In VitroActivity of Itraconazole Against SARS-CoV-2

Background

As 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.

Methods

Using cell-based phenotypic assays, thein vitroantiviral activity of itraconazole and 17-OH itraconazole was assessed against clinical isolates from a German and Belgian patient infected with SARS-CoV-2.

Results

Itraconazole demonstrated antiviral activity in human Caco-2 cells (EC₅₀= 2.3 μM; MTT assay). Similarly, its primary metabolite, 17-OH itraconazole, showed inhibition of SARS-CoV-2 activity (EC₅₀= 3.6 μM). Remdesivir inhibited viral replication with an EC₅₀= 0.4 μM. Itraconazole and 17-OH itraconazole resulted in a viral yield reductionin vitroof approximately 2-log₁₀and 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 log₁₀drop and >4 log₁₀drop in Caco-2 cells and VeroE6-eGFP cells, respectively.

Discussion

Itraconazole and 17-OH itraconazole exertin vitrolow micromolar activity against SARS-CoV-2. Despite thein vitroantiviral activity, itraconazole did not result in a beneficial effect in hospitalized COVID-19 patients in a clinical study (EudraCT Number: 2020-001243-15).

Highlights

• Itraconazole exertedin vitrolow micromolar activity against SARS-CoV-2 (EC₅₀= 2.3 μM)

• Remdesivir demonstrated potent antiviral activity, confirming validity of the assay

• Itraconazole has since shown no efficacy in a clinical study in hospitalized COVID-19 patients