RESUMO
The emergence of SARS-CoV-2 virus has resulted in a worldwide pandemic, but effective antiviral therapies are not widely available. To improve treatment options, we conducted a high-throughput screen to uncover compounds that block SARS-CoV-2 infection. A minimally pathogenic human betacoronavirus (OC43) was used to infect physiologically-relevant human pulmonary fibroblasts (MRC5) to facilitate rapid antiviral discovery in a preclinical model. Comprehensive profiling was conducted on more than 600 compounds, with each compound arrayed across 10 dose points. Our screening revealed several FDA-approved agents that can attenuate both OC43 and SARS-CoV-2 viral replication, including lapatinib, doramapimod, and 17-AAG. Importantly, lapatinib inhibited SARS-CoV-2 RNA replication by over 50,000-fold. Further, both lapatinib and doramapimod could be combined with remdesivir to improve antiviral activity in cells. These findings reveal novel therapeutic avenues that could limit SARS-CoV-2 infection.
Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/farmacologia , Tratamento Farmacológico da COVID-19 , Lapatinib/farmacologia , SARS-CoV-2/efeitos dos fármacos , Monofosfato de Adenosina/farmacologia , Alanina/farmacologia , Animais , Benzoquinonas/farmacologia , COVID-19/virologia , Linhagem Celular , Chlorocebus aethiops , Combinação de Medicamentos , Descoberta de Drogas , Sinergismo Farmacológico , Ensaios de Triagem em Larga Escala , Humanos , Lactamas Macrocíclicas/farmacologia , Naftalenos/farmacologia , Compostos de Fenilureia/farmacologia , Pirazóis/farmacologia , RNA Viral/metabolismo , Células Vero , Replicação Viral/efeitos dos fármacosRESUMO
Negative pressure ventilation (NPV) was applied for 6 to 8 h/day for 2 consecutive days in 13 patients with severe airflow limitation and chronic respiratory failure. After cessation of NPV, the mean arterial blood gases were improved in 10 patients, and this improvement was sustained for the nex 2 days in eight patients, for 3 days in seven patients, and was still present in four patients on the fourth day. Respiratory muscle strength improved in all patients, but there was no relationship between the increase in strength and sustained improvement in gas exchange. Ventilation and respiratory pattern were unchanged in all patients, but the mean VD/VT fell and VA rose while the VO2 and VCO2 fell. The ventilatory responses to hypoxia and hypercapnia increased in patients who demonstrated sustained improvement in blood gases. The mechanism underlying the sustained improvement in gas exchange following NPV is not clear but is likely multifactorial.