In vitro activity of itraconazole against SARS‐CoV‐2

Abstract

Although vaccination campaigns are currently being rolled out to prevent coronavirus disease (COVID‐19), antivirals will remain an important adjunct to vaccination. Antivirals against coronaviruses do not exist, hence global drug repurposing 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 activity against animal coronaviruses. Using 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. Itraconazole demonstrated antiviral activity in human Caco‐2 cells (EC 50 = 2.3 µM; MTT assay). Similarly, its primary metabolite, 17‐OH itraconazole, showed inhibition of SARS‐CoV‐2 activity (EC 50 = 3.6 µM). Remdesivir inhibited viral replication with an EC 50 = 0.4 µM. Itraconazole and 17‐OH itraconazole resulted in a viral yield reduction in vitro of approximately 2‐log 10 and approximately 1‐log 10 , 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‐log 10 drop and >4‐log 10 drop in Caco‐2 cells and VeroE6‐eGFP cells, respectively. Itraconazole 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). This article is protected by copyright. All rights reserved.

Simvastatin Downregulates the SARS-CoV-2-Induced Inflammatory Response and Impairs Viral Infection Through Disruption of Lipid Rafts

“…In this context, the pharmacological redistribution of cholesterol and impaired lipid raft formation hampers the SARS-CoV-2 SARS-CoV-2 entry, and consequently the virus replication (34,(43)(44)(45). In line with the results obtained here with simvastatin pretreatment, other drugs that affect not only the synthesis but also the traffic of cholesterol through the endosomal pathway, such as itraconazole, fluoxetine and amitriptyline showed promising results as adjuvant therapy for COVID-19 (42,46,47).…”

Development and optimisation of a high-throughput screening assay for in vitro anti–SARS-CoV-2 activity: evaluation of 5676 phase 1 passed structures

“…The findings of this study were comparable with other large screening studies that identified potential anti-SARS-CoV-2 agents and compounds, although in vivo efficacy, toxicity, and pharmacokinetic investigation of the selected hits in this report did not support novel application against SARS-CoV-2. 9,12,25,27,29,[46][47][48][49][50] Together, these studies demonstrate that drug repurposing technology can identify potential agents for rapidly spreading novel pathogens, as in the case of remdesivir, which has been used to treat patients with severe COVID-19. Although preclinical drug repurposing studies may provide a means of identifying potential agents and avoiding some of the limitations of traditional clinical development, the findings of this study suggest that results from in silico or in vitro studies should be interpreted with caution.…”

Repurposing Antifungals for Host-Directed Antiviral Therapy?

“…Aspergillosis, candidiasis, and cryptococcosis [22]. SARS-CoV-2 [23,24], influenza virus [25], Ebola virus [26][27][28], Parechovirus A3 [29],…”

“…Interestingly, NPC1 also emerged as a candidate drug target for other enveloped viruses, namely IAV and SARS-CoV-2. Viral replication rates were decreased in cells in which NPC1 was functionally blocked, and the increased endolysosomal cholesterol levels were suggested to interfere with the proper insertion of the fusogenic IAV hemagglutinin domains and the SARS-CoV-2 spike protein, thus affecting virus uncoating [23][24][25].…”