RESUMEN
The COVID-19 pandemic has highlighted the urgent need for the identification of new antiviral drug therapies for a variety of diseases. COVID-19 is caused by infection with the human coronavirus SARS-CoV-2, while other related human coronaviruses cause diseases ranging from severe respiratory infections to the common cold. We developed a computational approach to identify new antiviral drug targets and repurpose clinically-relevant drug compounds for the treatment of a range of human coronavirus diseases. Our approach is based on graph convolutional networks (GCN) and involves multiscale host-virus interactome analysis coupled to off-target drug predictions. Cell-based experimental assessment reveals several clinically-relevant drug repurposing candidates predicted by the in silico analyses to have antiviral activity against human coronavirus infection. In particular, we identify the MET inhibitor capmatinib as having potent and broad antiviral activity against several coronaviruses in a MET-independent manner, as well as novel roles for host cell proteins such as IRAK1/4 in supporting human coronavirus infection, which can inform further drug discovery studies.
Asunto(s)
Antivirales/farmacología , Coronavirus/efectos de los fármacos , Coronavirus/metabolismo , Desarrollo de Medicamentos/métodos , Reposicionamiento de Medicamentos/métodos , Benzamidas/farmacología , Línea Celular , Simulación por Computador , Coronavirus/química , Bases de Datos Farmacéuticas , Descubrimiento de Drogas/métodos , Interacciones Huésped-Patógeno , Humanos , Imidazoles/farmacología , Quinasas Asociadas a Receptores de Interleucina-1/metabolismo , SARS-CoV-2/química , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/metabolismo , SARS-CoV-2/fisiología , Triazinas/farmacología , Tratamiento Farmacológico de COVID-19RESUMEN
Type I interferons (IFNs) are our first line of defense against virus infection. Recent studies have suggested the ability of SARS-CoV-2 proteins to inhibit IFN responses. Emerging data also suggest that timing and extent of IFN production is associated with manifestation of COVID-19 severity. In spite of progress in understanding how SARS-CoV-2 activates antiviral responses, mechanistic studies into wild-type SARS-CoV-2-mediated induction and inhibition of human type I IFN responses are scarce. Here we demonstrate that SARS-CoV-2 infection induces a type I IFN response in vitro and in moderate cases of COVID-19. In vitro stimulation of type I IFN expression and signaling in human airway epithelial cells is associated with activation of canonical transcriptions factors, and SARS-CoV-2 is unable to inhibit exogenous induction of these responses. Furthermore, we show that physiological levels of IFNα detected in patients with moderate COVID-19 is sufficient to suppress SARS-CoV-2 replication in human airway cells.