Novel antiviral activity and mechanism of bromocriptine as a Zika virus NS2B-NS3 protease inhibitor

• Published in: Antiviral research Vol. 141; pp. 29 - 37
• Main Authors: Chan, Jasper Fuk-Woo, Chik, Kenn Ka-Heng, Yuan, Shuofeng, Yip, Cyril Chik-Yan, Zhu, Zheng, Tee, Kah-Meng, Tsang, Jessica Oi-Ling, Chan, Chris Chung-Sing, Poon, Vincent Kwok-Man, Lu, Gang, Zhang, Anna Jinxia, Lai, Kin-Kui, Chan, Kwok-Hung, Kao, Richard Yi-Tsun, Yuen, Kwok-Yung
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2017
• Subjects: Antiviral; Antiviral Agents - pharmacology; Bromocriptine; Bromocriptine - pharmacology; Bromocriptine - therapeutic use; Enzyme Assays; Fluorescence; Humans; Interferon; Interferon-alpha - pharmacology; Peptide Hydrolases - drug effects; Protease; Recombinant Proteins - pharmacology; Serine Proteases - metabolism; Serine Proteinase Inhibitors - chemistry; Serine Proteinase Inhibitors - pharmacology; Treatment; Viral Nonstructural Proteins - antagonists & inhibitors; Virus Replication - drug effects; Zika; Zika Virus - drug effects; Zika Virus - enzymology; Zika Virus - physiology; Antiviral; Interferon; Treatment; Protease; Bromocriptine; Zika
• ISSN: 0166-3542; 1872-9096
• DOI: 10.1016/j.antiviral.2017.02.002

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. •Bromocriptine inhibited Zika virus replication in multiple in vitro assays.•Bromocriptine exhibited synergistic effect with interferon-α2b against Zika virus replication in vitro.•Bromocriptine interacted with several active site residues of the proteolytic cavity in the Zika virus NS2B-NS3 protease.•Bromocriptine inhibited Zika virus protease activity in a fluorescence-based enzymatic assay.•Bromocriptine may be a readily available treatment option for Zika virus infection in pregnant and non-pregnant patients.