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Nat Commun ; 12(1): 3309, 2021 06 03.
Artículo en Inglés | MEDLINE | ID: mdl-34083527

RESUMEN

The ongoing pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), necessitates strategies to identify prophylactic and therapeutic drug candidates for rapid clinical deployment. Here, we describe a screening pipeline for the discovery of efficacious SARS-CoV-2 inhibitors. We screen a best-in-class drug repurposing library, ReFRAME, against two high-throughput, high-content imaging infection assays: one using HeLa cells expressing SARS-CoV-2 receptor ACE2 and the other using lung epithelial Calu-3 cells. From nearly 12,000 compounds, we identify 49 (in HeLa-ACE2) and 41 (in Calu-3) compounds capable of selectively inhibiting SARS-CoV-2 replication. Notably, most screen hits are cell-line specific, likely due to different virus entry mechanisms or host cell-specific sensitivities to modulators. Among these promising hits, the antivirals nelfinavir and the parent of prodrug MK-4482 possess desirable in vitro activity, pharmacokinetic and human safety profiles, and both reduce SARS-CoV-2 replication in an orthogonal human differentiated primary cell model. Furthermore, MK-4482 effectively blocks SARS-CoV-2 infection in a hamster model. Overall, we identify direct-acting antivirals as the most promising compounds for drug repurposing, additional compounds that may have value in combination therapies, and tool compounds for identification of viral host cell targets.


Asunto(s)
Antivirales/farmacología , Tratamiento Farmacológico de COVID-19 , Reposicionamiento de Medicamentos/métodos , Pandemias , SARS-CoV-2 , Animales , COVID-19/prevención & control , COVID-19/virología , Línea Celular , Citidina/administración & dosificación , Citidina/análogos & derivados , Citidina/farmacología , Bases de Datos Farmacéuticas , Descubrimiento de Drogas/métodos , Evaluación Preclínica de Medicamentos/métodos , Células HeLa , Ensayos Analíticos de Alto Rendimiento/métodos , Humanos , Hidroxilaminas/administración & dosificación , Hidroxilaminas/farmacología , Mesocricetus , Nelfinavir/farmacología , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/fisiología , Replicación Viral/efectos de los fármacos
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