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.
| Original language | English |
|---|---|
| Article number | 105766 |
| Pages (from-to) | 1-13 |
| Number of pages | 13 |
| Journal | Antiviral Research |
| Volume | 221 |
| Early online date | 30 Nov 2023 |
| DOIs | |
| Publication status | Published - 1 Jan 2024 |
Bibliographical note
Funding Information:ILS acknowledges Institutional funding from the Faculty of Life Sciences (University of Bristol, grant code U102054-101). ADD is a member of the G2P-UK National Virology consortium funded by the Medical Research Council/UKRI (Grant MR/W005611/1) that supplied SARS-CoV-2 variants and is funded by U.S. Food and Drug Administration Medical Countermeasures Initiative contract (75F40120C00085). The authors acknowledge support from the University of Bristol's Alumni and Friends, who funded the ImageXpress Pico Imaging System. The authors thank Dr. Irene Carlon-Andres and Dr. David Williamson (King's College London, UK) for helpful suggestions on Fiji macro coding and Dr. Andrea Savarino (Italian Institute of Health, Italy) for critical reading of the manuscript.
Funding Information:
ILS acknowledges Institutional funding from the Faculty of Life Sciences ( University of Bristol , grant code U102054-101 ). ADD is a member of the G2P-UK National Virology consortium funded by the Medical Research Council/UKRI (Grant MR/W005611/1 ) that supplied SARS-CoV-2 variants and is funded by U.S. Food and Drug Administration Medical Countermeasures Initiative contract ( 75F40120C00085 ). The authors acknowledge support from the University of Bristol's Alumni and Friends , who funded the ImageXpress Pico Imaging System. The authors thank Dr. Irene Carlon-Andres and Dr. David Williamson (King's College London, UK) for helpful suggestions on Fiji macro coding and Dr. Andrea Savarino (Italian Institute of Health, Italy) for critical reading of the manuscript.
Publisher Copyright:
© 2023 The Authors