, Giorgio; Novellino, Ettore; Cosconati, Sandro; Métifiot, Mathieu; Andreola, Marie-Line; Esposito, Francesca; Grandi, Nicole; Tramontano, Enzo; Costi, Roberta; Di Santo, Roberto. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 64:12(2021), pp. 8579-8598. [10.1021/acs.jmedchem.1c00535]
File allegati a questo prodotto
File Dimensione Formato  
Messore_Quinolinonyl-Non-Diketo_2021.pdf

solo gestori archivio

Tipologia: Versione editoriale (versione pubblicata con il layout dell'editore)
Licenza: Tutti i diritti riservati (All rights reserved)
Dimensione 3.04 MB
Formato Adobe PDF
3.04 MB Adobe PDF   Contatta l'autore

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1556284
Citazioni
  • ???jsp.display-item.citation.pmc??? 2
  • Scopus 8
  • ???jsp.display-item.citation.isi??? 9
social impact