AKNIN, Cindy; SMITH, Elena; MARCHAND, Christophe; ANDRÉOLA, Marie-Line; POMMIER, Yves; MÉTIFIOT, Mathieu

doi:10.3390/molecules24203675

AKNIN, Cindy
Université de Bordeaux [UB]

SMITH, Elena

MARCHAND, Christophe

Langue

Article de revue

Ce document a été publié dans

Molecules. 2019-10, vol. 24, n° 20, p. 3675

Résumé en anglais

Currently, an increasing number of drugs are becoming available to clinics for the treatment of HIV infection. Even if this targeted therapy is highly effective at suppressing viral replication, caregivers are facing growing therapeutic failures in patients, due to resistance with or without treatment adherence concerns. Accordingly, it is important to continue to discover small molecules that have a novel mechanism of inhibition. In this work, HIV integrase inhibitors were selected by high-throughput screening. Chemical structure comparisons enabled the identification of stilbene disulfonic acids as a potential new chemotype. Biochemical characterization of the lead compound stilbenavir (NSC34931) and a few derivatives was performed. Stilbene disulfonic acid derivatives exhibit low to sub-micromolar antiviral activity, and they inhibit integrase through DNA-binding inhibition. They probably bind to the C-terminal domain of integrase, in the cavity normally occupied by the noncleaved strand of the viral DNA substrate. Because of this original mode of action compared to active site strand transfer inhibitors, they do not exhibit cross-resistance to the three main resistance pathways to integrase inhibitors (G140S-Q148H, N155H, and Y143R). Further structure-activity optimization should enable the development of more active and less toxic derivatives with potential clinical relevance.< Réduire

Mots clés en anglais

HIV-1

INSTI resistance

DNA-binding inhibitor

high-throughput screening

drug discovery

URI

https://oskar-bordeaux.fr/handle/20.500.12278/182653

DOI

http://dx.doi.org/10.3390/molecules24203675

Unités de recherche

MFP (Laboratoire Microbiologie Fondamentale et Pathogénicité) - UMR 5234

Voir/Ouvrir

Métadonnées

Partager cette publication !

Licence d’utilisation du document

Discovery of Novel Integrase Inhibitors Acting outside the Active Site Through High-Throughput Screening

Langue

Ce document a été publié dans

Résumé en anglais

Mots clés en anglais

URI

DOI

Unités de recherche