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Repurposing screen ...
Repurposing screen identifies novel candidates for broad-spectrum coronavirus antivirals and druggable host targets
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- Haid, Sibylle (författare)
- Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany
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- Matthaei, Alina (författare)
- Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany
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- Winkler, Melina (författare)
- Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany
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- Sake, Svenja M. (författare)
- Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany
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- Gunesch, Antonia P. (författare)
- Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany
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- Milke, Vanessa (författare)
- Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany
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- Köhler, Natalie M. (författare)
- Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany
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- Rückert, Jessica (författare)
- Institute of Virology, Hannover Medical School, Hannover, Germany; German Center for Infection Research, Hannover-Braunschweig Site, Hannover, Germany
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- Vieyres, Gabrielle (författare)
- Junior Research Group “Cell Biology of RNA Viruses”, Leibniz Institute of Experimental Virology, Hamburg, Germany; Integrative Analysis of Pathogen-Induced Compartments, Leibniz ScienceCampus InterACt, Hamburg, Germany
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- Kühl, David (författare)
- Junior Research Group “Cell Biology of RNA Viruses”, Leibniz Institute of Experimental Virology, Hamburg, Germany
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- Nguyen, Tu-Trinh (författare)
- Calibr, a Division, The Scripps Research Institute, La Jolla, CA, United States
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- Göhl, Matthias (författare)
- German Center for Infection Research, Hannover-Braunschweig Site, Hannover, Germany; Helmholtz Centre for Infection Research, Braunschweig, Germany
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- Lasswitz, Lisa (författare)
- Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany; Department of Biochemistry, Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany
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- Zapatero-Belinchón, Francisco J. (författare)
- Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany; Department of Biochemistry, Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany
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- Brogden, Graham (författare)
- Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany; Department of Biochemistry, Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany
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- Gerold, Gisa, 1979- (författare)
- Umeå universitet,Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM),Avdelningen för virologi,Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany; Department of Biochemistry, Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany; Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
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- Wiegmann, Bettina (författare)
- Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany; Lower Saxony Center for Biomedical Engineering, Implant Research and Development, Hannover Medical School, Hannover, Germany; BREATH (Biomedical Research in Endstage and Obstructive Lung Disease Hannover), German Center for Lung Research (DZL), Carl-Neuberg Str. 1, Hannover, Germany
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- Bilitewski, Ursula (författare)
- Helmholtz Centre for Infection Research, Braunschweig, Germany
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- Brown, Richard J.P. (författare)
- Division of Veterinary Medicine, Paul Ehrlich Institute, Langen, Germany; Department of Molecular and Medical Virology, Ruhr University, Bochum, Germany
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- Brönstrup, Mark (författare)
- German Center for Infection Research, Hannover-Braunschweig Site, Hannover, Germany; Helmholtz Centre for Infection Research, Braunschweig, Germany
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- Schulz, Thomas F. (författare)
- Institute of Virology, Hannover Medical School, Hannover, Germany; German Center for Infection Research, Hannover-Braunschweig Site, Hannover, Germany; Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
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- Pietschmann, Thomas (författare)
- Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany; German Center for Infection Research, Hannover-Braunschweig Site, Hannover, Germany; Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
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(creator_code:org_t)
- American Society for Microbiology, 2024
- 2024
- Engelska.
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Ingår i: Antimicrobial Agents and Chemotherapy. - : American Society for Microbiology. - 0066-4804 .- 1098-6596. ; 68:3
- Relaterad länk:
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https://doi.org/10.1...
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https://umu.diva-por... (primary) (Raw object)
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Libraries composed of licensed drugs represent a vast repertoire of molecules modulating physiological processes in humans, providing unique opportunities for the discovery of host-targeting antivirals. We screened the Repurposing, Focused Rescue, and Accelerated Medchem (ReFRAME) repurposing library with approximately 12,000 molecules for broad-spectrum coronavirus antivirals and discovered 134 compounds inhibiting an alphacoronavirus and mapping to 58 molecular target categories. Dominant targets included the 5-hydroxytryptamine receptor, the dopamine receptor, and cyclin-dependent kinases. Gene knock-out of the drugs’ host targets including cathepsin B and L (CTSB/L; VBY-825), the aryl hydrocarbon receptor (AHR; Phortress), the farnesyl-diphosphate farnesyltransferase 1 (FDFT1; P-3622), and the kelch-like ECH-associated protein 1 (KEAP1; Omaveloxolone), significantly modulated HCoV-229E infection, providing evidence that these compounds inhibited the virus through acting on their respective host targets. Counter-screening of all 134 primary compound candidates with SARS-CoV-2 and validation in primary cells identified Phortress, an AHR activating ligand, P-3622-targeting FDFT1, and Omaveloxolone, which activates the NFE2-like bZIP transcription factor 2 (NFE2L2) by liberating it from its endogenous inhibitor KEAP1, as antiviral candidates for both an Alpha- and a Betacoronavirus. This study provides an overview of HCoV-229E repurposing candidates and reveals novel potentially druggable viral host dependency factors hijacked by diverse coronaviruses.
Ämnesord
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Nyckelord
- antivirals
- coronavirus
- CRISPR/Cas9
- HCoV-229E
- host-targeting antiviral therapy
- repurposing
- SARS-CoV-2
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Haid, Sibylle
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Matthaei, Alina
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Winkler, Melina
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Sake, Svenja M.
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Gunesch, Antonia ...
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Milke, Vanessa
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visa fler...
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Köhler, Natalie ...
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Rückert, Jessica
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Vieyres, Gabriel ...
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Kühl, David
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Nguyen, Tu-Trinh
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Göhl, Matthias
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Lasswitz, Lisa
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Zapatero-Belinch ...
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Brogden, Graham
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Gerold, Gisa, 19 ...
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Wiegmann, Bettin ...
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Bilitewski, Ursu ...
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Brown, Richard J ...
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Brönstrup, Mark
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Schulz, Thomas F ...
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Pietschmann, Tho ...
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