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X-206 exhibits broad-spectrum anti-β-coronavirus activity, covering SARS-CoV-2 variants and drug-resistant isolates
Jiei Sasaki1, Akihiko Sato2, Michihito Sasaki3
1Laboratory of Medical Virology, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan.
Abstract:
Coronaviruses such as the Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV), and SARS-CoV-2, causing MERS, SARS, and Coronavirus disease-19, respectively, are highly pathogenic to humans. Notably, several antiviral drugs against SARS-CoV-2, such as nirmatrelvir and remdesivir, have been approved. However, no approved vaccines or antiviral agents are available for other highly pathogenic β-coronaviruses. In this study, we identified two compounds, thapsigargin and X-206, that exhibit antiviral activities against SARS-CoV, MERS-CoV, and SARS-CoV-2. Notably, both compounds effectively inhibited the cell-to-cell fusion mediated by the Spike proteins of all three β-coronaviruses. X-206 exhibited antiviral activity against nirmatrelvir- and remdesivir-resistant SARS-CoV-2 isolates and SARS-CoV-2 variants, including Delta, BA.5, and XBB.1. Consequently, the mechanism of action of these compounds with anti-β-coronavirus activities may differ from that of the approved direct-acting drugs for SARS-CoV-2, thereby offering potential use as a cocktail with other antivirals, and serving as a chemical basis for developing therapeutic agents against β-coronaviruses in preparation for the next spillover and pandemic.
Insights
Two compounds, thapsigargin and X-206, show broad antiviral activity against pathogenic coronaviruses like SARS-CoV, MERS-CoV, and SARS-CoV-2. These agents inhibit viral cell-to-cell fusion and may offer new therapeutic options.
Area of Science:
- Virology
- Drug Discovery
- Infectious Diseases
Background:
- Highly pathogenic betacoronaviruses (β-coronaviruses) like MERS-CoV, SARS-CoV, and SARS-CoV-2 pose significant threats to human health.
- While effective treatments exist for SARS-CoV-2, other β-coronaviruses lack approved vaccines or antiviral therapies.
Purpose of the Study:
- To identify novel compounds with broad-spectrum antiviral activity against pathogenic β-coronaviruses.
- To investigate the potential of these compounds as therapeutic agents for current and future coronavirus outbreaks.
Main Methods:
- Screening of compounds for antiviral activity against SARS-CoV, MERS-CoV, and SARS-CoV-2.
- Assessing the inhibition of cell-to-cell fusion mediated by viral Spike proteins.
- Evaluating antiviral efficacy against drug-resistant isolates and variants of SARS-CoV-2.
Main Results:
- Thapsigargin and X-206 demonstrated significant antiviral activity against SARS-CoV, MERS-CoV, and SARS-CoV-2.
- Both compounds effectively inhibited Spike protein-mediated cell-to-cell fusion across these viruses.
- X-206 showed efficacy against remdesivir- and nirmatrelvir-resistant SARS-CoV-2, including variants like Delta, BA.5, and XBB.1.
Conclusions:
- Thapsigargin and X-206 represent promising candidates for broad-spectrum antiviral therapy against β-coronaviruses.
- Their distinct mechanism of action may complement existing treatments, offering potential for combination therapy.
- These compounds provide a foundation for developing new agents to combat future coronavirus pandemics.
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