title: A natural component from Euphorbia humifusa Willd displays novel, broad-spectrum anti-influenza activity by blocking nuclear export of viral ribonucleoprotein.
abstract: The need to develop anti-influenza drugs with novel antiviral mechanisms is urgent because of the rapid rate of antigenic mutation and the emergence of drug-resistant viruses. We identified a novel anti-influenza molecule by screening 861 plant-derived natural components using a high-throughput image-based assay that measures inhibition of the influenza virus infection. 1,3,4,6-tetra-O-galloyl-β-D-glucopyranoside (TGBG) from Euphorbia humifusa Willd showed broad-spectrum anti-influenza activity against two seasonal influenza A strains, A/California/07/2009 (H1N1) and A/Perth/16/2009 (H3N2), and seasonal influenza B strain B/Florida/04/2006. We investigated the mode of action of TGBG using neuraminidase activity inhibition and time-of-addition assays, which evaluate the viral release and entry steps, respectively. We found that TGBG exhibits a novel antiviral mechanism that differs from the FDA-approved anti-influenza drugs oseltamivir which inhibits viral release, and amantadine which inhibits viral entry. Immunofluorescence assay demonstrated that TGBG significantly inhibits nuclear export of influenza nucleoproteins (NP) during the early stages of infection causing NP to accumulate in the nucleus. In addition, influenza-induced activation of the Akt signaling pathway was suppressed by TGBG in a dose-dependent manner. These data suggest that a putative mode of action of TGBG involves inhibition of viral ribonucleoprotein (vRNP) export from the nucleus to the cytoplasm consequently disrupting the assembly of progeny virions. In summary, TGBG has potential as novel anti-influenza therapeutic with a novel mechanism of action.
authors: Respiratory Viruses Research Laboratory, Discovery Biology Department, Institut Pasteur Korea, 16, Daewangpangyo-ro 712 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400, Republic of Korea.
authors: So Young
authors: SY
authors: Chang
authors: Respiratory Viruses Research Laboratory, Discovery Biology Department, Institut Pasteur Korea, 16, Daewangpangyo-ro 712 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400, Republic of Korea.
authors: Ji Hoon
authors: JH
authors: Park
authors: College of Pharmacy, Chungnam National University, Daejeon, 305-764, Republic of Korea.
authors: Young Ho
authors: YH
authors: Kim
authors: College of Pharmacy, Chungnam National University, Daejeon, 305-764, Republic of Korea.
authors: Jong Seong
authors: JS
authors: Kang
authors: Respiratory Viruses Research Laboratory, Discovery Biology Department, Institut Pasteur Korea, 16, Daewangpangyo-ro 712 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400, Republic of Korea. Electronic address: jiyoung.min@ip-korea.org.
authors: Ji-Young
authors: JY
authors: Min
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D028481:Euphorbia / Q000737:chemistry*; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects / Q000502:physiology*; D009981:Influenza B virus / Q000187:drug effects / Q000502:physiology*; D007251:Influenza, Human / Q000517:prevention & control / Q000821:virology; D061985:Madin Darby Canine Kidney Cells; D010936:Plant Extracts / Q000008:administration & dosage; D012261:Ribonucleoproteins / Q000378:metabolism*; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D010936:Plant Extracts; D012261:Ribonucleoproteins
keywords: Antiviral; High-throughput screening; Influenza virus; Natural component; Nuclear export