Repurposing screen identifies novel candidates for broad-spectrum coronavirus antivirals and druggable host targets.
Sibylle HaidAlina MatthaeiMelina WinklerSvenja M SakeAntonia P GuneschVanessa MilkeNatalie M KöhlerJessica RückertGabrielle VieyresDavid KühlTu-Trinh NguyenMatthias GöhlLisa LasswitzFrancisco J Zapatero-BelinchónGraham BrogdenGisa GeroldBettina WiegmannUrsula BilitewskiRichard J P BrownMark BrönstrupThomas F SchulzThomas PietschmannPublished in: Antimicrobial agents and chemotherapy (2024)
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.
Keyphrases
- sars cov
- transcription factor
- respiratory syndrome coronavirus
- signaling pathway
- high throughput
- cancer therapy
- induced apoptosis
- genome wide
- cell cycle arrest
- high resolution
- metabolic syndrome
- uric acid
- genome wide identification
- protein protein
- drug induced
- mass spectrometry
- dna binding
- endoplasmic reticulum stress
- coronavirus disease