基于金属有机框架材料的酶固定化策略及药物筛选研究进展

常香蕾; 张瑛; Stanislas Nsanzamahoro; 王铖博; 王伟峰; 杨军丽

doi:10.16495/j.1006-3757.2023.02.001

基于金属有机框架材料的酶固定化策略及药物筛选研究进展

doi: 10.16495/j.1006-3757.2023.02.001

常香蕾^{1, 2,},
张瑛¹,
Stanislas Nsanzamahoro^{1, 2},
王铖博¹,
王伟峰^1, ,,
杨军丽^1, ,

1.
中国科学院兰州化学物理研究所，中国科学院西北特色植物资源化学重点实验室，甘肃省天然药物重点实验室，甘肃兰州　730000
2.
中国科学院大学，北京　100049

基金项目: 国家自然科学基金国际(地区)合作研究项目（32161143019），中国科学院西部之光

详细信息

作者简介:
常香蕾（1999−），女，硕士生，研究方向：分离分析科学，E-mail：changxianglei@licp.cas.cn

通讯作者:
王伟峰，男，副研究员，研究方向：药物分离分析新技术和方法，E-mail：wangwf@licp.cas.cn

杨军丽，男，研究员，《分析测试技术与仪器》编委，Tel：13893659437，E-mail：yangjl@licp.cas.cn

中图分类号: O657
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- 文章访问数: 77
- HTML全文浏览量: 43
- PDF下载量: 13
- 被引次数: 0
出版历程
- 收稿日期: 2023-03-09
- 录用日期: 2023-05-08
- 修回日期: 2023-05-08
- 刊出日期: 2023-06-30

Progress of Enzyme Immobilization Strategies and Drug Screening Based on Metal-Organic Framework Materials

1.
Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Key Laboratory of Chemistry of Northwestern Plant Resources, Key Laboratory for Natural Medicines of Gansu Province, Lanzhou 730000, China
2.
University of Chinese Academy of Sciences, Beijing 100049, China

Funds: National Natural Science Foundation of China (32161143019), CAS "Light of West China" Program

摘要

摘要: 酶抑制剂筛选是药物开发的重要途径之一. 酶的三维结构易受到温度、盐浓度等外界因素的干扰，导致其催化活性和稳定性降低，增加了药物筛选成本. 因此，通过酶与载体之间的相互作用对其进行固定化，提高酶结构稳定性，已成为保持酶活力的重要策略. 基于固定化酶从复杂样品中筛选酶抑制剂也成为了药物研发的热点领域. 近年来，金属有机框架材料（metal-organic frameworks, MOFs）因其具有孔径可调、比表面积大、结构简单、环境稳定等特点，被认为是酶固定化的理想载体，为实现酶抑制剂高效筛选提供了新的解决方案. 总结了以MOFs为载体的酶固定化方法及其在抑制剂筛选和应用的相关研究进展，对MOFs酶固定化和药物筛选的机遇和挑战进行了展望.
- 金属有机框架材料 /
- 酶固定化 /
- 酶抑制剂 /
- 药物筛选
Abstract: Screening of enzyme inhibitors is one of the important approaches for drug development. The three-dimensional structure of enzymes is susceptible to the interference of external factors such as temperature and salt concentration, leading to a decrease in its catalytic activity and stability and increasing the cost of drug screening. Therefore, immobilization through enzyme-carrier interactions to improve the stability of enzyme structure has become an important strategy to maintain the enzyme activity. Screening enzyme inhibitors from complex samples based on immobilized enzymes has also become a hot field of drug research and development. In recent years, metal-organic frameworks (MOFs) are known as the ideal carrier for enzyme immobilization due to their characteristics of adjustable aperture, large surface area, simple structure, stable environment, and so on, and it provides a novel method to achieve the efficient screening of enzyme inhibitors. The method of enzyme immobilization using MOFs as the carrier, the research progress of inhibitor screening and application were summarized. The opportunities and challenges of MOFs enzyme immobilization and drug screening were prospected.
- MOFs /
- enzyme immobilization /
- enzyme inhibitors /
- drug screening

HTML全文

图 1 胰蛋白酶固定在DCC激活的MOFs上^[23]

Figure 1. Trypsin immobilization onto DCC-activated MOFs^[23]

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图 2 (a) BCL@MTV-ZIF-8的合成，(b) MTV-ZIFs作用下BCL的闭盖构象和开盖构象^[5]

Figure 2. (a) Synthesis of BCL@MTV-ZIF-8, (b) Closed-Lid conformation and Open-Lid conformation of BCL regulated by MTV-ZIFs^[5]

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图 3 (a) PmHS2@Mg-BMOM微反应器的合成示意图及其在肝素二糖、三糖和多糖合成中的应用^[22]（ICA, Imidazole-2-carboxaldehyde），(b) 通过Y-支架交联多种酶网络并在ZIF-8中固定的示意图^[30]

Figure 3. (a) Schematics of synthesizing a PmHS2@Mg-BMOM microreactor and its applications for synthesis of heparosan disaccharide, trisaccharide, and polysaccharide^[22](ICA, Imidazole-2-carboxaldehyde), (b) schematic for cross-linking multiple enzymes network by Y-scaffold and entrapment in zeolitic imidazolate framework (ZIF-8)^[30]

