title: Fragment-wise design of inhibitors to 3C proteinase from enterovirus 71.
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
  The data presented here provide a basis for designing a new generation of non-peptidomimetics to target EV71 3C(pro).
authors.affiliation: The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China; State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
authors.forename: Caiming
authors.initials: C
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
authors.forename: Lanjun
authors.initials: L
authors.lastname: Zhang
authors.affiliation: State Key Laboratory on Lead Compound Research, Wuxi AppTec Co., Ltd., Shanghai, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
authors.forename: Qixu
authors.initials: Q
authors.lastname: Cai
authors.affiliation: State Key Laboratory on Lead Compound Research, Wuxi AppTec Co., Ltd., Shanghai, China.
authors.forename: Xuanjia
authors.initials: X
authors.lastname: Peng
authors.affiliation: State Key Laboratory on Lead Compound Research, Wuxi AppTec Co., Ltd., Shanghai, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Yin
authors.affiliation: State Key Laboratory on Lead Compound Research, Wuxi AppTec Co., Ltd., Shanghai, China.
authors.forename: Xinsheng
authors.initials: X
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
authors.forename: Haixia
authors.initials: H
authors.lastname: Ren
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
authors.forename: Shilin
authors.initials: S
authors.lastname: Zhong
authors.affiliation: Fujian Center for Disease Control, Fuzhou, Fujian, China.
authors.forename: Yuwei
authors.initials: Y
authors.lastname: Weng
authors.affiliation: State Key Laboratory for Emerging Infectious Diseases, The University of Hong Kong, Hong Kong SAR, PR China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Guan
authors.affiliation: State Key Laboratory on Lead Compound Research, Wuxi AppTec Co., Ltd., Shanghai, China.
authors.forename: Shuhui
authors.initials: S
authors.lastname: Chen
authors.affiliation: The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China. Electronic address: 1923731201@qq.com.
authors.forename: Jinzhun
authors.initials: J
authors.lastname: Wu
authors.affiliation: State Key Laboratory on Lead Compound Research, Wuxi AppTec Co., Ltd., Shanghai, China. Electronic address: jian_li@wuxiapptec.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, School of Life Sciences, Xiamen University, Xiamen, Fujian, China. Electronic address: twlin@xmu.edu.cn.
authors.forename: Tianwei
authors.initials: T
authors.lastname: Lin
mesh_terms: D000086042:3C Viral Proteases; D000595:Amino Acid Sequence; D003546:Cysteine Endopeptidases / Q000737:chemistry; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D015195:Drug Design; D029821:Enterovirus A, Human / Q000187:drug effects* / Q000201:enzymology; D008969:Molecular Sequence Data; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D015853:Cysteine Proteinase Inhibitors; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases
keywords: 3C proteinase; Drug design; Hand, foot and mouth disease; Peptidomimetics; Rupintrivir