Broad-spectrum antiviral activity of two structurally analogous CYP3A inhibitors against pathogenic human coronaviruses in vitro
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Early Viral Entry Assays for the Identification and Evaluation of Antiviral Compounds
Published on: October 29, 2015
Lara Gallucci1, James Bazire1, Andrew D Davidson1
1School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
Abstract:
Coronaviruses pose a permanent risk of outbreaks, with three highly pathogenic species and strains (SARS-CoV, MERS-CoV, SARS-CoV-2) having emerged in the last twenty years. Limited antiviral therapies are currently available and their efficacy in randomized clinical trials enrolling SARS-CoV-2 patients has not been consistent, highlighting the need for more potent treatments. We previously showed that cobicistat, a clinically approved inhibitor of Cytochrome P450-3A (CYP3A), has direct antiviral activity against early circulating SARS-CoV-2 strains in vitro and in Syrian hamsters. Cobicistat is a derivative of ritonavir, which is co-administered as pharmacoenhancer with the SARS-CoV-2 protease inhibitor nirmatrelvir, to inhibit its metabolization by CPY3A and preserve its antiviral efficacy. Here, we used automated image analysis for a screening and parallel comparison of the anti-coronavirus effects of cobicistat and ritonavir. Our data show that both drugs display antiviral activity at low micromolar concentrations against multiple SARS-CoV-2 variants in vitro, including epidemiologically relevant Omicron subvariants. Despite their close structural similarity, we found that cobicistat is more potent than ritonavir, as shown by significantly lower EC50 values in monotherapy and higher levels of viral suppression when used in combination with nirmatrelvir. Finally, we show that the antiviral activity of both cobicistat and ritonavir is maintained against other human coronaviruses, including HCoV-229E and the highly pathogenic MERS-CoV. Overall, our results demonstrate that cobicistat has more potent anti-coronavirus activity than ritonavir and suggest that dose adjustments could pave the way to the use of both drugs as broad-spectrum antivirals against highly pathogenic human coronaviruses.
Insights
Cobicistat shows stronger antiviral activity against SARS-CoV-2 and other coronaviruses than ritonavir. This suggests cobicistat could be a more effective broad-spectrum antiviral treatment for future coronavirus outbreaks.
Area of Science:
- Virology
- Pharmacology
- Infectious Diseases
Background:
- Coronaviruses, including SARS-CoV-2, pose a persistent threat due to frequent outbreaks.
- Existing antiviral therapies for SARS-CoV-2 have shown inconsistent efficacy, necessitating the development of more potent treatments.
- Cobicistat, a Cytochrome P450-3A (CYP3A) inhibitor, previously demonstrated in vitro and in vivo antiviral activity against SARS-CoV-2.
Purpose of the Study:
- To screen and compare the anti-coronavirus effects of cobicistat and ritonavir using automated image analysis.
- To evaluate the potency of cobicistat versus ritonavir as monotherapy and in combination with nirmatrelvir against SARS-CoV-2 variants.
- To assess the antiviral activity of cobicistat and ritonavir against other human coronaviruses, including MERS-CoV.
Main Methods:
- Automated image analysis was employed for high-throughput screening and parallel comparison of cobicistat and ritonavir.
- In vitro antiviral activity was assessed against multiple SARS-CoV-2 variants and other human coronaviruses.
- Drug potency was quantified by EC50 values and viral suppression levels, particularly when combined with nirmatrelvir.
Main Results:
- Both cobicistat and ritonavir exhibited antiviral activity against SARS-CoV-2 variants, including Omicron subvariants, at low micromolar concentrations.
- Cobicistat demonstrated significantly greater potency than ritonavir in monotherapy (lower EC50) and in combination with nirmatrelvir.
- Antiviral activity of both drugs was confirmed against HCoV-229E and MERS-CoV, indicating broad-spectrum potential.
Conclusions:
- Cobicistat possesses more potent anti-coronavirus activity compared to ritonavir.
- The findings suggest cobicistat's potential as a superior broad-spectrum antiviral agent against highly pathogenic human coronaviruses.
- Further research into dose adjustments may facilitate the clinical use of cobicistat and ritonavir for treating various coronavirus infections.
