Identification of side effects of COVID-19 drug candidates on embryogenesis using an integrated zebrafish screening platform.

Autor: Ernst A; Institute of Anatomy, University of Bern, Bern, Switzerland., Piragyte I; Institute of Anatomy, University of Bern, Bern, Switzerland.; Department for Biomedical Research DBMR, University of Bern, Bern, Switzerland., Mp AM; Institute of Anatomy, University of Bern, Bern, Switzerland.; Department for Biomedical Research DBMR, University of Bern, Bern, Switzerland., Le ND; Institute for Infectious Diseases, University of Bern, Bern, Switzerland., Grandgirard D; Institute for Infectious Diseases, University of Bern, Bern, Switzerland., Leib SL; Institute for Infectious Diseases, University of Bern, Bern, Switzerland., Oates A; School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland., Mercader N; Institute of Anatomy, University of Bern, Bern, Switzerland. nadia.mercader@unibe.ch.; Department for Biomedical Research DBMR, University of Bern, Bern, Switzerland. nadia.mercader@unibe.ch.; Centro Nacional de Investigaciones Cardiovasculares, CNIC, Madrid, Spain. nadia.mercader@unibe.ch.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2023 Oct 09; Vol. 13 (1), pp. 17037. Date of Electronic Publication: 2023 Oct 09.
DOI: 10.1038/s41598-023-43911-3
Abstrakt: Drug repurposing is an important strategy in COVID-19 treatment, but many clinically approved compounds have not been extensively studied in the context of embryogenesis, thus limiting their administration during pregnancy. Here we used the zebrafish embryo model organism to test the effects of 162 marketed drugs on cardiovascular development. Among the compounds used in the clinic for COVD-19 treatment, we found that Remdesivir led to reduced body size and heart functionality at clinically relevant doses. Ritonavir and Baricitinib showed reduced heart functionality and Molnupiravir and Baricitinib showed effects on embryo activity. Sabizabulin was highly toxic at concentrations only 5 times higher than C max and led to a mean mortality of 20% at C max . Furthermore, we tested if zebrafish could be used as a model to study inflammatory response in response to spike protein treatment and found that Remdesivir, Ritonavir, Molnupiravir, Baricitinib as well as Sabizabulin counteracted the inflammatory response related gene expression upon SARS-CoV-2 spike protein treatment. Our results show that the zebrafish allows to study immune-modulating properties of COVID-19 compounds and highlights the need to rule out secondary defects of compound treatment on embryogenesis. All results are available on a user friendly web-interface https://share.streamlit.io/alernst/covasc_dataapp/main/CoVasc_DataApp.py that provides a comprehensive overview of all observed phenotypic effects and allows personalized search on specific compounds or group of compounds. Furthermore, the presented platform can be expanded for rapid detection of developmental side effects of new compounds for treatment of COVID-19 and further viral infectious diseases.
(© 2023. Springer Nature Limited.)
Databáze: MEDLINE
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