组蛋白去乙酰化酶抑制剂MGCD0103对小反刍兽疫病毒体外复制的影响

doi:10.11843/j.issn.0366-6964.2024.10.025

畜牧兽医学报 ›› 2024, Vol. 55 ›› Issue (10): 4542-4552.doi: 10.11843/j.issn.0366-6964.2024.10.025

组蛋白去乙酰化酶抑制剂MGCD0103对小反刍兽疫病毒体外复制的影响

邓瑞雪¹^,²^,³(), 潘春容¹^,²^,³, 朱学亮², 胡林杰², 孙跃峰², 曾巧英¹^,*(), 蒙学莲²^,*()

1. 甘肃农业大学动物医学院, 兰州 730070
2. 中国农业科学院兰州兽医研究所动物疫病防控全国重点实验室, 兰州 730046
3. 中农威特生物科技股份有限公司, 兰州 730046

收稿日期:2023-12-11 出版日期:2024-10-23 发布日期:2024-11-04
通讯作者: 曾巧英,蒙学莲 E-mail:drxd1@163.com;zengqy@gsau.edu.cn;mengxuelian@caas.cn
作者简介:邓瑞雪(1990-), 男, 甘肃临洮人, 博士, 主要从事病毒与分子免疫学研究作, Email: drxd1@163.com
基金资助:
2022年甘肃省动物用生物制品创新联合体项目(22ZD6NA012-1);兰州国家高新区“百园”行动专项

Suppressive Effect of Histone Deacetylase Inhibitor MGCD0103 on Peste Des Petits Rumants Virus Replication in vitro

Ruixue DENG¹^,²^,³(), Chunrong PAN¹^,²^,³, Xueliang ZHU², Linjie HU², Yuefeng SUN², Qiaoying ZENG¹^,*(), Xuelian MENG²^,*()

1. College of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China
2. State Key Laboratory for Animal Disease Control and Prevention, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730046, China
3. China Agricultural Vet Biology and Technology Co., Ltd, Lanzhou 730046, China

Received:2023-12-11 Online:2024-10-23 Published:2024-11-04
Contact: Qiaoying ZENG, Xuelian MENG E-mail:drxd1@163.com;zengqy@gsau.edu.cn;mengxuelian@caas.cn

摘要/Abstract

摘要：

旨在探究组蛋白去乙酰化酶(HDACs)选择性抑制剂MGCD0103(Mocetinostat)对小反刍兽疫病毒(peste des petits ruminants virus，PPRV)在山羊子宫内膜上皮细胞(EEC细胞)复制的影响。本研究通过RT-qPCR法测定PPRV感染后宿主细胞HDACs和抑制剂处理细胞中PPRV N基因的转录水平，通过Time of Addition Assay确定MGCD0103在PPRV复制过程的作用阶段，用Western blot检测PPRV N蛋白的相对表达量，并采用TCID₅₀方法测定了病毒滴度。结果表明，PPRV感染引起EEC细胞HDAC1(P < 0.001)和HDAC2(P < 0.002)转录水平明显上升；MGCD0103在病毒入侵和复制阶段均发挥了抑制作用，且在复制阶段抑制作用更明显；MGCD0103显著降低PPRV N基因转录水平和表达水平及病毒滴度(P < 0.002)，且其抑制PPRV在EEC中的半数有效浓度(EC₅₀)和药物选择指数(SI)分别是0.43 μmol·L^-1和4.35。本研究确定MGCD0103显著抑制PPRV的复制，这对研发有效抗PPRV药物具有重要意义，为高效率产毒细胞株的构建提供新思路。

关键词: 组蛋白去乙酰化酶抑制剂, MGCD0103, 抑制, 小反刍兽疫病毒, 病毒复制

Abstract:

