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2021-12-15Zeitschriftenartikel
Pharmacologically induced endolysosomal cholesterol imbalance through clinically licensed drugs itraconazole and fluoxetine impairs Ebola virus infection in vitro
dc.contributor.authorKummer, Susann
dc.contributor.authorLander, Angelika
dc.contributor.authorGoretzko, Jonas
dc.contributor.authorKirchoff, Norman
dc.contributor.authorRescher, Ursula
dc.contributor.authorSchloer, Sebastian
dc.date.accessioned2024-07-09T16:55:44Z
dc.date.available2024-07-09T16:55:44Z
dc.date.issued2021-12-15none
dc.identifier.other10.1080/22221751.2021.2020598
dc.identifier.urihttp://edoc.rki.de/176904/11772
dc.description.abstractEbola virus disease (EVD) is a severe and frequently lethal disease caused by Ebola virus (EBOV). The latest occasional EVD outbreak (2013–2016) in Western African, which was accompanied by a high fatality rate, showed the great potential of epidemic and pandemic spread. Antiviral therapies against EBOV are very limited, strain-dependent (only antibody therapies are available) and mostly restricted to symptomatic treatment, illustrating the urgent need for novel antiviral strategies. Thus, we evaluated the effect of the clinically widely used antifungal itraconazole and the antidepressant fluoxetine for a repurposing against EBOV infection. While itraconazole, similar to U18666A, directly binds to and inhibits the endosomal membrane protein Niemann-Pick C1 (NPC1), fluoxetine, which belongs to the structurally unrelated group of weakly basic, amphiphile so-called “functional inhibitors of acid sphingomyelinase” (FIASMA) indirectly acts on the lysosome-residing acid sphingomyelinase via enzyme detachment leading to subsequent lysosomal degradation. Both, the drug-induced endolysosomal cholesterol accumulation and the altered endolysosomal pH, might interfere with the fusion of viral and endolysosomal membrane, preventing infection with EBOV. We further provide evidence that cholesterol imbalance is a conserved cross-species mechanism to hamper EBOV infection. Thus, exploring the endolysosomal host–pathogen interface as a suitable antiviral treatment may offer a general strategy to combat EBOV infection.eng
dc.language.isoundnone
dc.publisherRobert Koch-Institut
dc.rights(CC BY 3.0 DE) Namensnennung 3.0 Deutschlandger
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/de/
dc.subjectebola viruseng
dc.subjectniemann-pick C1eng
dc.subjectitraconazoleeng
dc.subjectFIASMAeng
dc.subjectfluoxetineeng
dc.subjectviral entryeng
dc.subjectendolysosomal interferenceeng
dc.subject.ddc610 Medizin und Gesundheitnone
dc.titlePharmacologically induced endolysosomal cholesterol imbalance through clinically licensed drugs itraconazole and fluoxetine impairs Ebola virus infection in vitronone
dc.typearticle
dc.identifier.urnurn:nbn:de:0257-176904/11772-2
dc.type.versionpublishedVersionnone
local.edoc.container-titleEmerging Microbes & Infectionsnone
local.edoc.container-issn2222-1751none
local.edoc.pages14none
local.edoc.type-nameZeitschriftenartikel
local.edoc.container-typeperiodical
local.edoc.container-type-nameZeitschrift
local.edoc.container-urlhttps://www.tandfonline.com/journals/temi20none
local.edoc.container-publisher-nameTaylor & Francisnone
local.edoc.container-volume11none
local.edoc.container-issue1none
local.edoc.container-reportyear2021none
dc.description.versionPeer Reviewednone

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