Title :

Magnesium Chelating 2-Hydroxyisoquinoline-1,3(2H,4H)-diones, as Inhibitors of HIV-1 Integrase and/or the HIV-1 Reverse Transcriptase Ribonuclease H Domain: Discovery of a Novel Selective Inhibitor of the Ribonuclease H Function

Author(s) :

Billamboz, Muriel [Auteur]
Chimie Moléculaire et Formulation - EA 4478 [CMF]
Bailly, Fabrice [Auteur]
Chimie Moléculaire et Formulation - EA 4478 [CMF]
Lion, Cédric [Auteur]
Chimie Moléculaire et Formulation - EA 4478 [CMF]
Touati, Nadia [Auteur]
Laboratoire de Chimie Organique et Macromoleculaire [UMR CNRS 8009]
Vezin, Herve [Auteur]
Laboratoire de Chimie Organique et Macromoleculaire [UMR CNRS 8009]
Calmels, Christina [Auteur]
Andréola, Marie-Line [Auteur]
Christ, Frauke [Auteur]
Debyser, Zeger [Auteur]
Cotelle, Philippe [Auteur]
Chimie Moléculaire et Formulation - EA 4478 [CMF]

Journal title :

Journal of Medicinal Chemistry

Abbreviated title :

J. Med. Chem.

Volume number :

54

Pages :

1812-1824

Publisher :

American Chemical Society (ACS)

Publication date :

2011-03-24

ISSN :

0022-2623

English keyword(s) :

Peptides and proteins
Ligands
Inhibitors
Magnesium
Transition metals

HAL domain(s) :

Chimie/Chimie théorique et/ou physique

English abstract : [en]

2-Hydroxyisoquinoline-1,3(2H,4H)-dione was recently discovered as a scaffold for the inhibition of HIV-1 integrase and the ribonuclease H function of HIV-1 reverse transcriptase. First, we investigate its interaction with ...
Show more >2-Hydroxyisoquinoline-1,3(2H,4H)-dione was recently discovered as a scaffold for the inhibition of HIV-1 integrase and the ribonuclease H function of HIV-1 reverse transcriptase. First, we investigate its interaction with Mg2+ and Mn2+ using different spectroscopic techniques and report that 2-hydroxyisoquinoline-1,3(2H,4H)-dione forms a 1:1 complex with Mg2+ but a 1:2 complex with Mn2+. The complex formation requires enolization of the ligand. ESR spectroscopy shows a redox reaction between the ligand and Mn2+ producing superoxide anions. Second, 2-hydroxyisoquinoline-1,3(2H,4H)-dione, its magnesium complex, and its 4-methyl and 2-hydroxy-4-methoxycarbonylisoquinoline-1,3(2H,4H)-diones were tested as inhibitors of HIV-1 integrase, reverse transcriptase ribonuclease H, and DNA polymerase functions. Their antiviral activities were evaluated and 2-hydroxy-4-methoxycarbonyl-isoquinoline-1,3(2H,4H)-dione was found to inhibit the viral replication of HIV-1 in MT-4 cells. Cross-resistance was measured for this compound on three different viral strains. Experimental data suggest that the antiviral activity of 2-hydroxy-4-methoxycarbonylisoquinoline-1,3(2H,4H)-dione is probably due to the RNase H inhibition.Show less >

Language :

Anglais

Audience :

Internationale

Popular science :

Non

Administrative institution(s) :

Université de Lille
CNRS

Collections :

• Autres travaux scientifiques

Submission date :

2021-06-18T08:07:31Z
2021-10-08T11:41:08Z