Targeting the Integrated Stress Response Kinase GCN2 to Modulate Retroviral Integration.
Chloé TorresAsja GarlingSaïd TaoujiChristina CalmelsMarie-Line AndreolaMathieu MétifiotPublished in: Molecules (Basel, Switzerland) (2021)
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.
Keyphrases
- antiretroviral therapy
- hiv positive
- hiv infected
- hiv testing
- human immunodeficiency virus
- hiv aids
- hepatitis c virus
- protein kinase
- men who have sex with men
- transcription factor
- sars cov
- high throughput
- ejection fraction
- newly diagnosed
- south africa
- primary care
- cancer therapy
- palliative care
- randomized controlled trial
- metabolic syndrome
- chronic kidney disease
- patient reported outcomes
- clinical trial
- skeletal muscle
- prognostic factors
- drug delivery
- drug administration
- combination therapy
- weight loss