RESUMEN
Emerging new variants of SARS-CoV-2 and inevitable acquired drug resistance call for the continued search of new pharmacological targets to fight the potentially fatal infection. Here, we describe the mechanisms by which the E protein of SARS-CoV-2 hijacks the human transcriptional regulator BRD4. We found that SARS-CoV-2 E is acetylated in vivo and co-immunoprecipitates with BRD4 in human cells. Bromodomains (BDs) of BRD4 bind to the C-terminus of the E protein, acetylated by human acetyltransferase p300, whereas the ET domain of BRD4 recognizes the unmodified motif of the E protein. Inhibitors of BRD4 BDs, JQ1 or OTX015, decrease SARS-CoV-2 infectivity in lung bronchial epithelial cells, indicating that the acetyllysine binding function of BDs is necessary for the virus fitness and that BRD4 represents a potential anti-COVID-19 target. Our findings provide insight into molecular mechanisms that contribute to SARS-CoV-2 pathogenesis and shed light on a new strategy to block SARS-CoV-2 infection.
Asunto(s)
COVID-19 , Proteínas de Ciclo Celular/metabolismo , Proteínas de la Envoltura de Coronavirus/metabolismo , SARS-CoV-2/fisiología , Factores de Transcripción/metabolismo , COVID-19/virología , Humanos , Proteínas Nucleares/metabolismo , Unión Proteica , Dominios ProteicosAsunto(s)
Tratamiento Farmacológico de COVID-19 , Inhibidores de las Quinasa Fosfoinosítidos-3 , SARS-CoV-2 , Antivirales/farmacología , Proteínas de Ciclo Celular/antagonistas & inhibidores , Humanos , Fosfatidilinositol 3-Quinasas , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , SARS-CoV-2/efectos de los fármacos , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Factores de Transcripción/antagonistas & inhibidores , Replicación Viral/efectos de los fármacosRESUMEN
The coronavirus disease 2019 (COVID-19) is a viral disease caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that affects the respiratory system of infected individuals. COVID-19 spreads between humans through respiratory droplets produced when an infected person coughs or sneezes. The COVID-19 outbreak originated in Wuhan, China at the end of 2019. As of 29 Sept 2020, over 235 countries, areas or territories across the globe reported a total of 33,441,919 confirmed cases, and 1,003,497 confirmed deaths due to COVID-19. Individuals of all ages are at risk for infection, but in most cases disease severity is associated with age and pre-existing diseases that compromise immunity, like cancer. Numerous reports suggest that people with cancer can be at higher risk of severe illness and related deaths from COVID-19. Therefore, managing cancer care under this pandemic is challenging and requires a collaborative multidisciplinary approach for optimal care of cancer patients in hospital settings. In this comprehensive review, we discuss the impact of the COVID-19 pandemic on cancer patients, their care, and treatment. Further, this review covers the SARS-CoV-2 pandemic, genome characterization, COVID-19 pathophysiology, and associated signaling pathways in cancer, and the choice of anticancer agents as repurposed drugs for treating COVID-19.