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- Title
Structure-Based Virtual Screening: Identification of a Novel NS2B-NS3 Protease Inhibitor with Potent Antiviral Activity against Zika and Dengue Viruses.
- Authors
Shin, Hye Jin; Kim, Mi-Hwa; Lee, Joo-Youn; Hwang, Insu; Yoon, Gun Young; Kim, Hae Soo; Kwon, Young-Chan; Ahn, Dae-Gyun; Kim, Kyun-Do; Kim, Bum-Tae; Kim, Seong-Jun; Kim, Chonsaeng; Zandi, Keivan
- 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.
- Subjects
ZIKA virus; PROTEASE inhibitors; DENGUE viruses; ZIKA virus infections; ANTIVIRAL agents; MOLECULAR docking
- Publication
Microorganisms, 2021, Vol 9, Issue 3, p545
- ISSN
2076-2607
- Publication type
Article
- DOI
10.3390/microorganisms9030545