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  • Haid, SibylleInstitute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany (författare)

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

  • Artikel/kapitelEngelska2024

Förlag, utgivningsår, omfång ...

  • American Society for Microbiology,2024
  • electronicrdacarrier

Nummerbeteckningar

  • LIBRIS-ID:oai:DiVA.org:umu-222422
  • https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-222422URI
  • https://doi.org/10.1128/aac.01210-23DOI

Kompletterande språkuppgifter

  • Språk:engelska
  • Sammanfattning på:engelska

Ingår i deldatabas

Klassifikation

  • Ämneskategori:ref swepub-contenttype
  • Ämneskategori:art swepub-publicationtype

Anmärkningar

  • 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 och genrebeteckningar

Biuppslag (personer, institutioner, konferenser, titlar ...)

  • Matthaei, AlinaInstitute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany (författare)
  • Winkler, MelinaInstitute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany (författare)
  • Sake, Svenja M.Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany (författare)
  • Gunesch, Antonia P.Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany (författare)
  • Milke, VanessaInstitute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany (författare)
  • Köhler, Natalie M.Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany (författare)
  • Rückert, JessicaInstitute of Virology, Hannover Medical School, Hannover, Germany; German Center for Infection Research, Hannover-Braunschweig Site, Hannover, Germany (författare)
  • Vieyres, GabrielleJunior 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 (författare)
  • Kühl, DavidJunior Research Group “Cell Biology of RNA Viruses”, Leibniz Institute of Experimental Virology, Hamburg, Germany (författare)
  • Nguyen, Tu-TrinhCalibr, a Division, The Scripps Research Institute, La Jolla, CA, United States (författare)
  • Göhl, MatthiasGerman Center for Infection Research, Hannover-Braunschweig Site, Hannover, Germany; Helmholtz Centre for Infection Research, Braunschweig, Germany (författare)
  • Lasswitz, LisaInstitute 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 (författare)
  • Zapatero-Belinchón, Francisco J.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 (författare)
  • Brogden, GrahamInstitute 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 (författare)
  • Gerold, Gisa,1979-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(Swepub:umu)gige0003 (författare)
  • Wiegmann, BettinaDepartment 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 (författare)
  • Bilitewski, UrsulaHelmholtz Centre for Infection Research, Braunschweig, Germany (författare)
  • Brown, Richard J.P.Division of Veterinary Medicine, Paul Ehrlich Institute, Langen, Germany; Department of Molecular and Medical Virology, Ruhr University, Bochum, Germany (författare)
  • Brönstrup, MarkGerman Center for Infection Research, Hannover-Braunschweig Site, Hannover, Germany; Helmholtz Centre for Infection Research, Braunschweig, Germany (författare)
  • Schulz, Thomas F.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 (författare)
  • Pietschmann, ThomasInstitute 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 (författare)
  • Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, GermanyInstitute of Virology, Hannover Medical School, Hannover, Germany; German Center for Infection Research, Hannover-Braunschweig Site, Hannover, Germany (creator_code:org_t)

Sammanhörande titlar

  • Ingår i:Antimicrobial Agents and Chemotherapy: American Society for Microbiology68:30066-48041098-6596

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