lancet-header

Preprints with The Lancet is part of SSRN´s First Look, a place where journals identify content of interest prior to publication. Authors have opted in at submission to The Lancet family of journals to post their preprints on Preprints with The Lancet. The usual SSRN checks and a Lancet-specific check for appropriateness and transparency have been applied. Preprints available here are not Lancet publications or necessarily under review with a Lancet journal. These preprints are early stage research papers that have not been peer-reviewed. The findings should not be used for clinical or public health decision making and should not be presented to a lay audience without highlighting that they are preliminary and have not been peer-reviewed. For more information on this collaboration, see the comments published in The Lancet about the trial period, and our decision to make this a permanent offering, or visit The Lancet´s FAQ page, and for any feedback please contact preprints@lancet.com.

Identification of Broad Anti-Coronavirus Chemical Agents for Repurposing Against SARS-CoV-2 and Variants of Concern

58 Pages Posted: 8 Sep 2021

See all articles by Luca Murer

Luca Murer

University of Zurich - Department of Molecular Life Sciences

Romain Volle

University of Zurich - Department of Molecular Life Sciences

Vardan Andriasyan

University of Zurich - Department of Molecular Life Sciences

Anthony Petkidis

University of Zurich - Department of Molecular Life Sciences

Alfonso Gomez-Gonzalez

University of Zurich - Department of Molecular Life Sciences

Liliane Yang

University of Zurich - Department of Molecular Life Sciences

Nicole Meili

University of Zurich - Department of Molecular Life Sciences

Maarit Suomalainen

University of Zurich - Department of Molecular Life Sciences

Michael Bauer

University of Zurich - Department of Molecular Life Sciences

Daniela Sequeira

University of Zurich - Department of Molecular Life Sciences

Dominik Olszewski

University of Zurich - Department of Molecular Life Sciences

Fanny Georgi

University of Zurich - Department of Molecular Life Sciences

Fabien Kuttler

Ecole Polytechnique Fédérale de Lausanne - Biomolecular Screening Facility

Gerardo Turcatti

Ecole Polytechnique Fédérale de Lausanne - Biomolecular Screening Facility

Urs Greber

University of Zurich - Department of Molecular Life Sciences

More...

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’éthique de la recherche CCER de Genève).

Coronavirus storage and procedures have been registered and validated by the Swiss Federal Office for the Environment (Bundesamt für Umwelt, BAFU) and the Swiss Federal Office of Public Health (Bundesamt für 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).

Keywords: Human coronavirus drug screen at single cell resolution in arrayed format; Human explant nasal and bronchial epithelial cells; Repurposing Methylene blue, Mycophenolic acid, Posaconazole; Drug synergy in vitro; Post-entry coronavirus inhibition; SARS-CoV-2 variants of concern

Suggested Citation

Murer, Luca and Volle, Romain and Andriasyan, Vardan and Petkidis, Anthony and Gomez-Gonzalez, Alfonso and Yang, Liliane and Meili, Nicole and Suomalainen, Maarit and Bauer, Michael and Sequeira, Daniela and Olszewski, Dominik and Georgi, Fanny and Kuttler, Fabien and Turcatti, Gerardo and Greber, Urs, Identification of Broad Anti-Coronavirus Chemical Agents for Repurposing Against SARS-CoV-2 and Variants of Concern. Available at SSRN: https://ssrn.com/abstract=3914634 or http://dx.doi.org/10.2139/ssrn.3914634

Luca Murer

University of Zurich - Department of Molecular Life Sciences ( email )

Zurich
Switzerland

Romain Volle

University of Zurich - Department of Molecular Life Sciences ( email )

Zurich
Switzerland

Vardan Andriasyan

University of Zurich - Department of Molecular Life Sciences ( email )

Zurich
Switzerland

Anthony Petkidis

University of Zurich - Department of Molecular Life Sciences ( email )

Zurich
Switzerland

Alfonso Gomez-Gonzalez

University of Zurich - Department of Molecular Life Sciences ( email )

Zurich
Switzerland

Liliane Yang

University of Zurich - Department of Molecular Life Sciences ( email )

Zurich
Switzerland

Nicole Meili

University of Zurich - Department of Molecular Life Sciences ( email )

Zurich
Switzerland

Maarit Suomalainen

University of Zurich - Department of Molecular Life Sciences ( email )

Zurich
Switzerland

Michael Bauer

University of Zurich - Department of Molecular Life Sciences

Zurich
Switzerland

Daniela Sequeira

University of Zurich - Department of Molecular Life Sciences ( email )

Zurich
Switzerland

Dominik Olszewski

University of Zurich - Department of Molecular Life Sciences ( email )

Zurich
Switzerland

Fanny Georgi

University of Zurich - Department of Molecular Life Sciences ( email )

Zurich
Switzerland

Fabien Kuttler

Ecole Polytechnique Fédérale de Lausanne - Biomolecular Screening Facility ( email )

Switzerland

Gerardo Turcatti

Ecole Polytechnique Fédérale de Lausanne - Biomolecular Screening Facility ( email )

Switzerland

Urs Greber (Contact Author)

University of Zurich - Department of Molecular Life Sciences ( email )

Zurich
Switzerland

Click here to go to TheLancet.com

Paper statistics

Abstract Views
77
Downloads
10
PlumX Metrics