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

Marceline Côté, John Misasi, Tao Ren, Anna Bruchez, Kyungae Lee, Claire Marie Filone, Lisa Hensley, Qi Li, Daniel Ory, Kartik Chandran, James Cunningham

Research output: Contribution to journalArticle

377 Citations (Scopus)

Abstract

Ebola virus (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 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. 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 antiviral 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 amino-terminal domain, which is a ligand for NPC1 and regulates membrane fusion by the GP2 subunit. Thus, NPC1 is essential for EboV entry and a target for antiviral therapy.

Original languageEnglish (US)
Pages (from-to)344-348
Number of pages5
JournalNature
Volume477
Issue number7364
DOIs
StatePublished - Sep 15 2011

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Ebola Hemorrhagic Fever
Ebolavirus
Glycoproteins
Antiviral Agents
Disease Outbreaks
Adamantane
Diamide
Viruses
Cathepsins
Active Immunotherapy
Virus Internalization
Membrane Fusion
Mortality
Zoonoses
Infection
Disease Progression
Membrane Proteins
Peptide Hydrolases
Cytokines
Ligands

ASJC Scopus subject areas

  • General

Cite this

Côté, M., Misasi, J., Ren, T., Bruchez, A., Lee, K., Filone, C. M., ... Cunningham, J. (2011). Small molecule inhibitors reveal Niemann-Pick C1 is essential for Ebola virus infection. Nature, 477(7364), 344-348. https://doi.org/10.1038/nature10380

Small molecule inhibitors reveal Niemann-Pick C1 is essential for Ebola virus infection. / Côté, Marceline; Misasi, John; Ren, Tao; Bruchez, Anna; Lee, Kyungae; Filone, Claire Marie; Hensley, Lisa; Li, Qi; Ory, Daniel; Chandran, Kartik; Cunningham, James.

In: Nature, Vol. 477, No. 7364, 15.09.2011, p. 344-348.

Research output: Contribution to journalArticle

Côté, M, Misasi, J, Ren, T, Bruchez, A, Lee, K, Filone, CM, Hensley, L, Li, Q, Ory, D, Chandran, K & Cunningham, J 2011, 'Small molecule inhibitors reveal Niemann-Pick C1 is essential for Ebola virus infection', Nature, vol. 477, no. 7364, pp. 344-348. https://doi.org/10.1038/nature10380
Côté M, Misasi J, Ren T, Bruchez A, Lee K, Filone CM et al. Small molecule inhibitors reveal Niemann-Pick C1 is essential for Ebola virus infection. Nature. 2011 Sep 15;477(7364):344-348. https://doi.org/10.1038/nature10380
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 Ebola virus infection. In: Nature. 2011 ; Vol. 477, No. 7364. pp. 344-348.
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