The cholesterol transport inhibitor U18666A inhibits type I feline coronavirus infection

Takano, Tomomi; Endoh, Misaki; Fukatsu, Hiroaki; Sakurada, Haruko; Doki, Tomoyoshi; Hohdatsu, Tsutomu

doi:10.1016/j.antiviral.2017.07.022

Cited by 46 publications

(65 citation statements)

References 39 publications

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“…Our previous study demonstrated that the triazole antifungal agent itraconazole blocks the intracellular trafficking of cholesterol and inhibits type I FCoV infection in a feline cell line (felis catus whole fetus-4 cells: fcwf-4 cells) [12]. Similar results were observed with U18666A, the widely studied cholesterol transport inhibitor [11]. Other researchers reported that itraconazole and U18666A blocked cholesterol egress from late endosomes [13][14][15].…”

Section: Introductionsupporting

confidence: 67%

“…Based on the above results and our previous study [11,12], different FCoV serotypes may enter feline cells through different endocytic routes: FCoV-I KU2 is released from late endosomes into the cytosol, whereas FCoV-II 79-1146 is released from early endosomes into the cytosol. Cholesterol accumulation was previously reported to disrupt late endosome function [16,17].…”

Section: The Effects Of Late Endosomal Function On Fcov In Fcwf-4 Cellssupporting

confidence: 61%

“…Both FCoV serotypes use the endosomal pathway for cell entry [11,44]. However, the timing of cytosol entry of each serotype was unclear.…”

Section: Discussionmentioning

confidence: 99%

“…FCoV infection is dependent on intracellular cholesterol [11]. Our previous study demonstrated that the triazole antifungal agent itraconazole blocks the intracellular trafficking of cholesterol and inhibits type I FCoV infection in a feline cell line (felis catus whole fetus-4 cells: fcwf-4 cells) [12].…”

Section: Introductionmentioning

confidence: 99%

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Endocytic Pathway of Feline Coronavirus for Cell Entry: Differences in Serotype-Dependent Viral Entry Pathway

2019

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Feline coronavirus (FCoV) is a pathogen causing a lethal infectious disease in cats, feline infectious peritonitis. It has two serotypes (type I FCoV and type II FCoV). According to our previous study, type I FCoV infection is inhibited by compounds inducing intracellular cholesterol accumulation, whereas type II FCoV infection is not inhibited. Intracellular cholesterol accumulation was reported to disrupt late endosome function. Based on these findings, types I and II FCoV are considered to enter the cytosol through late and early endosomes, respectively. We investigated whether the antiviral activities of a late endosome trafficking inhibitor and cholesterol-accumulating agents are different between the FCoV serotypes. The late endosome trafficking inhibitor did not inhibit type II FCoV infection, but it inhibited type I FCoV infection. Type I FCoV infection was inhibited by cholesterol-accumulating triazoles, but not by non-cholesterol-accumulating triazoles. These phenomena were observed in both feline cell lines and feline primary macrophages. This study provides additional information on the differences in intracellular reproductive cycle between type I and type II FCoV.

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Section: Introductionsupporting

confidence: 67%

Section: The Effects Of Late Endosomal Function On Fcov In Fcwf-4 Cellssupporting

confidence: 61%

“…Both FCoV serotypes use the endosomal pathway for cell entry [11,44]. However, the timing of cytosol entry of each serotype was unclear.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Endocytic Pathway of Feline Coronavirus for Cell Entry: Differences in Serotype-Dependent Viral Entry Pathway

2019

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“…We suggest that our understanding of FIP should consider the presence of these two distinct viruses, in order to determine whether or not it has implications in clinical settings. Such distinctions are suggested based on documented differences seen in cell culture between type I and type II viruses, for example with regard to interferon responses and the activity of antiviral drugs [30,31].…”

Section: Introductionmentioning

confidence: 99%

A Tale of Two Viruses: The Distinct Spike Glycoproteins of Feline Coronaviruses

Jaimes

Millet

Stout

et al. 2020

Viruses

128

122

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Feline coronavirus (FCoV) is a complex viral agent that causes a variety of clinical manifestations in cats, commonly known as feline infectious peritonitis (FIP). It is recognized that FCoV can occur in two different serotypes. However, differences in the S protein are much more than serological or antigenic variants, resulting in the effective presence of two distinct viruses. Here, we review the distinct differences in the S proteins of these viruses, which are likely to translate into distinct biological outcomes. We introduce a new concept related to the non-taxonomical classification and differentiation among FCoVs by analyzing and comparing the genetic, structural, and functional characteristics of FCoV and the FCoV S protein among the two serotypes and FCoV biotypes. Based on our analysis, we suggest that our understanding of FIP needs to consider whether the presence of these two distinct viruses has implications in clinical settings.

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In vitro activity of itraconazole against SARS‐CoV‐2

Damme

Meyer

Bojkova

et al. 2021

Journal of Medical Virology

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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.

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The cholesterol transport inhibitor U18666A inhibits type I feline coronavirus infection

Cited by 46 publications

References 39 publications

Endocytic Pathway of Feline Coronavirus for Cell Entry: Differences in Serotype-Dependent Viral Entry Pathway

Endocytic Pathway of Feline Coronavirus for Cell Entry: Differences in Serotype-Dependent Viral Entry Pathway

A Tale of Two Viruses: The Distinct Spike Glycoproteins of Feline Coronaviruses

In vitro activity of itraconazole against SARS‐CoV‐2

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