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

• Published in: Biochimica et biophysica acta Vol. 1860; no. 6; pp. 1299 - 1307
• Main Authors: Wu, Caiming, Zhang, Lanjun, Li, Peng, Cai, Qixu, Peng, Xuanjia, Yin, Ke, Chen, Xinsheng, Ren, Haixia, Zhong, Shilin, Weng, Yuwei, Guan, Yi, Chen, Shuhui, Wu, Jinzhun, Li, Jian, Lin, Tianwei
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.06.2016
• Subjects: 3C proteinase; 3C Viral Proteases; Amino Acid Sequence; antiviral agents; bioavailability; Cysteine Endopeptidases - chemistry; Cysteine Proteinase Inhibitors - pharmacology; digestion; Drug Design; drugs; Enterovirus A; Enterovirus A, Human - drug effects; Enterovirus A, Human - enzymology; enzyme inhibitors; Hand, foot and mouth disease; hydrophobicity; Molecular Sequence Data; Peptidomimetics; proteinases; Rupintrivir; Structure-Activity Relationship; Viral Proteins - antagonists & inhibitors; Viral Proteins - chemistry; DMSO; MS; EV71; HRV; TFA; DCM; RP-HPLC; μM; TEA; NMR; Hand, foot and mouth disease; 3Cpro; 3C proteinase; Rupintrivir; HFMD; Peptidomimetics; LC; IC50; r.m.s.d; EC50; r.t; FRET; Drug design; HATU
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2016.03.017

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 (3Cpro), 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. A series of compounds of different lengths targeting 3Cpro 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. 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. The data presented here provide a basis for designing a new generation of non-peptidomimetics to target EV71 3Cpro. •Contribution of sub-components to inhibitor potency to EV71 3Cpro were investigated•P2 groups need to be oriented to bind at the S2 subsite•S3 and S4 interacting moieties were required to generate sufficient potency•Hydrophobicity in S4 interacting moiety is helpful for cellular uptake•The data provide the basis for designing a new generation of inhibitors to 3Cpro