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Title: Structural insights into the inhibition of Zika virus NS2B-NS3 protease by a small-molecule inhibitor
Authors: Li, Yan
Zhang, Zhenzhen
Phoo, Wint Wint
Loh, Ying Ru
Li, Rong
Yang, Hai Yan
Jansson, Anna E.
Hill, Jeffrey
Keller, Thomas H.
Nacro, Kassoum
Luo, Dahai
Kang, CongBao
Keywords: Science::Biological sciences
Issue Date: 2018
Source: Li, Y., Zhang, Z., Phoo, W. W., Loh, Y. R., Li, R., Yang, H. Y., . . . Kang, C. (2018). Structural insights into the inhibition of Zika virus NS2B-NS3 protease by a small-molecule inhibitor. Structure, 26(4), 555-564. doi:10.1016/j.str.2018.02.005
Journal: Structure
Abstract: Zika virus (ZIKV) infection has become a global public health concern. The viral NS2B-NS3 protease is an attractive antiviral target because of its role in maturation of viral non-structural proteins. Substrate-derived protease inhibitors have been investigated, but it remains challenging to develop them into drugs. Small-molecule inhibitors are of great interest in antiviral drug development. Here we report the structure and dynamics of ZIKV NS2B-NS3 protease covalently bound to a small-molecule inhibitor. Our crystallographic and NMR studies demonstrate that the inhibitor further stabilizes the closed conformation of ZIKV protease. Upon hydrolysis in situ into two fragments, the benzoyl group of the inhibitor forms a covalent bond with the side chain of catalytic residue S135, whereas the second fragment exhibits no obvious molecular interactions with the protease. This study provides a detailed mechanism of action for a covalent inhibitor, which will guide further development of ZIKV protease inhibitors.
ISSN: 0969-2126
DOI: 10.1016/j.str.2018.02.005
Rights: © 2018 Elsevier Ltd. All rights reserved.
Fulltext Permission: none
Fulltext Availability: No Fulltext
Appears in Collections:LKCMedicine Journal Articles

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