title: Novel antiviral activity and mechanism of bromocriptine as a Zika virus NS2B-NS3 protease inhibitor.
abstract: Zika virus (ZIKV) infection is associated with congenital malformations in infected fetuses and severe neurological and other systemic complications in adults. There are currently limited anti-ZIKV treatment options that are readily available and safe for use in pregnancy. In this drug repurposing study, bromocriptine was found to have inhibitory effects on ZIKV replication in cytopathic effect inhibition, virus yield reduction, and plaque reduction assays. Time-of-drug-addition assay showed that bromocriptine exerted anti-ZIKV activity between 0 and 12 h post-ZIKV inoculation, corroborating with post-entry events in the virus replication cycle prior to budding. Our docking model showed that bromocriptine interacted with several active site residues of the proteolytic cavity involving H51 and S135 in the ZIKV-NS2B-NS3 protease protein, and might occupy the active site and inhibit the protease activity of the ZIKV-NS2B-NS3 protein. A fluorescence-based protease inhibition assay confirmed that bromocriptine inhibited ZIKV protease activity. Moreover, bromocriptine exhibited synergistic effect with interferon-α2b against ZIKV replication in cytopathic effect inhibition assay. The availability of per vagina administration of bromocriptine as suppositories or vaginoadhesive discs and the synergistic anti-ZIKV activity between bromocriptine and type I interferon may make bromocriptine a potentially useful and readily available treatment option for ZIKV infection. The anti-ZIKV effects of bromocriptine should be evaluated in a suitable animal model.
authors.affiliation: State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, China; Department of Microbiology, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China; Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong, China; Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong, China. Electronic address: jfwchan@hku.hk.
authors.forename: Jasper Fuk-Woo
authors.initials: JF
authors.lastname: Chan
authors.affiliation: Department of Microbiology, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China.
authors.forename: Kenn Ka-Heng
authors.initials: KK
authors.lastname: Chik
authors.affiliation: Department of Microbiology, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China.
authors.forename: Shuofeng
authors.initials: S
authors.lastname: Yuan
authors.affiliation: Department of Microbiology, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China.
authors.forename: Cyril Chik-Yan
authors.initials: CC
authors.lastname: Yip
authors.affiliation: Department of Microbiology, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Department of Microbiology, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China.
authors.forename: Kah-Meng
authors.initials: KM
authors.lastname: Tee
authors.affiliation: Department of Microbiology, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China.
authors.forename: Jessica Oi-Ling
authors.initials: JO
authors.lastname: Tsang
authors.affiliation: Department of Microbiology, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China.
authors.forename: Chris Chung-Sing
authors.initials: CC
authors.lastname: Chan
authors.affiliation: Department of Microbiology, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China.
authors.forename: Vincent Kwok-Man
authors.initials: VK
authors.lastname: Poon
authors.affiliation: Department of Pathogen Biology, Hainan Medical University, Haikou, Hainan, Hong Kong, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Lu
authors.affiliation: Department of Microbiology, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China.
authors.forename: Anna Jinxia
authors.initials: AJ
authors.lastname: Zhang
authors.affiliation: Department of Microbiology, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China.
authors.forename: Kin-Kui
authors.initials: KK
authors.lastname: Lai
authors.affiliation: State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, China; Department of Microbiology, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China; Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong, China; Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong, China.
authors.forename: Kwok-Hung
authors.initials: KH
authors.lastname: Chan
authors.affiliation: State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, China; Department of Microbiology, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China; Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong, China; Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong, China.
authors.forename: Richard Yi-Tsun
authors.initials: RY
authors.lastname: Kao
authors.affiliation: State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, China; Department of Microbiology, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China; Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong, China; Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong, China; The Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The University of Hong Kong, Hong Kong, China. Electronic address: kyyuen@hku.hk.
authors.forename: Kwok-Yung
authors.initials: KY
authors.lastname: Yuen
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D001971:Bromocriptine / Q000494:pharmacology* / Q000627:therapeutic use; D057075:Enzyme Assays; D005453:Fluorescence; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology; D010447:Peptide Hydrolases / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology; D057057:Serine Proteases / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects; D000071244:Zika Virus / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology
chemical_list: D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D015842:Serine Proteinase Inhibitors; D017361:Viral Nonstructural Proteins; D001971:Bromocriptine; D010447:Peptide Hydrolases; D057057:Serine Proteases
keywords: Antiviral; Bromocriptine; Interferon; Protease; Treatment; Zika