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Molecules. 2018 Aug 20;23(8). pii: E2084. doi: 10.3390/molecules23082084.

Synthesis and Evolution of Berberine Derivatives as a New Class of Antiviral Agents against Enterovirus 71 through the MEK/ERK Pathway and Autophagy.

Author information

1
Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. wangyanxiang@imb.pumc.edu.cn.
2
Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. yolo2022@163.com.
3
Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. hq_wangimb@163.com.
4
Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. xiaoqiangzhao2017@126.com.
5
Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. lutyliu@126.com.
6
Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. liyinghong@imb.pumc.edu.cn.
7
Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. zqx50810793@163.com.
8
Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. yuhuanlibj@126.com.
9
Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. songdanqingsdq@hotmail.com.

Abstract

Taking berberine (BBR) as the lead, 23 new BBR derivatives were synthesized and examined for their antiviral activities against four different genotype enterovirus 71 (EV71) strains with a cytopathic effect (CPE) assay. Structure-activity relationship (SAR) studies indicated that introduction of a suitable substituent at the 9-position might be beneficial for potency. Among them, compound 2d exhibited most potent activities with IC50 values of 7.12⁻14.8 μM, similar to that of BBR. The effect of 2d was further confirmed in a dose-dependent manner both in RNA and protein level. The mechanism revealed that 2d could inhibit the activation of MEK/ERK signaling pathway. Meanwhile, it could suppress the EV71-induced autophagy by activating AKT and inhibiting the phosphorylation of JNK and PI3KIII proteins. We consider BBR derivatives to be a new family of anti-EV71 agents through targeting host components, with an advantage of broad-spectrum anti-EV71 potency.

KEYWORDS:

MEK/ERK pathway; autophagy; berberine; enterovirus 71; structure-activity relationship

PMID:
30127288
PMCID:
PMC6222558
DOI:
10.3390/molecules23082084
[Indexed for MEDLINE]
Free PMC Article

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