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
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.
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.
Biochim Biophys Acta. 2016 Jun;1860(6):1299-307. doi: 10.1016/j.bbagen.2016.03.017. Epub 2016 Mar 15.
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.
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.
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 3C(pro).
肠道病毒71型（EV71）是手足口病（HFMD）的病原体，可将感染扩散至中枢神经系统和其他系统，后果严重。EV71复制的一个关键因素是其3C蛋白酶（3C(pro)），这是一个重要的药物靶点。拟肽被用作该酶的抑制剂以开发抗病毒药物。然而，这些拟肽中的肽键由于易受蛋白酶消化，是生物利用度低的一个原因。为了通过取代这些肽键来生产非拟肽抑制剂，更深入了解每个组分对相互作用和效力的贡献将很重要。
合成了一系列针对3C(pro)且以α,β-不饱和酯作为弹头的不同长度的化合物，并通过复合物结构分析和效力测定评估它们与该酶的相互作用，以便更好地理解效力与相互作用演变之间的关系。
化合物的P2部分需要定向以在底物结合裂隙的S2位点相互作用，并且P3 - P4部分需要产生足够的效力。一个疏水末端基团将有利于细胞摄取并提高体内活性。
本文提供的数据为设计新一代靶向EV71 3C(pro)的非拟肽提供了依据。
