Fragment-wise design of inhibitors to 3C proteinase from enterovirus 71

Biochim Biophys Acta. 2016 Jun;1860(6):1299-307. doi: 10.1016/j.bbagen.2016.03.017. Epub 2016 Mar 15.

Abstract

Background: Enterovirus 71 (EV71) is a causative agent of hand, foot and mouth disease (HFMD), which can spread its infection to central nervous and other systems with severe consequence. A key factor in the replication of EV71 is its 3C proteinase (3C(pro)), a significant drug target. Peptidomimetics were employed as inhibitors of this enzyme for developing antivirals. However, the peptide bonds in these peptidomimetics are a source of low bioavailability due to their susceptibility to protease digestion. To produce non-peptidomimetic inhibitors by replacing these peptide bonds, it would be important to gain better understanding on the contribution of each component to the interaction and potency.

Methods: A series of compounds of different lengths targeting 3C(pro) and having an α,β-unsaturated ester as the warhead were synthesized and their interactions with the enzyme were evaluated by complex structure analyses and potency assays for a better understanding on the relationship between potency and evolution of interaction.

Results: The P2 moiety of the compound would need to be oriented to interact in the S2 site in the substrate binding cleft and the P3-P4 moieties were required to generate sufficient potency. A hydrophobic terminal group will benefit the cellular uptake and improve the activity in vivo.

Conclusions and general significance: The data presented here provide a basis for designing a new generation of non-peptidomimetics to target EV71 3C(pro).

Keywords: 3C proteinase; Drug design; Hand, foot and mouth disease; Peptidomimetics; Rupintrivir.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3C Viral Proteases
  • Amino Acid Sequence
  • Cysteine Endopeptidases / chemistry
  • Cysteine Proteinase Inhibitors / pharmacology*
  • Drug Design
  • Enterovirus A, Human / drug effects*
  • Enterovirus A, Human / enzymology
  • Molecular Sequence Data
  • Structure-Activity Relationship
  • Viral Proteins / antagonists & inhibitors*
  • Viral Proteins / chemistry

Substances

  • Cysteine Proteinase Inhibitors
  • Viral Proteins
  • Cysteine Endopeptidases
  • 3C Viral Proteases