The Prolyl-tRNA Synthetase Inhibitor Halofuginone Inhibits SARS-CoV-2 Infection

Daniel R. Sandoval(University of California San Diego), Thomas Mandel Clausen(University of Copenhagen), Chelsea Nora(University of California San Diego), Adam P. Cribbs(University of Oxford), Andrea Denardo(University of California San Diego), Alex E. Clark(University of California San Diego), Aaron F. Garretson(University of California San Diego), Joanna Coker(University of California San Diego), Anoop Narayanan(University of California San Diego), Sydney A. Majowicz(University of California San Diego), Martin Philpott(University of Oxford), C. Johansson(University of Oxford), James E. Dunford(University of Oxford), Charlotte B. Spliid(University of California San Diego), Gregory J. Golden(University of California San Diego), N. Connor Payne(Harvard University), Mark A. Tye(Harvard University), Cameron J. Nowell, Eric R. Griffis(Nikon (United States)), Ann Piermatteo(University of California San Diego), Kaare V. Grunddal(University of California San Diego), Thibault Alle(University of California San Diego), Jason A. Magida(Salk Institute for Biological Studies), Blake M. Hauser(Ragon Institute of MGH, MIT and Harvard), Jared Feldman(Sanford Burnham Prebys Medical Discovery Institute), Timothy M. Caradonna(Sanford Burnham Prebys Medical Discovery Institute), Yuan Pu(Sanford Consortium for Regenerative Medicine), Xin Yin(Sanford Burnham Prebys Medical Discovery Institute), Rachael N. McVicar(Sanford Burnham Prebys Medical Discovery Institute), Elizabeth M. Kwong(Sanford Burnham Prebys Medical Discovery Institute), Ryan J. Weiss(University of California San Diego), Michael Downes(Salk Institute for Biological Studies), Sotirios Tsimikas(University of California San Diego), A Smidt(Harvard University), Carlo Ballatore(University of California San Diego), Karsten Zengler(University of California San Diego), Ronald M. Evans(Salk Institute for Biological Studies), Sumit K. Chanda(Sanford Burnham Prebys Medical Discovery Institute), Ben A. Croker(University of California San Diego), Sandra L. Leibel(Sanford Burnham Prebys Medical Discovery Institute), Joyce Jose(Pennsylvania State University), Ralph Mazitschek(Broad Institute), Udo Oppermann(University of Oxford), Jeffrey D. Esko(University of California San Diego), Aaron F. Carlin(University of California San Diego), Philip L.S.M. Gordts(University of California San Diego)
bioRxiv (Cold Spring Harbor Laboratory)
March 23, 2021
10.1101/2021.03.22.436522
Cited by 23Open Access
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Abstract

Summary Paragraph We identify the prolyl-tRNA synthetase (PRS) inhibitor halofuginone 1 , a compound in clinical trials for anti-fibrotic and anti-inflammatory applications 2 , 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 entry 3 . 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 Remdesivir 4 . 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.

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