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

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

bioRxiv : the preprint server for biology (2021-04-02)
Daniel R Sandoval, Thomas Mandel Clausen, Chelsea Nora, Adam P Cribbs, Andrea Denardo, Alex E Clark, Aaron F Garretson, Joanna K C Coker, Anoop Narayanan, Sydney A Majowicz, Martin Philpott, Catrine Johansson, James E Dunford, Charlotte B Spliid, Gregory J Golden, N Connor Payne, Mark A Tye, Cameron J Nowell, Eric R Griffis, Ann Piermatteo, Kaare V Grunddal, Thibault Alle, Jason A Magida, Blake M Hauser, Jared Feldman, Timothy M Caradonna, Yuan Pu, Xin Yin, Rachael N McVicar, Elizabeth M Kwong, Ryan J Weiss, Michael Downes, Sotirios Tsimikas, Aaron G Smidt, Carlo Ballatore, Karsten Zengler, Ron M Evans, Sumit K Chanda, Ben A Croker, Sandra L Leibel, Joyce Jose, Ralph Mazitschek, Udo Oppermann, Jeffrey D Esko, Aaron F Carlin, Philip L S M Gordts
PMID33791697
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description
SML0843
Sigma-Aldrich
ISRIB, ≥98% (HPLC)
516535
Sigma-Aldrich
PERK Inhibitor I, GSK2606414, GSK2606414 is a cell-permeable, highly potent inhibitor of EIF2AK3/PERK (IC₅₀ = 0.4 nM; [ATP] = 5 µM). Targets PERK in its inactive DFG conformation at the ATP-binding region.