Structure-Based Stabilization of Non-native Protein–Protein Interactions of Coronavirus Nucleocapsid Proteins in Antiviral Drug Design
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 interfa...
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| Published in | Journal of medicinal chemistry Vol. 63; no. 6; pp. 3131 - 3141 |
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| Main Authors | , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
American Chemical Society
26.03.2020
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| Online Access | Get full text |
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| Abstract | 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. |
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| AbstractList | 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. 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.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. 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. |
| Author | Wu, Hung-Yi Hou, Ming-Hon Chien, Ching-Ming Lin, Shih-Chao Lin, Shan-Meng Jeng, U-Ser Hsu, Jia-Ning Chang, Chung-ke Kehn-Hall, Kylene Wang, Yong-Sheng |
| AuthorAffiliation | National Chung Hsing University National Center for Biodefense and Infectious Diseases, School of Systems Biology Department of Life Sciences Institute of Biomedical Sciences, Academia Sinica National Tsing Hua University Department of Chemical Engineering Institute of Genomics and Bioinformatics Graduate Institute of Veterinary Pathobiology, College of Veterinary Medicine |
| AuthorAffiliation_xml | – name: Department of Chemical Engineering – name: National Tsing Hua University – name: Graduate Institute of Veterinary Pathobiology, College of Veterinary Medicine – name: Department of Life Sciences – name: Institute of Genomics and Bioinformatics – name: National Center for Biodefense and Infectious Diseases, School of Systems Biology – name: National Chung Hsing University – name: Institute of Biomedical Sciences, Academia Sinica |
| Author_xml | – sequence: 1 givenname: Shan-Meng surname: Lin fullname: Lin, Shan-Meng organization: National Chung Hsing University – sequence: 2 givenname: Shih-Chao orcidid: 0000-0003-2942-5937 surname: Lin fullname: Lin, Shih-Chao organization: National Center for Biodefense and Infectious Diseases, School of Systems Biology – sequence: 3 givenname: Jia-Ning surname: Hsu fullname: Hsu, Jia-Ning organization: National Chung Hsing University – sequence: 4 givenname: Chung-ke surname: Chang fullname: Chang, Chung-ke organization: Institute of Biomedical Sciences, Academia Sinica – sequence: 5 givenname: Ching-Ming surname: Chien fullname: Chien, Ching-Ming organization: National Chung Hsing University – sequence: 6 givenname: Yong-Sheng surname: Wang fullname: Wang, Yong-Sheng organization: Institute of Genomics and Bioinformatics – sequence: 7 givenname: Hung-Yi surname: Wu fullname: Wu, Hung-Yi organization: National Chung Hsing University – sequence: 8 givenname: U-Ser orcidid: 0000-0002-2247-5061 surname: Jeng fullname: Jeng, U-Ser organization: National Tsing Hua University – sequence: 9 givenname: Kylene surname: Kehn-Hall fullname: Kehn-Hall, Kylene organization: National Center for Biodefense and Infectious Diseases, School of Systems Biology – sequence: 10 givenname: Ming-Hon orcidid: 0000-0003-4170-1527 surname: Hou fullname: Hou, Ming-Hon email: mhho@nchu.edu.tw organization: National Chung Hsing University |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/32105468$$D View this record in MEDLINE/PubMed |
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| Title | Structure-Based Stabilization of Non-native Protein–Protein Interactions of Coronavirus Nucleocapsid Proteins in Antiviral Drug Design |
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