In Vitro Activity of Itraconazole Against SARS-CoV-2

Van Damme, E.; De Meyer, S.; Bojkova, D.; Ciesek, S.; Cinatl, J.; De Jonghe, S.; Jochmans, D.; Leyssen, P.; Buyck, C.; Neyts, J.; Van Loock, M.

doi:10.1101/2020.11.13.381194

bioRxiv · 10.1101/2020.11.13.381194

In Vitro Activity of Itraconazole Against SARS-CoV-2

Van Damme, E.·De Meyer, S.·Bojkova, D.·Ciesek, S.·Cinatl, J.·De Jonghe, S.·Jochmans, D.·Leyssen, P.·Buyck, C.·Neyts, J.·Van Loock, M.

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Abstract

BackgroundAs long as there is no vaccine available, having access to inhibitors of SARS-CoV-2 will be of utmost importance. Antivirals against coronaviruses do not exist, hence global drug re-purposing efforts have been carried out to identify agents that may provide clinical benefit to patients with COVID-19. Itraconazole, an antifungal agent, has been reported to have potential activity against animal coronaviruses. MethodsUsing cell-based phenotypic assays, the in vitro antiviral activity of itraconazole and 17-OH itraconazole was assessed against clinical isolates from a German and Belgian patient infected with SARS-CoV-2. ResultsItraconazole demonstrated antiviral activity in human Caco-2 cells (EC50 = 2.3 M; MTT assay). Similarly, its primary metabolite, 17-OH itraconazole, showed inhibition of SARS-CoV-2 activity (EC50 = 3.6 M). Remdesivir inhibited viral replication with an EC50 = 0.4 M. Itraconazole and 17-OH itraconazole resulted in a viral yield reduction in vitro of approximately 2-log10 and approximately 1-log10, as measured in both Caco-2 cells and VeroE6-eGFP cells, respectively. The viral yield reduction brought about by remdesivir or GS-441524 (parent nucleoside of the antiviral prodrug remdesivir; positive control) was more pronounced, with an approximately 3 log10 drop and >4 log10 drop in Caco-2 cells and VeroE6-eGFP cells, respectively. DiscussionItraconazole and 17-OH itraconazole exert in vitro low micromolar activity against SARS-CoV-2. Despite the in vitro antiviral activity, itraconazole did not result in a beneficial effect in hospitalized COVID-19 patients in a clinical study (EudraCT Number: 2020-001243-15). HighlightsO_LIItraconazole exerted in vitro low micromolar activity against SARS-CoV-2 (EC50 = 2.3 M) C_LIO_LIRemdesivir demonstrated potent antiviral activity, confirming validity of the assay C_LIO_LIItraconazole has since shown no efficacy in a clinical study in hospitalized COVID-19 patients C_LI

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Van Damme, E., De Meyer, S., Bojkova, D., Ciesek, S., Cinatl, J., De Jonghe, S., Jochmans, D., Leyssen, P., Buyck, C., Neyts, J., Van Loock, M.. 2020-11-13. In Vitro Activity of Itraconazole Against SARS-CoV-2. https://doi.org/10.1101/2020.11.13.381194

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