A novel druggable interprotomer pocket in the capsid of rhino- and enteroviruses

PLoS Biol. 2019 Jun 11;17(6):e3000281. doi: 10.1371/journal.pbio.3000281. eCollection 2019 Jun.


Rhino- and enteroviruses are important human pathogens, against which no antivirals are available. The best-studied inhibitors are "capsid binders" that fit in a hydrophobic pocket of the viral capsid. Employing a new class of entero-/rhinovirus inhibitors and by means of cryo-electron microscopy (EM), followed by resistance selection and reverse genetics, we discovered a hitherto unknown druggable pocket that is formed by viral proteins VP1 and VP3 and that is conserved across entero-/rhinovirus species. We propose that these inhibitors stabilize a key region of the virion, thereby preventing the conformational expansion needed for viral RNA release. A medicinal chemistry effort resulted in the identification of analogues targeting this pocket with broad-spectrum activity against Coxsackieviruses B (CVBs) and compounds with activity against enteroviruses (EV) of groups C and D, and even rhinoviruses (RV). Our findings provide novel insights in the biology of the entry of entero-/rhinoviruses and open new avenues for the design of broad-spectrum antivirals against these pathogens.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence / genetics
  • Amino Acids / genetics
  • Antigens, Viral
  • Antiviral Agents
  • Binding Sites
  • Capsid / drug effects*
  • Capsid / metabolism
  • Capsid / ultrastructure*
  • Capsid Proteins / metabolism
  • Capsid Proteins / ultrastructure*
  • Cryoelectron Microscopy / methods
  • Drug Development / methods
  • Enterovirus / drug effects
  • Enterovirus / ultrastructure
  • Humans
  • Models, Molecular
  • Molecular Conformation
  • Rhinovirus / drug effects
  • Rhinovirus / ultrastructure
  • Viral Proteins / chemistry
  • Viral Proteins / ultrastructure
  • Virion / genetics


  • Amino Acids
  • Antigens, Viral
  • Antiviral Agents
  • Capsid Proteins
  • Viral Proteins
  • viral protein 1, rhinovirus