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Repurposing screen identifies novel candidates for broad-spectrum coronavirus antivirals and druggable host targets.
Haid, Sibylle; Matthaei, Alina; Winkler, Melina; Sake, Svenja M; Gunesch, Antonia P; Milke, Vanessa; Köhler, Natalie M; Rückert, Jessica; Vieyres, Gabrielle; Kühl, David; Nguyen, Tu-Trinh; Göhl, Matthias; Lasswitz, Lisa; Zapatero-Belinchón, Francisco J; Brogden, Graham; Gerold, Gisa; Wiegmann, Bettina; Bilitewski, Ursula; Brown, Richard J P; Brönstrup, Mark; Schulz, Thomas F; Pietschmann, Thomas.
Afiliação
  • Haid S; Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany.
  • Matthaei A; Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany.
  • Winkler M; Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany.
  • Sake SM; Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany.
  • Gunesch AP; Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany.
  • Milke V; Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany.
  • Köhler NM; Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany.
  • Rückert J; Institute of Virology, Hannover Medical School, Hannover, Germany.
  • Vieyres G; German Center for Infection Research, Hannover-Braunschweig Site, Hannover, Germany.
  • Kühl D; Junior Research Group "Cell Biology of RNA Viruses", Leibniz Institute of Experimental Virology, Hamburg, Germany.
  • Nguyen T-T; Integrative Analysis of Pathogen-Induced Compartments, Leibniz ScienceCampus InterACt, Hamburg, Germany.
  • Göhl M; Junior Research Group "Cell Biology of RNA Viruses", Leibniz Institute of Experimental Virology, Hamburg, Germany.
  • Lasswitz L; Calibr, a Division of The Scripps Research Institute, La Jolla, California, USA.
  • Zapatero-Belinchón FJ; German Center for Infection Research, Hannover-Braunschweig Site, Hannover, Germany.
  • Brogden G; Helmholtz Centre for Infection Research, Braunschweig, Germany.
  • Gerold G; Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany.
  • Wiegmann B; Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany.
  • Bilitewski U; Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany.
  • Brown RJP; Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany.
  • Brönstrup M; Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany.
  • Schulz TF; Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany.
  • Pietschmann T; Institute for Experimental Virology, Twincore - Centre for Experimental and Clinical Infection Research, Hannover, Germany.
Antimicrob Agents Chemother ; 68(3): e0121023, 2024 Mar 06.
Article em En | MEDLINE | ID: mdl-38319076
ABSTRACT
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Tiazóis / Triterpenos / Infecções por Coronavirus / Coronavirus Humano 229E Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Antimicrob Agents Chemother Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Alemanha

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Tiazóis / Triterpenos / Infecções por Coronavirus / Coronavirus Humano 229E Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Antimicrob Agents Chemother Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Alemanha