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

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 alpha,beta-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). (C) 2016 Elsevier B.V. All rights reserved.