Abstract
Summary Paragraph We 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 halofuginone’s 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.
Competing Interest Statement
S.T. is a founding member of Oxitope, Inc, Covicept Therapeutics and Kleanthi Diagnostics. S.T. is a consultant for Ionis Pharmaceuticals. PL.S.M.G. is a is a founding member of Covicept Therapeutics. J.D.E. is a co-founder of TEGA Therapeutics and Covicept Therapeutics. J.D.E. and The Regents of the University of California have licensed a University invention to and have an equity interest in TEGA Therapeutics and Covicept Therapeutics. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies. NIH R01 AI146779 and a Massachusetts Consortium on Pathogenesis Readiness (MassCPR) grant to A.G.S.; training grants: NIGMS T32 GM007753 for B.M.H. and T.M.C; T32 AI007245 for J.F. R.M. is a scientific advisory board (SAB) member and equity holder of Regenacy Pharmaceuticals, ERX Pharmaceuticals, Frequency Therapeutics. D.R.S, T.M.C., C.N., A.D., RJ.W., J.D.E., P.L.S.M.G. R.M., M.A.T. and N.C.P. are inventors on patent applications related to PRS inhibitors. The other authors declare that they have no competing interests.
Footnotes
Author name. Conner to Connor.