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Open AccessArticle

Structure-Based Virtual Screening: Identification of a Novel NS2B-NS3 Protease Inhibitor with Potent Antiviral Activity against Zika and Dengue Viruses

1
Center for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon 34114, Korea
2
Bioenvironmental Science and Toxicology Division, Gyeongnam Branch Institute, Korea Institute of Toxicology, Jinju 52834, Korea
3
Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Korea
*
Authors to whom correspondence should be addressed.
Academic Editor: Keivan Zandi
Microorganisms 2021, 9(3), 545; https://doi.org/10.3390/microorganisms9030545
Received: 21 January 2021 / Revised: 25 February 2021 / Accepted: 2 March 2021 / Published: 6 March 2021
(This article belongs to the Special Issue Recent Advances in Antivirals for Emerging Viruses)
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. View Full-Text
Keywords: Zika virus; NS2B-NS3 protease; inhibitor; virtual screening Zika virus; NS2B-NS3 protease; inhibitor; virtual screening
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MDPI and ACS Style

Shin, H.J.; Kim, M.-H.; Lee, J.-Y.; Hwang, I.; Yoon, G.Y.; Kim, H.S.; Kwon, Y.-C.; Ahn, D.-G.; Kim, K.-D.; Kim, B.-T.; Kim, S.-J.; Kim, C. Structure-Based Virtual Screening: Identification of a Novel NS2B-NS3 Protease Inhibitor with Potent Antiviral Activity against Zika and Dengue Viruses. Microorganisms 2021, 9, 545. https://doi.org/10.3390/microorganisms9030545

AMA Style

Shin HJ, Kim M-H, Lee J-Y, Hwang I, Yoon GY, Kim HS, Kwon Y-C, Ahn D-G, Kim K-D, Kim B-T, Kim S-J, Kim C. Structure-Based Virtual Screening: Identification of a Novel NS2B-NS3 Protease Inhibitor with Potent Antiviral Activity against Zika and Dengue Viruses. Microorganisms. 2021; 9(3):545. https://doi.org/10.3390/microorganisms9030545

Chicago/Turabian Style

Shin, Hye J.; Kim, Mi-Hwa; Lee, Joo-Youn; Hwang, Insu; Yoon, Gun Y.; Kim, Hae S.; Kwon, Young-Chan; Ahn, Dae-Gyun; Kim, Kyun-Do; Kim, Bum-Tae; Kim, Seong-Jun; Kim, Chonsaeng. 2021. "Structure-Based Virtual Screening: Identification of a Novel NS2B-NS3 Protease Inhibitor with Potent Antiviral Activity against Zika and Dengue Viruses" Microorganisms 9, no. 3: 545. https://doi.org/10.3390/microorganisms9030545

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