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Evaluation of Broad Anti-Coronavirus Activity of Autophagy-Related Compounds Using Human Airway Organoids
Rina Hashimoto1, Tomokazu Tamura2, Yukio Watanabe1
1Center for iPS Cell Research and Application (CiRA), Kyoto University, Shogoin Kawaharacho 53, Sakyo-ku, Kyoto 606-8507, Japan.
Abstract:
To deal with the broad spectrum of coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), that threaten human health, it is essential to not only drugs develop that target viral proteins but also consider drugs that target host proteins/cellular processes to protect them from being hijacked for viral infection and replication. To this end, it has been reported that autophagy is deeply involved in coronavirus infection. In this study, we used airway organoids to screen a chemical library of autophagic modulators to identify compounds that could potentially be used to fight against infections by a broad range of coronaviruses. Among the 80 autophagy-related compounds tested, cycloheximide and thapsigargin reduced SARS-CoV-2 infection efficiency in a dose-dependent manner. Cycloheximide treatment reduced the infection efficiency of not only six SARS-CoV-2 variants but also human coronavirus (HCoV)-229E and HCoV-OC43. Cycloheximide treatment also reversed viral infection-induced innate immune responses. However, even low-dose (1 μM) cycloheximide treatment altered the expression profile of ribosomal RNAs; thus, side effects such as inhibition of protein synthesis in host cells must be considered. These results suggest that cycloheximide has broad-spectrum anti-coronavirus activity in vitro and warrants further investigation.
Insights
Cycloheximide shows broad-spectrum anti-coronavirus activity by inhibiting viral replication in airway organoids. While effective against SARS-CoV-2 variants and other human coronaviruses, potential host cell protein synthesis inhibition requires further study.
Area of Science:
- Virology
- Cellular Biology
- Drug Discovery
Background:
- Coronaviruses pose a significant threat to human health, necessitating diverse therapeutic strategies.
- Autophagy plays a crucial role in the lifecycle of coronaviruses, making it a potential therapeutic target.
Purpose of the Study:
- To screen autophagic modulators for broad-spectrum anti-coronavirus activity using airway organoids.
- To identify compounds effective against SARS-CoV-2 and other human coronaviruses.
Main Methods:
- Airway organoid model used for screening a chemical library of 80 autophagy-related compounds.
- Dose-dependent evaluation of compound efficacy against SARS-CoV-2 variants and human coronaviruses (HCoV-229E, HCoV-OC43).
- Assessment of cycloheximide's impact on viral infection-induced innate immune responses and host cell protein synthesis.
Main Results:
- Cycloheximide and thapsigargin demonstrated dose-dependent reduction of SARS-CoV-2 infection.
- Cycloheximide effectively inhibited infection by multiple SARS-CoV-2 variants, HCoV-229E, and HCoV-OC43.
- Cycloheximide reversed viral infection-induced innate immune responses but also affected ribosomal RNA expression at low doses.
Conclusions:
- Cycloheximide exhibits broad-spectrum anti-coronavirus activity in vitro.
- Further investigation is warranted to explore cycloheximide's therapeutic potential while considering its host cell side effects.
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