In this study, the effect of MGCD0103 (Mocetinostat), a selective HDACi, on the replication of peste des petits ruminants virus (PPRV) in goat endometrial epithelial cells (EEC cells) was investigated, aiming to clarify the role and activity of MGCD0103 in PPRV multiplication. The transcription levels of HDACs and PPRV N gene in different treated cells were determined by RT-qPCR, and the action stage of MGCD0103 in the viral proliferation cycle of PPRV was determined by the time of addition assay. The effect of MGCD0103 on the expression level of PPRV N protein and viral titer were further analyzed by Western blot and TCID₅₀, respectively. The results showed that the mRNA expression levels of HDAC1 (P < 0.001) and HDAC2 (P < 0.002) were increased significantly in PPRV-infected EEC cells. Although MGCD0103 has an excellent inhibitory effect on PPRV multiplication, its inhibitory effect in the virus entry is limited. MGCD0103 significantly reduced the transcription and expression levels of PPRV N gene, as well as the viral titer (P < 0.002). The half-maximal effective concentration (EC₅₀) and selectivity index (SI) of MGCD0103 against PPRV were 0.43 μmol·L^-1 and 4.35, respectively. These results indicated that MGCD0103 significantly inhibited PPRV replication, which is of great significance for the development of anti-PPRV drugs and provides a new idea for constructing sensitive cell lines for PPRV proliferation.

Key words: histone deacetylase inhibitor, MGCD0103, inhibit, peste des petits ruminants virus, replication

中图分类号:

邓瑞雪, 潘春容, 朱学亮, 胡林杰, 孙跃峰, 曾巧英, 蒙学莲. 组蛋白去乙酰化酶抑制剂MGCD0103对小反刍兽疫病毒体外复制的影响[J]. 畜牧兽医学报, 2024, 55(10): 4542-4552.

Ruixue DENG, Chunrong PAN, Xueliang ZHU, Linjie HU, Yuefeng SUN, Qiaoying ZENG, Xuelian MENG. Suppressive Effect of Histone Deacetylase Inhibitor MGCD0103 on Peste Des Petits Rumants Virus Replication in vitro[J]. Acta Veterinaria et Zootechnica Sinica, 2024, 55(10): 4542-4552.

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引物 Primer	NCBI参考序列 NCBI reference sequence	序列(5′→3′) Sequence (5′→3′)
N-F	KY628761.1	TCGCGAGAGTTCATCCTCTTG
N-R		AAAGCGAACACGCTCAGGAA
cACTB-F	NM_001314342.1	CCTGGACTTCGAGCAGGAGA
cACTB-R		AGGCTGGAAGAGAGCCTCAG
cHDAC1-F	XM_004005023.4	TGGAAATCTATCGCCCTCACAAAGC
cHDAC1-R		ACCGACGTTGAATCTCTGCATCTG
cHDAC2-F	XM_004011189.4	CAGTCAAGGAGGCGGCAAGAAG
cHDAC2-R		AGCAAGTTATGGGTCATGCGGATC
cHDAC3-F	XM_004008901.5	CATGCACCTAGCGTCCAGATTCAC
cHDAC3-R		TCTCCTCCGCATCAGCCTCATC
cHDAC4-F	XM_042244213.1	GCTTCTGAACCCAACCTGAAATTGC
cHDAC4-R		CGCCGAGTCTGTGACATCCAAG
cHDAC5-F	XM_042256050.1	AATGTGAATGTGGCATGGACAGGAG
cHDAC5-R		CAGGTGAGAACTCGTGGGCAATG
cHDAC6-F	XM_027962812.2	TTAGCCAAACAGCCGAGCAAGAC
cHDAC6-R		AACACCAAACCAGTGCCAGACAG
cHDAC7-F	XM_042246807.1	AAACCCAACCTCAATGCCATCCG
cHDAC7-R		CGTCACTGCCTCCACTTCTTCTG
cHDAC8-F	XM_004022188.5	GCTTCCACACCGATGCCTATCTG
cHDAC8-R		CTTCAGTGGCTGGGCAGTCATAAC
cHDAC9-F	XM_042248296.1	AAAGCCCAATAGCAGCCACCAAG
cHDAC9-R		GGAACTCCACCAGCCACAAGAAG
cHDAC10-F	XM_042247939.1	TACTTCTCCTGGCACCGCTACG
cHDAC10-R		CAGGGCAGGTTGACAGTGAAGC
cHDAC11-F	XM_042236456.1	CATCATCGCCGACTCCATCCTTAAC
cHDAC11-R		GCGTGTCTGAGTTCTGTGCTGAG

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组蛋白去乙酰化酶抑制剂MGCD0103对小反刍兽疫病毒体外复制的影响

Suppressive Effect of Histone Deacetylase Inhibitor MGCD0103 on Peste Des Petits Rumants Virus Replication in vitro

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