About: The phosphatidylinositol-3-phosphate 5-kinase inhibitor apilimod blocks filoviral entry and infection

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About: The phosphatidylinositol-3-phosphate 5-kinase inhibitor apilimod blocks filoviral entry and infection Goto Sponge NotDistinct Permalink

An Entity of Type : schema:ScholarlyArticle, within Data Space : wasabi.inria.fr associated with source document(s)

Attributes	Values
type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
title	The phosphatidylinositol-3-phosphate 5-kinase inhibitor apilimod blocks filoviral entry and infection
Creator	Jahrling, Peter Chen, Yu-Chi Dyall, Julie Guha, Rajarshi Hoenen, Thomas Hughes, Emma Klumpp-Thomas, Carleen Martin, Scott Michelotti, Julia Thomas, Craig Wang, Amy Xu, Xin Zhou, Huanying Hensley, Lisa Liang, Janie Olinger, Gene White, Judith Barnes, Alyson Bennett, Richard Dewey, William Evans Dewald, Lisa Mcknight, Crystal Morris, Patrick Nelson, Elizabeth
source	PMC
abstract	Phosphatidylinositol-3-phosphate 5-kinase (PIKfyve) is a lipid kinase involved in endosome maturation that emerged from a haploid genetic screen as being required for Ebola virus (EBOV) infection. Here we analyzed the effects of apilimod, a PIKfyve inhibitor that was reported to be well tolerated in humans in phase 2 clinical trials, for its effects on entry and infection of EBOV and Marburg virus (MARV). We first found that apilimod blocks infections by EBOV and MARV in Huh 7, Vero E6 and primary human macrophage cells, with notable potency in the macrophages (IC(50), 10 nM). We next observed that similar doses of apilimod block EBOV-glycoprotein-virus like particle (VLP) entry and transcription-replication competent VLP infection, suggesting that the primary mode of action of apilimod is as an entry inhibitor, preventing release of the viral genome into the cytoplasm to initiate replication. After providing evidence that the anti-EBOV action of apilimod is via PIKfyve, we showed that it blocks trafficking of EBOV VLPs to endolysosomes containing Niemann-Pick C1 (NPC1), the intracellular receptor for EBOV. Concurrently apilimod caused VLPs to accumulate in early endosome antigen 1-positive endosomes. We did not detect any effects of apilimod on bulk endosome acidification, on the activity of cathepsins B and L, or on cholesterol export from endolysosomes. Hence by antagonizing PIKfyve, apilimod appears to block EBOV trafficking to its site of fusion and entry into the cytoplasm. Given the drug’s observed anti-filoviral activity, relatively unexplored mechanism of entry inhibition, and reported tolerability in humans, we propose that apilimod be further explored as part of a therapeutic regimen to treat filoviral infections.
has issue date	2017-04-12(xsd:dateTime)
bibo:doi	10.1371/journal.pntd.0005540
bibo:pmid	28403145
has license	cc0
sha1sum (hex)	9018234c987db8e1aec9ca3cae1806b75e4835ad
schema:url	https://doi.org/10.1371/journal.pntd.0005540
resource representing a document's title	The phosphatidylinositol-3-phosphate 5-kinase inhibitor apilimod blocks filoviral entry and infection
has PubMed Central identifier	PMC5402990
has PubMed identifier	28403145
schema:publication	PLoS Negl Trop Dis
resource representing a document's body	covid:9018234c987db8e1aec9ca3cae1806b75e4835ad#body_text
is schema:about of	named entity 'product' named entity 'detect' named entity 'infections' named entity 'phosphate' named entity 'infection' named entity 'EBOV' named entity 'late' named entity 'endosome' named entity 'phosphate' named entity 'infection' named entity 'EBOV' named entity 'NPC1' named entity 'reaching' named entity 'EBOV' named entity 'https' named entity 'action' named entity 'tolerated' covid:arg/9018234c987db8e1aec9ca3cae1806b75e4835ad named entity 'PIKfyve' named entity 'phase 2 clinical trials' named entity 'endosome' named entity 'infection' named entity 'cytoplasm' named entity 'doi' named entity 'haploid' named entity 'globe' named entity 'VLP' named entity 'primary' named entity 'disease' named entity 'Here' named entity 'primary' named entity 'trafficking' named entity 'particles' named entity 'kinase' named entity 'PIKfyve' named entity 'EBOV' named entity 'antagonizing' named entity 'target' named entity 'Here' named entity 'proper' named entity 'maturation' named entity 'apilimod' named entity 'EBOV' named entity 'phosphatidylinositol 3,5-bisphosphate' named entity 'mode of action' named entity 'transcription' named entity 'Marburgvirus' named entity 'PIKfyve' named entity 'Niemann-Pick' named entity 'VLPs' named entity 'phase 2 clinical trials' named entity 'Marburg virus' named entity 'VLP' named entity 'apilimod' named entity 'infection' named entity 'EBOV' named entity 'haploid' named entity 'Niemann-Pick'

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