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• W3200301529 abstract "Endemic human coronaviruses (hCoVs) 229E and OC43 cause respiratory disease with recurrent infections, while severe acute respiratory syndrome (SARS)-CoV-2 spreads across the world with impact on health and societies. Here, we report an image-based multicycle infection procedure with α-coronavirus hCoV 229E-eGFP in an arrayed chemical library screen of 5440 clinical and preclinical compounds. Toxicity counterselection and challenge with the β-coronaviruses OC43 and SARS-CoV-2 in tissue culture and human airway epithelial explant cultures (HAEEC) identified four FDA-approved compounds with oral availability. Methylene blue (MB, used for the treatment of methemoglobinemia), Mycophenolic acid (MPA, used in organ transplantion) and the anti-fungal agent Posaconazole (POS) had the broadest anti-CoV spectrum. They inhibited the shedding of SARS CoV 2 and variants-of-concern (alpha, beta, gamma) from HAEEC in either pre- or post exposure regimens at clinically relevant dosage. Co-treatment of cultured cells with MB and the FDA-approved SARS-CoV-2 RNA-polymerase inhibitor Remdesivir reduced the effective anti-viral dosage of MB by 2-fold, and Remdesivir by 4 to 10-fold, indicated by BLISS independence syner-gy modelling. Neither MB, MPA or POS affected the cell delivery of SARS-CoV-2 or OC43 (+)sense RNA, but blocked subsequent viral RNA accumulation in cells. Unlike Remdesivir, MB, MPA or POS did not reduce the release of viral RNA in post exposure regimen, thus indicating infection inhibition at a post-replicating step as well. In summary, the data emphasize the power of unbiased, full cycle compound screens to identify and repurpose broadly acting drugs against coronaviruses.Funding Information: We acknowledge financial support from the Swiss National Science foundation (SNSF) to UFG and GT (31CA30_196177 / 1), the NCCR Chemical Biology supported by the SNSF for purchasing the BSF-EPFL repurposing collection, and a special Coronavirus Research grant from the University of Zurich to UFG. Declaration of Interests: UFG has been a consultant and stock owner in 3V-Biosciences (now Sagimet Biosciences), and a consultant to F. Hoffmann-La Roche Ltd. The authors filed a patent application on the use of MPA for the treatment of COVID-19 (EP20213904, European Patent Office, University of Zurich).Ethical Approval: Nasal polyp epithelial cells and bronchial epithelial cells were purchased from Epithelix SARL (Geneva, Switzerland). Mucilair™ cells were reconstituted from patients undergoing surgical nasal polypectomy or bronchial biopsies, respectively. All samples from Epithelix SARL were obtained with informed consent, according to the declaration of Helsinki on biomedical research (Hong Kong amendment, 1989), and received approval from local ethics committee (commission cantonale d’ethique de la recherche CCER de Geneve).Coronavirus storage and procedures have been registered and validated by the Swiss Federal Office for the Environment (Bundesamt fur Umwelt, BAFU) and the Swiss Federal Office of Public Health (Bundesamt fur Gesundheit, BAG); Ecogen A203032-00, registered the 01-Sep-2020 for a duration of 5-years for the University of Zurich (Department of Molecular Life Sciences)." @default.
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• W3200301529 date "2021-01-01" @default.
• W3200301529 modified "2023-09-30" @default.
• W3200301529 title "Identification of Broad Anti-Coronavirus Chemical Agents for Repurposing Against SARS-CoV-2 and Variants of Concern" @default.
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• W3200301529 doi "https://doi.org/10.2139/ssrn.3914634" @default.
• W3200301529 hasPublicationYear "2021" @default.
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