Quinolinonyl Non-Diketo Acid Derivatives as Inhibitors of HIV-1 Ribonuclease H and Polymerase Functions of Reverse Transcriptase.
J Med Chem
; 64(12): 8579-8598, 2021 06 24.
Article
en En
| MEDLINE
| ID: mdl-34106711
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.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
VIH-1
/
Quinolonas
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Inhibidores de la Transcriptasa Inversa
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Fármacos Anti-VIH
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Ribonucleasa H del Virus de la Inmunodeficiencia Humana
Límite:
Humans
Idioma:
En
Año:
2021
Tipo del documento:
Article