中文版 | English
题名

通过新型高通量测序平台筛选 SARS-COV-2 的 NSP14 的抑制剂

其他题名
IDENTIFICATION OF INHIBITORS TOWARDS SARS-COV-2 NSP14 BY A NOVEL HIGHTHROUGHPUT SCREENING PLATFORM
姓名
姓名拼音
ZHOU Hui
学号
12032606
学位类型
硕士
学位专业
071010 生物化学与分子生物学
学科门类/专业学位类别
07 理学
导师
陈浩
导师单位
人类细胞生物和遗传学系
论文答辩日期
2023-05-08
论文提交日期
2023-06-28
学位授予单位
南方科技大学
学位授予地点
深圳
摘要

由 严 重 急 性 呼 吸 系 统 综 合 症 冠 状 病 毒 2(SARS-CoV-2) 感 染 引 起 的 COVID-19 大流行对公共卫生和经济的影响,得到了前所未有的科学响应。 大量的针对新型冠状病毒的药物和疫苗进入研究阶段,科研人员对新型冠状病毒上的靶点开发了不同的治疗方式。针对于 SARS-CoV-2 的刺突蛋白与宿主细胞的血管紧张素酶 2 的结合,开发了一系列疫苗;针对于病毒的多 聚蛋白被 3CL 蛋白酶分解成 16 种非结构蛋白,开发出 3CL 蛋白酶抑制剂 Nirmatrelvir-ritonavir;针对于病毒复制的关键酶非结构蛋白 NSP12,开发了许多核苷酸类似物比如:Molnupiravi 和 Remdesivir,但是因为病毒具有自我修复的机制,基于 NSP14 的 3`到 5`的核酸外切酶活性,可以将核苷酸类似物这一类型的药物,形成的错配碱基从新合成的 RNA 链上清除,恢复病毒 RNA 聚合酶的复制功能,使其 RNA 链得以继续复制,维持病毒的正常的复制和翻译功能。因此,寻找一种基于 NSP14 的核酸外切酶抑制剂, 阻止 RNA 复制过程中的校对,对基于病毒 RDRP 靶点设计的抗病毒药物的发挥作用有重要意义。本课题的研究采用了药明康德的 DELopen 的试剂盒,借助了高通量筛选的技术,从 44 亿小分子化合物库中,筛选出了 11,241 个小分子,基于统计分析的结果,有 2,577 个小分子与新型冠状病毒的 NSP14 蛋白高度富集,因此经过进一步分析选择合成了 3 个最具有潜力的化合物,通过酶活检测,相互作用分析,以及分子模拟的方式对其化合物 的抗病毒活性进行了探究。通过高通量筛选得到的小分子化合物能够抑制 NSP14 发挥核酸外切酶的作用,能与 NSP14 的蛋白产生相互作用,且经过分子模拟的预测,对其结合位点有了初步的猜测。本课题为抗新冠病毒的药物研发提供了帮助,推进了高通量筛选技术应用于小分子化合物的研究 进程,提供了新的药物研究的靶点,对 NSP14 蛋白开展应用基础研究具有 重大的社会经济及学术价值。

关键词
语种
中文
培养类别
独立培养
入学年份
2020
学位授予年份
2023-07
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专题南方科技大学医学院
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周慧. 通过新型高通量测序平台筛选 SARS-COV-2 的 NSP14 的抑制剂[D]. 深圳. 南方科技大学,2023.
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