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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:68 |
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| Enthalten in: |
Antimicrobial agents and chemotherapy - 68(2024), 3 vom: 06. März, Seite e0121023 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Haid, Sibylle [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 07.03.2024 Date Revised 08.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1128/aac.01210-23 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a 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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| 700 | 1 | |a Gunesch, Antonia P |e verfasserin |4 aut | |
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| 700 | 1 | |a Vieyres, Gabrielle |e verfasserin |4 aut | |
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| 700 | 1 | |a Göhl, Matthias |e verfasserin |4 aut | |
| 700 | 1 | |a Lasswitz, Lisa |e verfasserin |4 aut | |
| 700 | 1 | |a Zapatero-Belinchón, Francisco J |e verfasserin |4 aut | |
| 700 | 1 | |a Brogden, Graham |e verfasserin |4 aut | |
| 700 | 1 | |a Gerold, Gisa |e verfasserin |4 aut | |
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| 700 | 1 | |a Pietschmann, Thomas |e verfasserin |4 aut | |
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