PMID:21866101

Citation	Côté, M, Misasi, J, Ren, T, Bruchez, A, Lee, K, Filone, CM, Hensley, L, Li, Q, Ory, D, Chandran, K and Cunningham, J (2011) Small molecule inhibitors reveal Niemann-Pick C1 is essential for Ebola virus infection. Nature 477:344-8
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.
Links	PubMed PMC3230319 Online version:10.1038/nature10380
Keywords	Adamantane/analogs & derivatives; Adamantane/chemistry; Animals; Antiviral Agents/chemistry; Antiviral Agents/pharmacology; Carrier Proteins/metabolism; Cathepsins/metabolism; Cell Line; Cercopithecus aethiops; Ebolavirus/drug effects; Ebolavirus/physiology; Endosomes/enzymology; Glycoproteins/metabolism; Hemorrhagic Fever, Ebola/drug therapy; Hemorrhagic Fever, Ebola/metabolism; Humans; Membrane Fusion/drug effects; Membrane Glycoproteins/metabolism; Molecular Weight; Piperazines/chemistry; Vero Cells; Viral Fusion Proteins/metabolism; Virus Internalization/drug effects
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:NPC1		GO:0046718: entry of virus into host cell	ECO:0000315:		P		Fig. 2B (infection) and 2C/2D (virus entry into cell)	complete CACAO 2104
HUMAN:NPC1	involved_in	GO:0046718: viral entry into host cell	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
MOUSE:NPC1		GO:0046718: entry of virus into host cell	ECO:0000315:		P		Fig. 2C and Fig. 2D	complete CACAO 2106
MOUSE:NPC1	involved_in	GO:0046718: viral entry into host cell	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete

References

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