title: Inhibition of herpes simplex virus type 1 entry by chloride channel inhibitors tamoxifen and NPPB.
abstract: Herpes simplex virus type 1 (HSV-1) infection is very common worldwide and can cause significant health problems from periodic skin and corneal lesions to encephalitis. Appearance of drug-resistant viruses in clinical therapy has made exploring novel antiviral agents emergent. Here we show that chloride channel inhibitors, including tamoxifen and 5-nitro-2-(3-phenyl-propylamino) benzoic acid (NPPB), exhibited extensive antiviral activities toward HSV-1 and ACV-resistant HSV viruses. HSV-1 infection induced chloride ion influx while treatment with inhibitors reduced the increase of intracellular chloride ion concentration. Pretreatment or treatment of inhibitors at different time points during HSV-1 infection all suppressed viral RNA synthesis, protein expression and virus production. More detailed studies demonstrated that tamoxifen and NPPB acted as potent inhibitors of HSV-1 early entry step by preventing viral binding, penetration and nuclear translocation. Specifically the compounds appeared to affect viral fusion process by inhibiting virus binding to lipid rafts and interrupting calcium homeostasis. Taken together, the observation that tamoxifen and NPPB can block viral entry suggests a stronger potential for these compounds as well as other ion channel inhibitors in antiviral therapy against HSV-1, especially the compound tamoxifen is an immediately actionable drug that can be reused for treatment of HSV-1 infections.
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, China; College of Life Science and Technology, Jinan University, Guangzhou, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Zheng
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, China; College of pharmacy, Jinan University, Guangzhou, China.
authors.forename: Maoyun
authors.initials: M
authors.lastname: Chen
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, China.
authors.forename: Yangfei
authors.initials: Y
authors.lastname: Xiang
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, China.
authors.forename: Kaiqi
authors.initials: K
authors.lastname: Ma
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, China; College of pharmacy, Jinan University, Guangzhou, China.
authors.forename: Fujun
authors.initials: F
authors.lastname: Jin
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wang
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, China.
authors.forename: Shaoxiang
authors.initials: S
authors.lastname: Wang
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, China. Electronic address: twang-yf@163.com.
authors.forename: Yifei
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D018118:Chloride Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002522:Chlorocebus aethiops; D006561:Herpes Simplex / Q000188:drug therapy / Q000821:virology*; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000502:physiology*; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006801:Humans; D009579:Nitrobenzoates / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology*; D014709:Vero Cells; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D018118:Chloride Channels; D009579:Nitrobenzoates; D013629:Tamoxifen; C058176:5-nitro-2-(3-phenylpropylamino)benzoic acid
keywords: 5-nitro-2-(3-pheny l-propylamino) benzoic acid; ACV; Chloride channels; CtxB; ER; Entry; FDA; HCV; HSV; MQAE; N-(Ethoxycarbonylmethyl)-6-methoxyquinolinium bromide; NPPB; Tamoxifen; acyclovir; choleratoxin beta subunit; estrogen receptor; food and drug administration; hepatitis C virus; herpes simplex virus