title: Luteolin restricts dengue virus replication through inhibition of the proprotein convertase furin.
abstract: In many countries afflicted with dengue fever, traditional medicines are widely used as panaceas for illness, and here we describe the systematic evaluation of a widely known natural product, luteolin, originating from the "heat clearing" class of herbs. We show that luteolin inhibits the replication of all four serotypes of dengue virus, but the selectivity of the inhibition was weak. In addition, ADE-mediated dengue virus infection of human cell lines and primary PBMCs was inhibited. In a time-of-drug-addition study, luteolin was found to reduce infectious virus particle formation, but not viral RNA synthesis, in Huh-7 cells. During the virus life cycle, the host protease furin cleaves the pr moiety from prM protein of immature virus particles in the trans-Golgi network to produce mature virions. Analysis of virus particles from luteolin-treated cells revealed that prM was not cleaved efficiently. Biochemical interrogation of human furin showed that luteolin inhibited the enzyme activity in an uncompetitive manner, with Ki value of 58.6 μM, suggesting that treatment may restrict the virion maturation process. Luteolin also exhibited in vivo antiviral activity in mice infected with DENV, causing reduced viremia. Given the mode of action of luteolin and its widespread source, it is possible that it can be tested in combination with other dengue virus inhibitors.
authors.affiliation: School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Program in Emerging Infectious Disease, Duke-NUS Medical School, Singapore 169857, Singapore.
authors.forename: Minhua
authors.initials: M
authors.lastname: Peng
authors.affiliation: Program in Emerging Infectious Disease, Duke-NUS Medical School, Singapore 169857, Singapore.
authors.forename: Satoru
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Program in Emerging Infectious Disease, Duke-NUS Medical School, Singapore 169857, Singapore.
authors.forename: Kitti Wing Ki
authors.initials: KWK
authors.lastname: Chan
authors.affiliation: School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
authors.forename: Qiuyan
authors.initials: Q
authors.lastname: He
authors.affiliation: School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Guangdong Provincial Academy of Chinese Medicine, Guangzhou 510120, China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Emergency Department, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou 510120, China.
authors.forename: Zhongde
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Lai
authors.affiliation: Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 636921, Singapore.
authors.forename: Dahai
authors.initials: D
authors.lastname: Luo
authors.affiliation: Program in Emerging Infectious Disease, Duke-NUS Medical School, Singapore 169857, Singapore. Electronic address: subhash.vasudevan@duke-nus.edu.sg.
authors.forename: Subhash G
authors.initials: SG
authors.lastname: Vasudevan
authors.affiliation: School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou 510006, China. Electronic address: lg@gzucm.edu.cn.
authors.forename: Geng
authors.initials: G
authors.lastname: Li
mesh_terms: D000072283:A549 Cells; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D004261:DNA Replication / Q000187:drug effects; D003715:Dengue / Q000188:drug therapy / Q000821:virology; D003716:Dengue Virus / Q000145:classification / Q000187:drug effects* / Q000235:genetics; D004195:Disease Models, Animal; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D045683:Furin / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D047311:Luteolin / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008297:Male; D051379:Mice; D043484:Proprotein Convertases / Q000187:drug effects* / Q000378:metabolism; D012367:RNA, Viral / Q000187:drug effects; D014766:Viremia / Q000188:drug therapy; D014771:Virion / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects*; D021601:trans-Golgi Network / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D004365:Drugs, Chinese Herbal; D012367:RNA, Viral; D043484:Proprotein Convertases; D045683:Furin; D047311:Luteolin
keywords: Antiviral therapy; Dengue virus; Furin; Luteolin; Traditional Chinese medicine; Virus maturation