RT Journal Article
SR Electronic
T1 The Prolyl-tRNA Synthetase Inhibitor Halofuginone Inhibits SARS-CoV-2 Infection
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.03.22.436522
DO 10.1101/2021.03.22.436522
A1 Daniel R. Sandoval
A1 Thomas Mandel Clausen
A1 Chelsea Nora
A1 Jason A. Magida
A1 Adam P. Cribbs
A1 Andrea Denardo
A1 Alex E. Clark
A1 Aaron F. Garretson
A1 Joanna K.C. Coker
A1 Anoop Narayanan
A1 Sydney A. Majowicz
A1 Martin Philpott
A1 Catrine Johansson
A1 James E. Dunford
A1 Charlotte B. Spliid
A1 Gregory J. Golden
A1 N. Connor Payne
A1 Mark A. Tye
A1 Cameron J. Nowell
A1 Eric R. Griffis
A1 Ann Piermatteo
A1 Kaare V. Grunddal
A1 Thibault Alle
A1 Blake M. Hauser
A1 Jared Feldman
A1 Timothy M. Caradonna
A1 Yuan Pu
A1 Xin Yin
A1 Rachael N. McVicar
A1 Elizabeth M. Kwong
A1 Sotirios Tsimikas
A1 Aaron G. Smidt
A1 Carlo Ballatore
A1 Karsten Zengler
A1 Sumit K. Chanda
A1 Ryan J. Weiss
A1 Michael Downes
A1 Ron M. Evans
A1 Ben A. Croker
A1 Sandra L. Leibel
A1 Joyce Jose
A1 Ralph Mazitschek
A1 Udo Oppermann
A1 Jeffrey D. Esko
A1 Aaron F. Carlin
A1 Philip L.S.M. Gordts
YR 2021
UL http://biorxiv.org/content/early/2021/03/23/2021.03.22.436522.abstract
AB We identify the prolyl-tRNA synthetase (PRS) inhibitor halofuginone, a compound in clinical trials for anti-fibrotic and anti-inflammatory applications, 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. 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. Utilizing analogues of halofuginone and small molecule inhibitors of the PRS, we establish that inhibition of HS presentation and viral replication is dependent on proline tRNA synthesis opposed to PRS activation of the integrated stress response (ISR). Moreover, we provide evidence that these effects are mediated by the depletion of proline tRNAs. In line with this, we find that SARS-CoV-2 polyproteins, as well as several HS proteoglycans, are particularly proline-rich, which may make them vulnerable to halofuginone 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 promising clinical trial candidate for the treatment of COVID-19.Competing Interest StatementS.T. is a founding member of Oxitope, Inc, and Kleanthi Diagnostics. S.T. is a consultant for Ionis Pharmaceuticals. The other authors declare that they have no competing interests. J.D.E. is a co-founder of TEGA 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. 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. R.M., M.A.T. and N.C.P. are inventors on patent applications related to PRS inhibitors.