Halofuginone is a potent inhibitor of SARS-CoV-2 Infection and Replication [Exp3]

Here we identify halofuginone, a Prolyl-tRNA Synthetase (PRS) inhibitors as a potent inhibitors of SARS-CoV-2 cellular entry and viral replication. To infect the host cell, the SARS-CoV-2 spike protein interacts with cell surface heparan sulfate (HS) and angiotensin-converting enzyme 2 (ACE2) through its Receptor Binding Domain. Removal of cell surface HS or blockade of HS biosynthesis represents a promising clinical target for treatment of SARS-CoV-2. In vitro studies confirm that halofuginone and PRS inhibitors prevent HS biosynthesis and thereby HS cell surface presentation and Spike protein binding. Halofuginone also suppresses authentic SARS-CoV-2 infection by inhibiting PRS activity, which decreases the translation efficiency of proline-rich HS biosynthetic enzymes and essential SARS-CoV-2 proteins after infection. Thus, halofuginone inhibits SARS-CoV-2 at both attachment and post-entry steps and blocks SARS-CoV-2 infection of human lung airway epithelial cells at low nanomolar concentrations. These findings support the use of halofuginone, an orally bioavailable anti-fibrotic and anti-inflammatory compound with encouraging clinical phase 1 safety data, as an antiviral drug to prevent SARS-CoV-2 infection. Overall design: Examination of the effect of Halofuginone, Borrelidin, ProSA, SerSA VeroE6 cells