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  • 1
    Publication Date: 2011-08-26
    Description: 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.〈br /〉〈br /〉〈a href="" target="_blank"〉〈img src="" border="0"〉〈/a〉   〈a href="" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cote, Marceline -- Misasi, John -- Ren, Tao -- Bruchez, Anna -- Lee, Kyungae -- Filone, Claire Marie -- Hensley, Lisa -- Li, Qi -- Ory, Daniel -- Chandran, Kartik -- Cunningham, James -- 5-T32-HL007623/HL/NHLBI NIH HHS/ -- 5K08AI079381/AI/NIAID NIH HHS/ -- K08 AI079381/AI/NIAID NIH HHS/ -- K12-HD052896/HD/NICHD NIH HHS/ -- R01 AI088027/AI/NIAID NIH HHS/ -- R01 CA104266/CA/NCI NIH HHS/ -- U54 AI057159/AI/NIAID NIH HHS/ -- U54 AI057159-09/AI/NIAID NIH HHS/ -- England -- Nature. 2011 Aug 24;477(7364):344-8. doi: 10.1038/nature10380.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="" target="_blank"〉PubMed〈/a〉
    Keywords: Adamantane/analogs & derivatives/chemistry ; Animals ; Antiviral Agents/*chemistry/*pharmacology ; Carrier Proteins/*metabolism ; Cathepsins/metabolism ; Cell Line ; Cercopithecus aethiops ; Ebolavirus/*drug effects/*physiology ; Endosomes/enzymology ; Glycoproteins/metabolism ; Hemorrhagic Fever, Ebola/drug therapy/metabolism ; Humans ; Membrane Fusion/drug effects ; Membrane Glycoproteins/*metabolism ; Molecular Weight ; Piperazines/chemistry ; Vero Cells ; Viral Fusion Proteins/metabolism ; Virus Internalization/*drug effects
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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