Summary 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.

Antibodies block Ebola virus entry The recent Ebola virus outbreak in West Africa illustrates the need for both an effective vaccine and therapies to treat infected individuals. Corti et al. isolated two monoclonal antibodies from a survivor of the 1995 Kikwit outbreak and demonstrated their therapeutic efficacy in Ebola virus–infected macaques. In fact, one antibody protected macaques when it was given up to 5 days after infection. Misasi et al. solved the crystal structures of fragments of the two antibodies bound to the Ebola virus glycoprotein (GP), which mediates viral cell entry. The two antibodies targeted different regions of GP, but in both cases blocked steps required for viral entry. Science , this issue pp. 1339 & 1343

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