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图 4 Fe₃O₄@CS@ZIF-8@α-葡萄糖苷酶的制备及酶抑制剂筛选示意图^[62]（TPP, Sodium tripolyphosphate）

Figure 4. Schematic illustration of fabrication of Fe₃O₄@CS@ZIF-8@α-glucosidase microspheres and inhibitors screening^[62](TPP, Sodium tripolyphosphate)

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图 5 (a) PPL@MOF：从天然草药中发现配体的新平台^[63]，(b) 基于针式过滤器的在线筛选系统^[66]

Figure 5. (a) PPL@MOF: new platform for discovery of ligands from natural herbs^[63], (b) syringe filter-based online screening system^[66]

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图 6 (a) 基于双功能杂化酶催化MOFs反应器的比色传感平台示意图^[64]（TMB, 3, 3', 5, 5'-Tetramethylbenzidine dihydrochloride），(b) 基于GAA@Cu-MOF和IrO₂/MnO₂纳米复合材料的GAA抑制剂筛选传感平台示意图^[87]

Figure 6. (a) Schematic illustration of colorimetric sensing platform based on hybrid enzyme-catalytic MOF reactor^[64](TMB, 3, 3', 5, 5'-Tetramethylbenzidine dihydrochloride), (b) schematic illustration of sensing platform for GAA inhibitor screening based on GAA@Cu-MOF and IrO₂/MnO₂ nanocomposite^[87]

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表 1 基于不同方法制备酶-MOFs复合材料的性能总结

Table 1. Summary of performances of enzyme-MOFs composites prepared based on different methods

MOFs	酶	固定方法	对酶活力的影响	性能	参考文献
MIL-88B-NH₂（Cr）	胰蛋白酶	共价	—	优越的蛋白水解性能	[23]
NH₂-MIL53（Al）、NH₂-MIL101（Cr）	葡萄糖氧化酶	共价	抑制	高选择性、低检测限	[19]
ILs/Fe₃O₄@MOF	脂肪酶	共价	提升	催化活性高、稳定性好	[24]
Fe₃O₄-COOH@UiO-66-NH₂	猪胰脂肪酶	交联	—	较高的负载量和固定化酶活性	[25]
Fe₃O₄@ZIF-67	α-葡萄糖苷酶	交联	抑制	高负载量	[20]
Cu-BTC	枯草芽孢杆菌脂肪酶	表面吸附	提升	较高的催化活性、优良的可重复使用性	[21]
HP-DUT-5	葡萄糖氧化酶、尿酸酶	表面吸附	—	稳定性好、特异性强	[26]
UiO-66-NH₂	乙酰胆碱酯酶	表面吸附	—	较高的负载量	[27]
Cu-MOF	β-葡萄糖苷酶	共沉淀法	—	优异的包封效率和酸性稳定性	[28]
MTV-ZIF-8	脂肪酶	仿生矿化	提升	较高的催化活性	[5]
UiO-66-NH₂（30）	漆酶	表面吸附、扩散	提升	负载量高、稳定性好	[29]
BMOMs	糖基转移酶	微反应器	提升	优异的催化活性	[22]
DNA/ZIF-8	辣根过氧化物酶、葡萄糖氧化酶	原位包埋	提升	催化效率高	[30]
—：未注明

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表 2 基于MOFs的固定化酶在抑制剂筛选中的应用

Table 2. Application of immobilized enzyme based on MOFs in inhibitor screening

MOFs	酶	固定方法	对酶活力的影响	检测技术	应用	参考文献
Fe₃O₄@CS@ZIF-8	α-葡萄糖苷酶	原位包埋	—	毛细管电泳	14种中药中α-葡萄糖苷酶抑制剂筛选	[62]
MnO₂-ZIF-67	乙酰胆碱酯酶	表面吸附	—	毛细管电泳	大叶旋覆花中AChE抑制剂筛选	[65]
UiO-66-NH₂	猪胰脂肪酶	交联、共价结合	提升	高效液相色谱-四级杆-飞行时间串联质谱	夏枯草中脂肪酶抑制剂筛选	[63]
Fe₃O₄-COOH@UiO-66-NH₂	猪胰脂肪酶	交联	抑制	超高效液相色谱-四级杆-飞行时间串联质谱	黄岑中分离鉴定脂肪酶抑制剂	[25]
ZIF-90	α-葡萄糖苷酶	共价结合	—	高效液相色谱	淮山药和地黄等多种植物中筛选α-葡萄糖苷酶抑制剂	[66]
Fe₃O₄@ZIF-67	α-葡萄糖苷酶	交联	抑制	高效液相色谱	信阳毛尖茶中筛选α-葡萄糖苷酶抑制剂	[20]
Cu-MOF	α-葡萄糖苷酶	原位包埋	提升	比色传感	齐墩果酸衍生物中筛选潜在的抗糖尿病药物	[64]
Au/Cu-MOFs	DNA甲基转移酶	共价结合	—	电化学检测法	检测酶活性并研究抑制剂筛选可行性	[67]
—：未注明

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