http://scholars.ntou.edu.tw/handle/123456789/3579
標題: | Structure-Based Stabilization of Non-native Protein-Protein Interactions of Coronavirus Nucleocapsid Proteins in Antiviral Drug Design | 作者: | Shan-Meng Lin Shih-Chao Lin Jia-Ning Hsu Chung-ke Chang Ching-Ming Chien Yong-Sheng Wang Hung-Yi Wu U-Ser Jeng Kylene Kehn-Hall Ming-Hon Hou |
公開日期: | 三月-2020 | 出版社: | American Chemical Society | 卷: | 63 | 期: | 6 | 起(迄)頁: | 3131–3141 | 來源出版物: | Journal of Medicinal Chemistry | 摘要: | Structure-based stabilization of protein–protein interactions (PPIs) is a promising strategy for drug discovery. However, this approach has mainly focused on the stabilization of native PPIs, and non-native PPIs have received little consideration. Here, we identified a non-native interaction interface on the three-dimensional dimeric structure of the N-terminal domain of the MERS-CoV nucleocapsid protein (MERS-CoV N-NTD). The interface formed a conserved hydrophobic cavity suitable for targeted drug screening. By considering the hydrophobic complementarity during the virtual screening step, we identified 5-benzyloxygramine as a new N protein PPI orthosteric stabilizer that exhibits both antiviral and N-NTD protein-stabilizing activities. X-ray crystallography and small-angle X-ray scattering showed that 5-benzyloxygramine stabilizes the N-NTD dimers through simultaneous hydrophobic interactions with both partners, resulting in abnormal N protein oligomerization that was further confirmed in the cell. This unique approach based on the identification and stabilization of non-native PPIs of N protein could be applied toward drug discovery against CoV diseases. |
URI: | http://scholars.ntou.edu.tw/handle/123456789/3579 | ISSN: | 0022-2623 | DOI: | 10.1021/acs.jmedchem.9b01913 |
顯示於: | 海洋生物科技學士學位學程(系) |
在 IR 系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。