RT Journal Article
SR Electronic
T1 Arrayed multicycle drug screens identify broadly acting chemical inhibitors for repurposing against SARS-CoV-2
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.03.30.437771
DO 10.1101/2021.03.30.437771
A1 Luca Murer
A1 Romain Volle
A1 Vardan Andriasyan
A1 Nicole Meili
A1 Liliane Yang
A1 Daniela Sequeira
A1 Afonso Gomez-Gonzalez
A1 Anthony Petkidis
A1 Dominik Olszewski
A1 Michael Bauer
A1 Maarit Suomalainen
A1 Fabien Kuttler
A1 Gerardo Turcatti
A1 Urs F. Greber
YR 2021
UL http://biorxiv.org/content/early/2021/03/31/2021.03.30.437771.abstract
AB Coronaviruses (CoVs) circulate in humans and animals, and expand their host range by zoonotic and anthroponotic transmissions. Endemic human CoVs, such as 229E and OC43 cause limited respiratory disease, and elicit short term anti-viral immunity favoring recurrent infections. Yet, severe acute respir-atory syndrome (SARS)-CoV-2 spreads across the globe with unprecedented impact on societies and economics. The world lacks broadly effective and affordable anti-viral agents to fight the pandemic and reduce the death toll. Here, we developed an image-based multicycle replication assay for focus for-mation of α-coronavirus hCoV-229E-eGFP infected cells for screening with a chemical library of 5440 compounds arrayed in 384 well format. The library contained about 39% clinically used compounds, 26% in phase I, II or III clinical trials, and 34% in preclinical development. Hits were counter-selected against toxicity, and challenged with hCoV-OC43 and SARS-CoV-2 in tissue culture and human bronchial and nasal epithelial explant cultures from healthy donors. Fifty three compounds inhibited hCoV-229E-GFP, 39 of which at 50% effective concentrations (EC50) < 2μM, and were at least 2-fold separated from toxicity. Thirty nine of the 53 compounds inhibited the replication of hCoV-OC43, while SARS-CoV-2 was inhibited by 11 compounds in at least two of four tested cell lines. Six of the 11 compounds are FDA-approved, one of which is used in mouth wash formulations, and five are systemic and orally available. Here, we demonstrate that methylene blue (MB) and mycophenolic acid (MPA), two broadly available low cost compounds, strongly inhibited shedding of infectious SARS-CoV-2 at the apical side of the cultures, in either pre- or post-exposure regimens, with somewhat weaker effects on viral RNA release indicated by RT-qPCR measurements. Our study illustrates the power of full cycle screens in repurposing clinical compounds against SARS-CoV-2. Importantly, both MB and MPA reportedly act as immunosuppressants, making them interesting candidates to counteract the cytokine storms affecting COVID-19 patients.Competing Interest StatementThe authors have declared no competing interest.