title: In vitro anti-influenza virus activities of a new lignan glycoside from the latex of Calotropis gigantea.
abstract: A new lignan glycoside, (+)-pinoresinol 4-O-[6″-O-vanilloyl]-β-D-glucopyranoside (1) and two known phenolic compounds, 6'-O-vanilloyltachioside (2) and 6'-O-vanilloylisotachioside (3) were isolated from the latex of Calotropis gigantea (Asclepiadaceae). The structure of the new compound was elucidated by using spectroscopic and chemical methods. Three isolates (1-3) and one authentic compound, (+)-pinoresinol 4-O-β-D-glucopyranoside, were screened for A/PR/8/34 (H1N1) inhibitory activity by cytopathic effect (CPE) inhibition assay on MDCK cells. Compound 1 showed inhibitory activity against A/PR/8/34 (H1N1). In sharp contrast, the other three compounds (2, 3 and (+)-pinoresinol 4-O-β-D-glucopyranoside) did not show such activity. An analysis of structure-activity relationship between 1 and (+)-pinoresinol 4-O-β-D-glucopyranoside revealed that the presence of a vanilloyl group in the sugar moiety of 1 is crucial for its anti-influenza virus activity. Compound 1 was further evaluated for in vitro inhibitory activities against a panel of human and avian influenza viruses by CPE inhibition assay. It showed inhibitory effect against human influenza viruses in both subtypes A and B (IC50 values around 13.4-39.8 µM with SI values of 3.7-11.4), while had no effect on avian influenza viruses. Its antiviral activity against human influenza viruses subtype A was further confirmed by plaque reduction assay. The time course assay indicated that 1 exerts its antiviral activity at the early stage of viral replication. A mechanistic study showed that 1 efficiently inhibited influenza virus-induced activation of NF-κB pathway in a dose-dependent manner, but had no effect on virus-induced activation of Raf/MEK/ERK pathway. Further studies demonstrated that nuclear translocation of transcription factor NF-κB induced by influenza virus was significantly blocked by 1, meanwhile, nuclear export of viral ribonucleoproteins was also effectively inhibited. These findings suggest that this new lignan glycoside from Calotropis gigantea, may have therapeutic potential in influenza virus infection through inhibition of NF-κB pathway and viral ribonucleoproteins nuclear export.
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau.
authors.forename: Supawadee
authors.initials: S
authors.lastname: Parhira
authors.affiliation: State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People's Republic of China.
authors.forename: Zi-Feng
authors.initials: ZF
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau.
authors.forename: Guo-Yuan
authors.initials: GY
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People's Republic of China.
authors.forename: Qiao-Lian
authors.initials: QL
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People's Republic of China.
authors.forename: Bei-Xian
authors.initials: BX
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People's Republic of China.
authors.forename: Yu-Tao
authors.initials: YT
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau.
authors.forename: Liang
authors.initials: L
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau.
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Bai
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau.
authors.forename: Zhi-Hong
authors.initials: ZH
authors.lastname: Jiang
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D004285:Dogs; D019669:Embryophyta / Q000737:chemistry*; D006027:Glycosides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000502:physiology*; D007840:Latex / Q000737:chemistry*; D017705:Lignans / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D061985:Madin Darby Canine Kidney Cells; D009976:Orthomyxoviridae Infections / Q000188:drug therapy*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D006027:Glycosides; D007840:Latex; D017705:Lignans
references.citation: EMBO J. 2003 Jun 2;22(11):2717-28
references.pmid: 12773387
references.citation: Cell Microbiol. 2007 Jul;9(7):1683-94
references.pmid: 17324159
references.citation: Chem Pharm Bull (Tokyo). 2005 Mar;53(3):339-41
references.pmid: 15744112
references.citation: Biol Pharm Bull. 2008 Mar;31(3):511-5
references.pmid: 18310920
references.citation: Antiviral Res. 2012 Feb;93(2):253-259
references.pmid: 22197247
references.citation: J Biol Chem. 2006 Apr 28;281(17):11678-84
references.pmid: 16517601
references.citation: PLoS Pathog. 2008 Nov;4(11):e1000196
references.pmid: 18989459
references.citation: Antiviral Res. 2007 Oct;76(1):38-47
references.pmid: 17572513
references.citation: Sci Rep. 2014 Apr 23;4:4748
references.pmid: 24756103
references.citation: Drug Discov Today. 2012 Oct;17(19-20):1111-20
references.pmid: 22704956
references.citation: Antiviral Res. 2012 May;94(2):139-46
references.pmid: 22453134
references.citation: Phytomedicine. 2012 Jan 15;19(2):111-4
references.pmid: 21899996
references.citation: PLoS One. 2013;8(1):e53962
references.pmid: 23335983
references.citation: Science. 2014 Apr 18;344(6181):235
references.pmid: 24744345
references.citation: Antiviral Res. 2011 Oct;92(1):45-56
references.pmid: 21641936
references.citation: N Engl J Med. 2013 Jun 13;368(24):2277-85
references.pmid: 23697469
references.citation: Nat Cell Biol. 2001 Mar;3(3):301-5
references.pmid: 11231581
references.citation: J Nat Prod. 2006 Aug;69(8):1249-51
references.pmid: 16933890
references.citation: Bioorg Med Chem Lett. 2012 Feb 15;22(4):1582-6
references.pmid: 22281188
references.citation: Planta Med. 2007 Oct;73(13):1415-7
references.pmid: 17918038
references.citation: Fitoterapia. 2014 Mar;93:47-53
references.pmid: 24370660
references.citation: J Biol Chem. 2004 Jul 23;279(30):30931-7
references.pmid: 15143063
references.citation: Chem Pharm Bull (Tokyo). 2002 Jan;50(1):137-9
references.pmid: 11824576
references.citation: J Biol Chem. 2006 Jun 16;281(24):16707-15
references.pmid: 16608852
references.citation: Annu Rev Immunol. 1998;16:225-60
references.pmid: 9597130
references.citation: J Infect Dis. 2007 Jul 15;196(2):249-57
references.pmid: 17570112
references.citation: J Nat Prod. 1998 Jan 23;61(1):102-4
references.pmid: 9548837
references.citation: J Ethnopharmacol. 2012 Aug 30;143(1):57-67
references.pmid: 22710290
references.citation: Lancet. 2013 Jun 29;381(9885):2273-9
references.pmid: 23726392