TORRES, Chloé; GARLING, Asja; TAOUJI, Saïd; CALMELS, Christina; ANDREOLA, Marie-Line; MÉTIFIOT, Mathieu

doi:10.3390/molecules26175423

TORRES, Chloé
Microbiologie Fondamentale et Pathogénicité [MFP]

GARLING, Asja
Microbiologie Fondamentale et Pathogénicité [MFP]

TAOUJI, Saïd

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Article de revue

Ce document a été publié dans

Molecules. 2021, vol. 26, n° 17, p. 5423

Résumé en anglais

Multiple viral targets are now available in the clinic to fight 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 glitches. Accordingly, it is important to better understand how HIV and other retroviruses replicate in order to propose alternative antiviral strategies. Recent studies have shown that multiple cellular factors are implicated during the integration step and, more specifically, that integrase can be regulated through post-translational modifications. We have shown that integrase is phosphorylated by GCN2, a cellular protein kinase of the integrated stress response, leading to a restriction of HIV replication. In addition, we found that this mechanism is conserved among other retroviruses. Accordingly, we developed an in vitro interaction assay, based on the AlphaLISA technology, to monitor the integrase-GCN2 interaction. From an initial library of 133 FDA-approved molecules, we identified nine compounds that either inhibited or stimulated the interaction between GCN2 and HIV integrase. In vitro characterization of these nine hits validated this pilot screen and demonstrated that the GCN2-integrase interaction could be a viable solution for targeting integrase out of its active site.< Réduire

Mots clés en anglais

high-throughput screening

protein–protein interaction

integrated stress response

HIV integration

AlphaLISA

drug repurposing

assay development

URI

https://oskar-bordeaux.fr/handle/20.500.12278/182321

DOI

http://dx.doi.org/10.3390/molecules26175423

Unités de recherche

MFP (Laboratoire Microbiologie Fondamentale et Pathogénicité) - UMR 5234

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Targeting the Integrated Stress Response Kinase GCN2 to Modulate Retroviral Integration

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Résumé en anglais

Mots clés en anglais

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