Abstract
Zika virus (ZIKV), which is associated with severe diseases in humans, has spread rapidly and globally since its emergence. ZIKV and dengue virus (DENV) are closely related, and antibody-dependent enhancement (ADE) of infection between cocirculating ZIKV and DENV may exacerbate disease. Despite these serious threats, there are currently no approved antiviral drugs against ZIKV and DENV. The NS2B-NS3 viral protease is an attractive antiviral target because it plays a pivotal role in polyprotein cleavage, which is required for viral replication. Thus, we sought to identify novel inhibitors of the NS2B-NS3 protease. To that aim, we performed structure-based virtual screening using 467,000 structurally diverse chemical compounds. Then, a fluorescence-based protease inhibition assay was used to test whether the selected candidates inhibited ZIKV protease activity. Among the 123 candidate inhibitors selected from virtual screening, compound 1 significantly inhibited ZIKV NS2B-NS3 protease activity in vitro. In addition, compound 1 effectively inhibited ZIKV and DENV infection of human cells. Molecular docking analysis suggested that compound 1 binds to the NS2B-NS3 protease of ZIKV and DENV. Thus, compound 1 could be used as a new therapeutic option for the development of more potent antiviral drugs against both ZIKV and DENV, reducing the risks of ADE.
Highlights
Zika virus (ZIKV) and dengue virus (DENV) are closely related mosquito-borne singlestranded positive-polarity RNA viruses of the genus flavivirus in the Flaviviridae family [1].ZIKV was first identified in a rhesus monkey in the Zika Forest region of Uganda in 1947 and has recently emerged in Brazil, rapidly spreading to other countries in South andNorth America in early 2015 [2,3,4]
Small-molecule inhibitor candidates showing an inhibitory interaction with the NS2B-NS3 protease active site were selected using primary structurebased screening
Compared with ZIKV, we could not observe hydrogen bonding between the nitrogen of the indazole ring and Tyr150. These results suggest that the inhibitory activity of compound 1 on the DENV type 4 (DENV-4) NS2B-NS3 protease is lower than that on the ZIKV NS2B-NS3 protease
Summary
Zika virus (ZIKV) and dengue virus (DENV) are closely related mosquito-borne singlestranded positive-polarity RNA viruses of the genus flavivirus in the Flaviviridae family [1].ZIKV was first identified in a rhesus monkey in the Zika Forest region of Uganda in 1947 and has recently emerged in Brazil, rapidly spreading to other countries in South andNorth America in early 2015 [2,3,4]. Zika virus (ZIKV) and dengue virus (DENV) are closely related mosquito-borne singlestranded positive-polarity RNA viruses of the genus flavivirus in the Flaviviridae family [1]. ZIKV was first identified in a rhesus monkey in the Zika Forest region of Uganda in 1947 and has recently emerged in Brazil, rapidly spreading to other countries in South and. ZIKV infection has been associated with neurological disorders such as Guillain-Barré syndrome in adults and microcephaly in newborns. DENV is transmitted between people by Aedes aegypti mosquitoes and has spread to more than 100 countries in Africa, the Americas, Asia, Pacific, and the Caribbean [5,6]. The four distinct serotypes of DENV have been reported to cause dengue fever (DF) and dengue shock syndrome (DSS).
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