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Quinolinonyl Non-Diketo Acid Derivatives as Inhibitors of HIV-1 Ribonuclease H and Polymerase Functions of Reverse Transcriptase.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2021 Jun 24; Vol. 64 (12), pp. 8579-8598. Date of Electronic Publication: 2021 Jun 09. - Publication Year :
- 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 Mg <superscript>2+</superscript> titration experiments demonstrated that our compounds coordinate the Mg <superscript>2+</superscript> 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.
- Subjects :
- Anti-HIV Agents chemical synthesis
Anti-HIV Agents metabolism
HeLa Cells
Humans
Magnesium metabolism
Microbial Sensitivity Tests
Molecular Docking Simulation
Mutagenesis, Site-Directed
Mutation
Protein Binding
Quinolones chemical synthesis
Quinolones metabolism
Reverse Transcriptase Inhibitors chemical synthesis
Reverse Transcriptase Inhibitors metabolism
Ribonuclease H, Human Immunodeficiency Virus genetics
Ribonuclease H, Human Immunodeficiency Virus metabolism
Virus Replication drug effects
Anti-HIV Agents pharmacology
HIV-1 enzymology
Quinolones pharmacology
Reverse Transcriptase Inhibitors pharmacology
Ribonuclease H, Human Immunodeficiency Virus antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 64
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 34106711
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.1c00535