A cocrystal structure of dengue capsid protein in complex of inhibitor

Proc Natl Acad Sci U S A. 2020 Jul 28;117(30):17992-18001. doi: 10.1073/pnas.2003056117. Epub 2020 Jul 15.


Dengue virus (DENV) was designated as a top 10 public health threat by the World Health Organization in 2019. No clinically approved anti-DENV drug is currently available. Here we report the high-resolution cocrystal structure (1.5 Å) of the DENV-2 capsid protein in complex with an inhibitor that potently suppresses DENV-2 but not other DENV serotypes. The inhibitor induces a "kissing" interaction between two capsid dimers. The inhibitor-bound capsid tetramers are assembled inside virions, resulting in defective uncoating of nucleocapsid when infecting new cells. Resistant DENV-2 emerges through one mutation that abolishes hydrogen bonds in the capsid structure, leading to a loss of compound binding. Structure-based analysis has defined the amino acids responsible for the inhibitor's inefficacy against other DENV serotypes. The results have uncovered an antiviral mechanism through inhibitor-induced tetramerization of the viral capsid and provided essential structural and functional knowledge for rational design of panserotype DENV capsid inhibitors.

Keywords: antiviral drug; capsid; dengue; flavivirus; virus assembly.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Antiviral Agents / chemistry*
  • Antiviral Agents / pharmacology
  • Binding Sites
  • Capsid Proteins / chemistry*
  • Capsid Proteins / genetics
  • Dengue Virus* / drug effects
  • Models, Molecular*
  • Mutation
  • Nucleocapsid / chemistry
  • Nucleocapsid / metabolism
  • Protein Binding
  • Protein Conformation*
  • Protein Interaction Domains and Motifs
  • Structure-Activity Relationship


  • Antiviral Agents
  • Capsid Proteins