Structural insights into the inhibition of Zika virus NS2B-NS3 protease by a small-molecule inhibitor
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...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
| Published: |
2020
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| Online Access: | https://hdl.handle.net/10356/140349 |
| _version_ | 1826129443281698816 |
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| author | 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 |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences 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 |
| author_sort | Li, Yan |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T07:40:42Z |
| format | Journal Article |
| id | ntu-10356/140349 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T07:40:42Z |
| publishDate | 2020 |
| record_format | dspace |
| spelling | ntu-10356/1403492020-05-28T04:44:25Z Structural insights into the inhibition of Zika virus NS2B-NS3 protease by a small-molecule inhibitor 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 School of Biological Sciences Lee Kong Chian School of Medicine (LKCMedicine) NTU Institute of Structural Biology Science::Biological sciences Zika Virus Protease 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. NRF (Natl Research Foundation, S’pore) ASTAR (Agency for Sci., Tech. and Research, S’pore) NMRC (Natl Medical Research Council, S’pore) 2020-05-28T04:44:24Z 2020-05-28T04:44:24Z 2018 Journal Article 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 0969-2126 https://hdl.handle.net/10356/140349 10.1016/j.str.2018.02.005 29526431 2-s2.0-85042905556 4 26 555 564 en Structure © 2018 Elsevier Ltd. All rights reserved. |
| spellingShingle | Science::Biological sciences Zika Virus Protease 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 Structural insights into the inhibition of Zika virus NS2B-NS3 protease by a small-molecule inhibitor |
| title | Structural insights into the inhibition of Zika virus NS2B-NS3 protease by a small-molecule inhibitor |
| title_full | Structural insights into the inhibition of Zika virus NS2B-NS3 protease by a small-molecule inhibitor |
| title_fullStr | Structural insights into the inhibition of Zika virus NS2B-NS3 protease by a small-molecule inhibitor |
| title_full_unstemmed | Structural insights into the inhibition of Zika virus NS2B-NS3 protease by a small-molecule inhibitor |
| title_short | Structural insights into the inhibition of Zika virus NS2B-NS3 protease by a small-molecule inhibitor |
| title_sort | structural insights into the inhibition of zika virus ns2b ns3 protease by a small molecule inhibitor |
| topic | Science::Biological sciences Zika Virus Protease |
| url | https://hdl.handle.net/10356/140349 |
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