Abstract
The World Health Organization has designated Zika virus (ZIKV) as a dangerous, mosquito-borne flaviviral pathogen that was recently found to be responsible for a dramatically increased number of microcephaly cases and other congenital abnormalities in fetuses and newborns. There is neither a vaccine to prevent nor a drug to treat ZIKA virus infections, at the present time. Berberine (BBR) is a promising drug approved by FDA against flaviviral dengue virus, and BBR derivatives are of great interest in antiviral drug development. In this study, we synthesized eight BBR derivatives by introducing benzyl groups at the C-13 position of BBR and converting to respective 8-oxoberberine derivatives, performed molecular docking analysis, and evaluated their anti-Zika virus activity utilizing a cell‐based phenotypic assay. Binding mode analysis, absolute binding free energy calculation, and structure-activity relationship studies of these compounds with ZIKV NS3 receptor were collected. Amongst these studied compounds, compound 4d with a structure of 13-(2,6-difluoro)-benzylberberine showed high binding affinity (docking score of −7.31 kcal/mol) towards ZIKV NS2B-NS3 protease with critical binding formed within the active site. In the cell-based assay, compound 4d displayed the highest antiviral efficacy against ZIKV with a selective index (SI) of 15.3, with 3.7-fold greater than that of berberine. Together, our study suggests that the potential ZIKV NS2B-NS3 protease inhibitor, compound 4d, is the best alternative to BBR and, further, extends an assuring platform for developing antiviral competitive inhibitors against ZIKV infection.
Highlights
Zika virus (ZIKV) was noticed as a major health risk by the World Health Organization
BBR which is FDA-approved drug to be effective against flaviviral dengue virus was selected for improving the bioavailability of BBR, enhancing its inhibitory activity against Zika virus NS2B-NS3 protease
E C-13 position of BBR was introduced with benzyl groups and followed by converting to respective 8-oxoberberine derivatives, eight BBR derivatives were synthesized, molecular docking study and experimental assays were conducted for evaluating their anti-ZIKV activity. e obtained results from the computational part suggested compound 4d as a potential NS2B-NS3 inhibitor and shed the light on the possible binding mode of BBR and its derivatives with this protein on the basis of molecular docking
Summary
Zika virus (ZIKV) was noticed as a major health risk by the World Health Organization. ZIKV is a mosquito-borne pathogen family having a positive-sense single-stranded RNA genome, belonging to Flaviviridae family including dengue, West Nile, and Japanese encephalitis viruses. Unlike its mosquito-borne relatives, ZIKV has emerged from obscurity by its association with a suspected “congenital Zika syndrome,” while causing asymptomatic or mild exanthematous febrile infections which are dengue or rubella-like in infected individuals [1]. There are no medicines or vaccines against ZIKV or specific antiviral treatment for clinical ZIKV infection. To address this medical need, novel ZIKV interventions suitable for prevention and therapeutic purposes are urgent
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