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

Alexander Ernst1, Indre Piragyte1,2, Ayisha Marwa Mp1,2

  • 1Institute of Anatomy, University of Bern, Bern, Switzerland.

Scientific Reports
|October 9, 2023
PubMed

Insights

Zebrafish embryos revealed developmental defects in cardiovascular function and embryo activity from COVID-19 drugs like Remdesivir and Molnupiravir. However, these drugs also counteracted inflammatory gene expression induced by the SARS-CoV-2 spike protein.

Area of Science:

  • Developmental biology
  • Pharmacology
  • Toxicology

Background:

  • Drug repurposing for COVID-19 treatment is crucial, but potential embryogenesis effects of approved drugs are often unexamined, limiting use during pregnancy.
  • Understanding the impact of COVID-19 therapeutics on embryonic development is essential for safe clinical application.

Purpose of the Study:

  • To evaluate the effects of 162 marketed drugs, including COVID-19 treatments, on zebrafish embryo cardiovascular development.
  • To assess the utility of zebrafish embryos as a model for studying the immune-modulating properties and developmental side effects of COVID-19 compounds.

Main Methods:

  • Screened 162 marketed drugs for effects on zebrafish embryo cardiovascular development and overall activity.
  • Investigated the anti-inflammatory effects of selected COVID-19 drugs against SARS-CoV-2 spike protein-induced gene expression in zebrafish.
  • Utilized a web interface for data visualization and analysis of observed phenotypic effects.

Main Results:

  • Remdesivir, Ritonavir, Molnupiravir, and Baricitinib exhibited varying degrees of cardiovascular dysfunction and/or reduced embryo activity at clinically relevant doses.
  • Sabizabulin demonstrated high toxicity and significant mortality at concentrations near its maximum observed concentration (Cmax).
  • Remdesivir, Ritonavir, Molnupiravir, Baricitinib, and Sabizabulin effectively counteracted inflammatory gene expression triggered by the SARS-CoV-2 spike protein.

Conclusions:

  • Zebrafish embryos serve as a valuable model for assessing both the developmental toxicity and immunomodulatory potential of COVID-19 drugs.
  • The study highlights the necessity of evaluating secondary embryogenesis defects for drugs considered for COVID-19 treatment, especially in pregnant individuals.
  • A user-friendly web platform was developed to share comprehensive data on drug effects, facilitating further research and drug screening.

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