Design, synthesis, and evaluation of a novel macrocyclic anti-EV71 agent

Peng Li; Siqi Wu; Tianyichen Xiao; Yunlong Li; Zhiming Su; Wei Wei; Fei Hao; Guoping Hu; Fusen Lin; Xinsheng Chen; Zhengxian Gu; Tianwei Lin; Haiying He; Jian Li; Shuhui Chen

doi:10.1016/j.bmc.2020.115551

Design, synthesis, and evaluation of a novel macrocyclic anti-EV71 agent

Bioorg Med Chem. 2020 Jun 15;28(12):115551. doi: 10.1016/j.bmc.2020.115551. Epub 2020 May 8.

Authors

Peng Li¹, Siqi Wu², Tianyichen Xiao², Yunlong Li², Zhiming Su², Wei Wei³, Fei Hao³, Guoping Hu³, Fusen Lin³, Xinsheng Chen³, Zhengxian Gu³, Tianwei Lin⁴, Haiying He³, Jian Li⁵, Shuhui Chen³

Affiliations

¹ 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; Cancer Research Center of Xiamen University, Xiamen, Fujian, China; State Key Laboratory of Drug Lead Compound Research, WuXi AppTec (Shanghai) Co., Ltd., Shanghai, China.
² 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; Cancer Research Center of Xiamen University, Xiamen, Fujian, China.
³ State Key Laboratory of Drug Lead Compound Research, WuXi AppTec (Shanghai) Co., Ltd., Shanghai, China.
⁴ 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; Cancer Research Center of Xiamen University, Xiamen, Fujian, China. Electronic address: twlin@xmu.edu.cn.
⁵ State Key Laboratory of Drug Lead Compound Research, WuXi AppTec (Shanghai) Co., Ltd., Shanghai, China. Electronic address: jian_li@wuxiapptec.com.

PMID: 32503695
DOI: 10.1016/j.bmc.2020.115551

Abstract

We describe here the design, synthesis, and evaluation of a macrocyclic peptidomimetic as a potent agent targeting enterovirus A71 (EV71). The compound has a 15-membered macrocyclic ring in a defined conformation. Yamaguchi esterification reaction was used to close the 15-membered macrocycle instead of the typical Ru-catalyzed ring-closing olefin metathesis reaction. The crystallographic characterization of the complex between this compound and its target, 3C protease from EV71, validated the design and paved the way for the generation of a new series of anti-EV71 agents.

Keywords: 3C Protease Inhibitor; Enterovirus 71; Macrocycles; X-ray crystallography.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3C Viral Proteases / chemistry
3C Viral Proteases / metabolism
Animals
Antiviral Agents / blood
Antiviral Agents / chemical synthesis*
Antiviral Agents / metabolism
Antiviral Agents / pharmacology
Binding Sites
Catalysis
Catalytic Domain
Cell Line, Tumor
Cell Survival / drug effects
Crystallography, X-Ray
Drug Design*
Drug Stability
Enterovirus A, Human / drug effects
Enterovirus A, Human / enzymology
Esterification
Humans
Macrocyclic Compounds / blood
Macrocyclic Compounds / chemistry*
Macrocyclic Compounds / metabolism
Macrocyclic Compounds / pharmacology
Mice
Molecular Dynamics Simulation
Ruthenium / chemistry

Substances

Antiviral Agents
Macrocyclic Compounds
Ruthenium
3C Viral Proteases