ABSTRACT
The current emergency of the novel coronavirus SARS-CoV-2 urged the need for broad-spectrum antiviral drugs as the first line of treatment. Coronaviruses are a large family of viruses that already challenged humanity in at least two other previous outbreaks and are likely to be a constant threat for the future. In this work we developed a pipeline based on in silico docking of known drugs on SARS-CoV RNA-dependent RNA polymerase combined with in vitro antiviral assays on both SARS-CoV-2 and the common cold human coronavirus HCoV-OC43. Results showed that certain drugs displayed activity for both viruses at a similar inhibitory concentration, while others were specific. In particular, the antipsychotic drug lurasidone and the antiviral drug elbasvir showed promising activity in the low micromolar range against both viruses with good selective index.
ABSTRACT
Repurposing clinically available drugs to treat the new coronavirus disease COVID-19 is an urgent need in these early stages of the SARS-CoV-2 pandemic, when very few treatment options are available. The iminosugar Miglustat is a well-characterized drug for the treatment of rare genetic lysosome storage diseases such as Gaucher and Niemann-Pick type C, and has also been described to be active against a variety of enveloped viruses. The activity of Miglustat is here demonstrated for SARS-CoV-2 at concentrations achievable in the plasma by current clinical regimens without cytotoxicity. The drug acts at the post-entry level and leads to a marked decrease of viral proteins and release of infectious virus. The mechanism resides in the inhibitory activity towards -glucosidases that are involved in early stages of glycoprotein N-linked oligosaccharide processing in the endoplasmic reticulum, leading to a marked decrease of the viral Spike protein. The wealth of available data on the clinical use of Miglustat for the treatment of lysosomal storage disorders and the antiviral properties against SARS-CoV-2 make it an ideal candidate for drug repurposing.