title: AR-12 suppresses dengue virus replication by down-regulation of PI3K/AKT and GRP78.
abstract: Dengue virus (DENV) infection has become a public health issue of worldwide concern and is a serious health problem in Taiwan, yet there are no approved effective antiviral drugs to treat DENV. The replication of DENV requires both viral and cellular factors. Targeting host factors may provide a potential antiviral strategy. It has been known that up-regulation of PI3K/AKT signaling and GRP78 by DENV infection supports its replication. AR-12, a celecoxib derivative with no inhibiting activity on cyclooxygenase, shows potent inhibitory activities on both PI3K/AKT signaling and GRP78 expression levels, and recently has been found to block the replication of several hemorrhagic fever viruses. However the efficacy of AR-12 in treating DENV infection is still unclear. Here, we provide evidence to show that AR-12 is able to suppress DENV replication before or after virus infection in cell culture and mice. The antiviral activities of AR-12 are positive against infection of the four different DENV serotypes. AR-12 significantly down-regulates the PI3K/AKT activity and GRP78 expression in DENV infected cells whereas AKT and GRP78 rescue are able to attenuate anti-DENV effect of AR-12. Using a DENV-infected suckling mice model, we further demonstrate that treatment of AR-12 before or after DENV infection reduces virus replication and mice mortality. In conclusion, we uncover the potential efficacy of AR-12 as a novel drug for treating dengue.
authors.affiliation: Department of Microbiology & Immunology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
authors.forename: Hsin-Hsin
authors.initials: HH
authors.lastname: Chen
authors.affiliation: Department of Pathology, Chia-Yi Christian Hospital, Chiayi 600, Taiwan; Department of Cosmetic Science, Chia Nan University of Pharmacy and Science, Tainan 701, Taiwan.
authors.forename: Chien-Chin
authors.initials: CC
authors.lastname: Chen
authors.affiliation: Department of Microbiology & Immunology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan; The Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan; Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan 701, Taiwan.
authors.forename: Yee-Shin
authors.initials: YS
authors.lastname: Lin
authors.affiliation: Department of Microbiology & Immunology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
authors.forename: Po-Chun
authors.initials: PC
authors.lastname: Chang
authors.affiliation: Department of Microbiology & Immunology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
authors.forename: Zi-Yi
authors.initials: ZY
authors.lastname: Lu
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
authors.forename: Chiou-Feng
authors.initials: CF
authors.lastname: Lin
authors.affiliation: Translational Research Center, Taipei Medical University, Taipei 110, Taiwan.
authors.forename: Chia-Ling
authors.initials: CL
authors.lastname: Chen
authors.affiliation: Department of Microbiology & Immunology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan; The Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan; Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan 701, Taiwan. Electronic address: cpchang@mail.ncku.edu.tw.
authors.forename: Chih-Peng
authors.initials: CP
authors.lastname: Chang
mesh_terms: D000072283:A549 Cells; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D018929:Cell Culture Techniques; D002460:Cell Line; D003715:Dengue / Q000188:drug therapy; D003716:Dengue Virus / Q000187:drug effects*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects*; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000187:drug effects*; D006801:Humans; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects*; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D020298:U937 Cells; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D019869:Phosphatidylinositol 3-Kinases; D011451:Prostaglandin-Endoperoxide Synthases; D011720:Pyrazoles; D013449:Sulfonamides; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; C500894:OSU 03012
keywords: AR-12; Antivirus; Dengue; GRP78; PI3K/AKT