2. Academic Validation
  3. Structure-Based Stabilization of Non-native Protein-Protein Interactions of Coronavirus Nucleocapsid Proteins in Antiviral Drug Design

Structure-Based Stabilization of Non-native Protein-Protein Interactions of Coronavirus Nucleocapsid Proteins in Antiviral Drug Design

  • J Med Chem. 2020 Mar 26;63(6):3131-3141. doi: 10.1021/acs.jmedchem.9b01913.
Shan-Meng Lin 1 2,  Shih-Chao Lin 3,  Jia-Ning Hsu 1 2,  Chung-Ke Chang 4,  Ching-Ming Chien 1 2,  Yong-Sheng Wang 1,  Hung-Yi Wu 5,  U-Ser Jeng 6 7,  Kylene Kehn-Hall 3,  Ming-Hon Hou 1 2
Affiliations

Affiliations

  • 1 Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung 402, Taiwan.
  • 2 Department of Life Sciences, National Chung Hsing University, Taichung 402, Taiwan.
  • 3 National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, Virginia 20110, United States.
  • 4 Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
  • 5 Graduate Institute of Veterinary Pathobiology, College of Veterinary Medicine, National Chung Hsing University, Taichung 40227, Taiwan.
  • 6 National Synchrotron Radiation Research Center, 101 Hsin-Ann Road, Hsinchu Science Park, Hsinchu 30076, Taiwan.
  • 7 Department of Chemical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan.
PMID: 32105468 DOI: 10.1021/acs.jmedchem.9b01913
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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