Science and Research

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

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.

  • Haid, S.
  • Matthaei, A.
  • Winkler, M.
  • Sake, S. M.
  • Gunesch, A. P.
  • Milke, V.
  • Köhler, N. M.
  • Rückert, J.
  • Vieyres, G.
  • Kühl, D.
  • Nguyen, T. T.
  • Göhl, M.
  • Lasswitz, L.
  • Zapatero-Belinchón, F. J.
  • Brogden, G.
  • Gerold, G.
  • Wiegmann, B.
  • Bilitewski, U.
  • Brown, R. J. P.
  • Brönstrup, M.
  • Schulz, T. F.
  • Pietschmann, T.

Keywords

  • CRISPR/Cas9
  • HCoV-229E
  • SARS-CoV-2
  • antivirals
  • coronavirus
  • host-targeting antiviral therapy
  • repurposing
Publication details
DOI: 10.1128/aac.01210-23
Journal: Antimicrob Agents Chemother
Pages: e0121023 
Work Type: Original
Location: BREATH
Disease Area: PALI
Partner / Member: MHH
Access-Number: 38319076

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