broad-spectrum antiviral targeting entry of enveloped viruses

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 107; no. 7; pp. 3157 - 3162
• Main Authors: Wolf, Mike C, Freiberg, Alexander N, Zhang, Tinghu, Akyol-Ataman, Zeynep, Grock, Andrew, Hong, Patrick W, Li, Jianrong, Watson, Natalya F, Fang, Angela Q, Aguilar, Hector C, Porotto, Matteo, Honko, Anna N, Damoiseaux, Robert, Miller, John P, Woodson, Sara E, Chantasirivisal, Steven, Fontanes, Vanessa, Negrete, Oscar A, Krogstad, Paul, Dasgupta, Asim, Moscona, Anne, Hensley, Lisa E, Whelan, Sean P, Faull, Kym F, Holbrook, Michael R, Jung, Michael E, Lee, Benhur
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 16.02.2010; National Acad Sciences
• Subjects: Animals; Antiviral activity; Antiviral Agents - pharmacology; Antiviral Agents - therapeutic use; Antivirals; Binding sites; Biological Sciences; Cell fusion; Cell lines; Cell membranes; Cells; Data processing; Ebola virus; Envelope protein; Female; Filovirus; Human immunodeficiency virus 1; Infection; Infections; Influenza A; Lipid membranes; Lipids; Liposomes; Membranes; Mice; Mice, Inbred BALB C; Mortality; P branes; Proteins; Rhodanine - analogs & derivatives; Rhodanine - chemistry; Rhodanine - pharmacology; Rhodanine - therapeutic use; Rift Valley fever; Structure-Activity Relationship; Structure-activity relationships; Toxicity; Vero cells; Viral Envelope Proteins - metabolism; Virions; Virus Diseases - drug therapy; Virus Internalization - drug effects; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0909587107

We describe an antiviral small molecule, LJ001, effective against numerous enveloped viruses including Influenza A, filoviruses, poxviruses, arenaviruses, bunyaviruses, paramyxoviruses, flaviviruses, and HIV-1. In sharp contrast, the compound had no effect on the infection of nonenveloped viruses. In vitro and in vivo assays showed no overt toxicity. LJ001 specifically intercalated into viral membranes, irreversibly inactivated virions while leaving functionally intact envelope proteins, and inhibited viral entry at a step after virus binding but before virus-cell fusion. LJ001 pretreatment also prevented virus-induced mortality from Ebola and Rift Valley fever viruses. Structure-activity relationship analyses of LJ001, a rhodanine derivative, implicated both the polar and nonpolar ends of LJ001 in its antiviral activity. LJ001 specifically inhibited virus-cell but not cell-cell fusion, and further studies with lipid biosynthesis inhibitors indicated that LJ001 exploits the therapeutic window that exists between static viral membranes and biogenic cellular membranes with reparative capacity. In sum, our data reveal a class of broad-spectrum antivirals effective against enveloped viruses that target the viral lipid membrane and compromises its ability to mediate virus-cell fusion.