The Prolyl-tRNA Synthetase Inhibitor Halofuginone Inhibits SARS-CoV-2 Infection
Sandoval, D. R.; Mandel Clausen, T.; Nora, C.; Magida, J. A.; Cribbs, A. P.; Denardo, A.; Clark, A. E.; Garretson, A. F.; Coker, J. K. C.; Narayanan, A.; Majowicz, S. A.; Philpott, M.; Johansson, C.; Dunford, J. E.; Spliid, C. B.; Golden, G. J.; Payne, N. C.; Tye, M. A.; Nowell, C. J.; Griffis, E. R.; Piermatteo, A.; Grunddal, K. V.; Alle, T.; Hauser, B. M.; Feldman, J.; Caradonna, T. M.; Pu, Y.; Yin, X.; McVicar, R. N.; Kwong, E. M.; Tsimikas, S.; Schmidt, A. G.; Ballatore, C.; Zengler, K.; Chanda, S. K.; Weiss, R. J.; Downes, M.; Evans, R. M.; Croker, B. A.; Leibel, S. L.; Jose, J.; Mazitsch
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Summary ParagraphWe identify the prolyl-tRNA synthetase (PRS) inhibitor halofuginone1, a compound in clinical trials for anti-fibrotic and anti-inflammatory applications2, as a potent inhibitor of SARS-CoV-2 infection and replication. The interaction of SARS-CoV-2 spike protein with cell surface heparan sulfate (HS) promotes viral entry3. We find that halofuginone reduces HS biosynthesis, thereby reducing spike protein binding, SARS-CoV-2 pseudotyped virus, and authentic SARS-CoV-2 infection. Halofuginone also potently suppresses SARS-CoV-2 replication post-entry and is 1,000-fold more potent than Remdesivir4. Inhibition of HS biosynthesis and SARS-CoV-2 infection depends on specific inhibition of PRS, possibly due to translational suppression of proline-rich proteins. We find that pp1a and pp1ab polyproteins of SARS-CoV-2, as well as several HS proteoglycans, are proline-rich, which may make them particularly vulnerable to halofuginones translational suppression. Halofuginone is orally bioavailable, has been evaluated in a phase I clinical trial in humans and distributes to SARS-CoV-2 target organs, including the lung, making it a near-term clinical trial candidate for the treatment of COVID-19.
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