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Repurposing screen identifies novel candidates for broad-spectrum coronavirus antivirals and druggable host targets

Haid, Sibylle (författare)
Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany
Matthaei, Alina (författare)
Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany
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
Gunesch, Antonia P. (författare)
Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany
Milke, Vanessa (författare)
Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany
Köhler, Natalie M. (författare)
Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany
Rückert, Jessica (författare)
Institute of Virology, Hannover Medical School, Hannover, Germany; German Center for Infection Research, Hannover-Braunschweig Site, Hannover, Germany
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
Kühl, David (författare)
Junior Research Group “Cell Biology of RNA Viruses”, Leibniz Institute of Experimental Virology, Hamburg, Germany
Nguyen, Tu-Trinh (författare)
Calibr, a Division, The Scripps Research Institute, La Jolla, CA, United States
Göhl, Matthias (författare)
German Center for Infection Research, Hannover-Braunschweig Site, Hannover, Germany; Helmholtz Centre for Infection Research, Braunschweig, Germany
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
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
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
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
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
Bilitewski, Ursula (författare)
Helmholtz Centre for Infection Research, Braunschweig, Germany
Brown, Richard J.P. (författare)
Division of Veterinary Medicine, Paul Ehrlich Institute, Langen, Germany; Department of Molecular and Medical Virology, Ruhr University, Bochum, Germany
Brönstrup, Mark (författare)
German Center for Infection Research, Hannover-Braunschweig Site, Hannover, Germany; Helmholtz Centre for Infection Research, Braunschweig, Germany
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
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.
Ingår i: Antimicrobial Agents and Chemotherapy. - : American Society for Microbiology. - 0066-4804 .- 1098-6596. ; 68:3
  • Tidskriftsartikel (refereegranskat)
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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