학술논문
Quinolinonyl Non-Diketo Acid Derivatives as Inhibitors of HIV-1 Ribonuclease H and Polymerase Functions of Reverse Transcriptase
Document Type
Article
Author
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
Source
Journal of Medicinal Chemistry; June 2021, Vol. 64 Issue: 12 p8579-8598, 20p
Subject
Language
ISSN
00222623; 15204804
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.