The Prolyl-tRNA Synthetase Inhibitor Halofuginone Inhibits SARS-CoV-2 Infection
| Autor: | Racheal N. McVicar, Karsten Zengler, Adam P. Cribbs, Alex E. Clark, Andrea Denardo, Elizabeth M. Kwong, Sydney A. Majowicz, Xin Yin, Ann Piermatteo, Daniel R. Sandoval, Joanna K.C. Coker, Chelsea Nora, Ben A. Croker, Udo Oppermann, Kaare V. Grunddal, Blake M. Hauser, Catrine Johansson, Mark A Tye, Gregory J. Golden, Timothy M. Caradonna, Jeffrey D. Esko, Martin Philpott, Anoop Narayanan, Philip L.S.M. Gordts, N Connor Payne, Joyce Jose, Eric R. Griffis, Sotirios Tsimikas, Ryan J. Weiss, Micheal Downes, Jason A. Magida, Thomas Mandel Clausen, Aaron G. Schmidt, Yuan Pu, Cameron J. Nowell, Carlo Ballatore, Thibault Alle, Charlotte B. Spliid, Jared Feldman, Ronald M. Evans, Sumit K. Chanda, Sandra L. Leibel, Aaron F. Garretson, James E. Dunford, Ralph Mazitschek, Aaron F. Carlin |
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| Rok vydání: | 2021 |
| Předmět: |
Polyproteins
Halofuginone viruses Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) fungi Cell Heparan sulfate Pharmacology Article Virus respiratory tract diseases body regions chemistry.chemical_compound medicine.anatomical_structure Biosynthesis chemistry Viral entry medicine skin and connective tissue diseases medicine.drug |
| Zdroj: | bioRxiv |
| Popis: | 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 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. |
| Databáze: | OpenAIRE |
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