Small molecule inhibitors reveal Niemann-Pick C1 is essential for ebolavirus infection

Ebolavirus (EboV) is a highly pathogenic enveloped virus that causes outbreaks of zoonotic infection in Africa. The clinical symptoms are manifestations of the massive production of pro-inflammatory cytokines in response to infection1 and in many outbreaks, mortality exceeds 75%. The unpredictable o...

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Main Authors:	Côté, Marceline, Misasi, John, Ren, Tao, Bruchez, Anna, Lee, Kyungae, Filone, Claire Marie, Hensley, Lisa, Li, Qi, Ory, Daniel, Chandran, Kartik, Cunningham, James
Format:	Online
Language:	English
Published:	2011
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3230319/

id	pubmed-3230319
recordtype	oai_dc
spelling	pubmed-32303192012-03-15 Small molecule inhibitors reveal Niemann-Pick C1 is essential for ebolavirus infection Côté, Marceline Misasi, John Ren, Tao Bruchez, Anna Lee, Kyungae Filone, Claire Marie Hensley, Lisa Li, Qi Ory, Daniel Chandran, Kartik Cunningham, James Article Ebolavirus (EboV) is a highly pathogenic enveloped virus that causes outbreaks of zoonotic infection in Africa. The clinical symptoms are manifestations of the massive production of pro-inflammatory cytokines in response to infection1 and in many outbreaks, mortality exceeds 75%. The unpredictable onset, ease of transmission, rapid progression of disease, high mortality and lack of effective vaccine or therapy have created a high level of public concern about EboV2. Here we report the identification of a novel benzylpiperazine adamantane diamide-derived compound that inhibits EboV infection. Using mutant cell lines and informative derivatives of the lead compound, we show that the target of the inhibitor is the endosomal membrane protein Niemann-Pick C1 (NPC1). We find that NPC1 is essential for infection, that it binds to the virus glycoprotein (GP), and that the anti-viral compounds interfere with GP binding to NPC1. Combined with the results of previous studies of GP structure and function, our findings support a model of EboV infection in which cleavage of the GP1 subunit by endosomal cathepsin proteases removes heavily glycosylated domains to expose the N-terminal domain3–7, which is a ligand for NPC1 and regulates membrane fusion by the GP2 subunit8. Thus, NPC1 is essential for EboV entry and a target for anti-viral therapy. 2011-08-24 /pmc/articles/PMC3230319/ /pubmed/21866101 http://dx.doi.org/10.1038/nature10380 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Côté, Marceline Misasi, John Ren, Tao Bruchez, Anna Lee, Kyungae Filone, Claire Marie Hensley, Lisa Li, Qi Ory, Daniel Chandran, Kartik Cunningham, James
spellingShingle	Côté, Marceline Misasi, John Ren, Tao Bruchez, Anna Lee, Kyungae Filone, Claire Marie Hensley, Lisa Li, Qi Ory, Daniel Chandran, Kartik Cunningham, James Small molecule inhibitors reveal Niemann-Pick C1 is essential for ebolavirus infection
author_facet	Côté, Marceline Misasi, John Ren, Tao Bruchez, Anna Lee, Kyungae Filone, Claire Marie Hensley, Lisa Li, Qi Ory, Daniel Chandran, Kartik Cunningham, James
author_sort	Côté, Marceline
title	Small molecule inhibitors reveal Niemann-Pick C1 is essential for ebolavirus infection
title_short	Small molecule inhibitors reveal Niemann-Pick C1 is essential for ebolavirus infection
title_full	Small molecule inhibitors reveal Niemann-Pick C1 is essential for ebolavirus infection
title_fullStr	Small molecule inhibitors reveal Niemann-Pick C1 is essential for ebolavirus infection
title_full_unstemmed	Small molecule inhibitors reveal Niemann-Pick C1 is essential for ebolavirus infection
title_sort	small molecule inhibitors reveal niemann-pick c1 is essential for ebolavirus infection
description	Ebolavirus (EboV) is a highly pathogenic enveloped virus that causes outbreaks of zoonotic infection in Africa. The clinical symptoms are manifestations of the massive production of pro-inflammatory cytokines in response to infection1 and in many outbreaks, mortality exceeds 75%. The unpredictable onset, ease of transmission, rapid progression of disease, high mortality and lack of effective vaccine or therapy have created a high level of public concern about EboV2. Here we report the identification of a novel benzylpiperazine adamantane diamide-derived compound that inhibits EboV infection. Using mutant cell lines and informative derivatives of the lead compound, we show that the target of the inhibitor is the endosomal membrane protein Niemann-Pick C1 (NPC1). We find that NPC1 is essential for infection, that it binds to the virus glycoprotein (GP), and that the anti-viral compounds interfere with GP binding to NPC1. Combined with the results of previous studies of GP structure and function, our findings support a model of EboV infection in which cleavage of the GP1 subunit by endosomal cathepsin proteases removes heavily glycosylated domains to expose the N-terminal domain3–7, which is a ligand for NPC1 and regulates membrane fusion by the GP2 subunit8. Thus, NPC1 is essential for EboV entry and a target for anti-viral therapy.
publishDate	2011
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3230319/
_version_	1611491763492487168

Small molecule inhibitors reveal Niemann-Pick C1 is essential for ebolavirus infection

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