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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 infection(1) and in many outbreaks, mortality exceeds 75%. The unpredictable...

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Autores principales: Côté, Marceline, Misasi, John, Ren, Tao, Bruchez, Anna, Lee, Kyungae, Filone, Claire Marie, Hensley, Lisa, Li, Qi, Ory, Daniel, Chandran, Kartik, Cunningham, James
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3230319/
https://www.ncbi.nlm.nih.gov/pubmed/21866101
http://dx.doi.org/10.1038/nature10380
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author Côté, Marceline
Misasi, John
Ren, Tao
Bruchez, Anna
Lee, Kyungae
Filone, Claire Marie
Hensley, Lisa
Li, Qi
Ory, Daniel
Chandran, Kartik
Cunningham, James
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
collection PubMed
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 infection(1) 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 EboV(2). 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 domain(3–7), which is a ligand for NPC1 and regulates membrane fusion by the GP2 subunit(8). Thus, NPC1 is essential for EboV entry and a target for anti-viral therapy.
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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 Nature 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 infection(1) 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 EboV(2). 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 domain(3–7), which is a ligand for NPC1 and regulates membrane fusion by the GP2 subunit(8). 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
spellingShingle Article
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
title 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_short 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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3230319/
https://www.ncbi.nlm.nih.gov/pubmed/21866101
http://dx.doi.org/10.1038/nature10380
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