Label-free Protein Analysis Methods for Active Compound Targets Identification

doi:10.6023/A24030082

Acta Chimica Sinica ›› 2024, Vol. 82 ›› Issue (6): 629-640.DOI: 10.6023/A24030082 Previous Articles Next Articles

Review

适用于活性化合物靶点鉴定的无标记蛋白质分析方法

吕博海^a^,^b, 勾文峰^b, 许飞飞^b, 李艳丽^b, 李祎亮^b^,^*(), 侯文彬^b^,^*()

a 天津中医药大学中医药研究院天津 301617
b 北京协和医学院&中国医学科学院放射医学研究所天津 300192

投稿日期:2024-03-14 发布日期:2024-04-02

作者简介:

吕博海, 2022年毕业于天津中医药大学, 同年9月继续攻读中药学硕士研究生. 研究方向为基于化学生物学的靶点发掘和蛋白质的结构、功能对信号通路的过程影响.

李祎亮, 中国医学科学院放射医学研究所研究员, 天津市“131”创新人才第一层次人才获得者, 北京协和医学院博士生导师. 长期从事新药研发工作, 重点专注于“分子影像”示踪技术与“药物设计”新策略结合, 开展新靶点药物和分子显像剂的研发. 曾参与并主持完成镇痛新药“地佐辛”、术后肠梗阻新药“爱维莫潘”等新药研发, 获得临床批件16项, 新药证书6项. 2018年, 主持承担天津市重大新药“正电子药物制备及其关键技术”平台建设, 2020年, 荣获天津市创新人才推进计划重点领域创新团队负责人. 近5年来, 带领团队陆续开展AND1、CDK19等原创靶点药物和分子显像剂开发, 已在Clin. Transl. Med., Eur. J. Nucl. Med. Mol. Imaging., Eur. J. Med. Chem.等学术期刊杂志发表高水平论文20余篇, 获得授权发明专利22项.

侯文彬, 中国医学科学院放射医学研究所研究员, 国务院特殊津贴专家、天津市有突出贡献专家和天津市优秀科技工作者, 天津市“131”人才第1层次人选和“131”人才团队负责人. 主要从事天然药物创新药的研究与开发. 先后主持承担国家支撑计划课题1项, 重大新药创制4项, 主持天津市重大科技攻关7项, 获市科技进步奖一、二、三等奖共3项, 滨海新区科技进步一等奖1项. 作为课题负责人主持完成新药研究20余项, 获新药证书2项, 临床批件10项, 包括胡黄连总苷及胶囊、淫羊藿素及其软胶囊获临床批件等, 申请专利24项, 授权10余项, 作为编委编著7部, 发表论文60余篇.

基金资助:
国家自然科学基金(82104012); 国家自然科学基金(82202950); 国家自然科学基金(82303681); 中国医学科学院医学与健康科技创新工程重大协同创新项目(2021-I2M-1-042); 中央高校基本科研业务费专项资金(3332022063)

Label-free Protein Analysis Methods for Active Compound Targets Identification

Bohai Lyu^a^,^b, Wenfeng Gou^b, Feifei Xu^b, Yanli Li^b, Yiliang Li^b,*(), Wenbin Hou^b,*()

a Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617
b Institute of Radiation Medicine, Peking Union Medical College & Chinese Academy of Medical Sciences, Tianjin 300192

Received:2024-03-14 Published:2024-04-02
Contact: * E-mail: liyiliang@irm-cams.ac.cn; houwenbin@irm-cams.ac.cn
Supported by:
National Natural Science Foundation of China(82104012); National Natural Science Foundation of China(82202950); National Natural Science Foundation of China(82303681); Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2021-I2M-1-042); Fundamental Research Funds for the Central Universities(3332022063)

As more and more active ingredients are discovered, there is an increasing demand to explore the pharmacological mechanisms of these drugs and identify their effective targets. Chemical biology, as a newly developed interdisciplinary field in recent years, is the best choice to undertake this task. The identification method of unlabeled targets does not involve any chemical modification of small molecular drugs and has attracted wide attention in recent years. Most of the target identification methods based on interaction belong to the type of unlabeled deconvolution. Label-free protein analysis can also help predict potential drug targets or candidates, develop new biomarker assays and diagnostic reagents, and evaluate the selectivity and range of active compounds to reduce the risk of off-target effects. It can achieve these goals using techniques such as changing protein thermal stability, enzyme sensitivity, and molecular structure and using mass spectrometry. In this paper, we review the reported Label-free protein analysis techniques for identifying different types of targets. Based on different principles from three perspectives, hydrogen deuterium exchange mass spectrometry, surface plasmon resonance, microscale thermophoresis, fluorescence correlation spectroscopy, and other techniques are introduced, and the principles and scope of application of these techniques are introduced to readers through figures, texts, and tables. The combined use of various techniques can improve the success rate of target discovery, but this review still has the limitation of incomplete summary of the techniques. To give the reader an initial impression of Label-free protein analysis techniques that can provide valuable insights for drug target discovery. The target identification of active compounds can deepen our understanding of the mode of action of clinical drugs, help to discover new undruggable proteins, and provide the possibility for innovative treatments. With the development of mass spectrometry-based proteomics and computational biology, it can provide more help and possibility for us to explore the targets of active compounds. The popularization of these techniques can provide more options for researchers and facilitate the improvement of drug properties.

Key words: target identification, label-free, protein analysis, thermodynamic action, ligand binding, fluorescence reporting

Cite this article

Bohai Lyu, Wenfeng Gou, Feifei Xu, Yanli Li, Yiliang Li, Wenbin Hou. Label-free Protein Analysis Methods for Active Compound Targets Identification[J]. Acta Chimica Sinica, 2024, 82(6): 629-640.

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方法	化合物	靶点蛋白	参考文献
药物亲和力反应靶点稳定性(DARTS)	Bruceine D (BD)	Inhibitor of β-catenin/T-cell factor (ICAT)	[38]
DIA-DARTS	Azelastine	ADP ribosylation factor 1 (ARF1)	[39]
氧化速率蛋白稳定性(SPROX)	NAB5	RAB1A, member RAS oncogene family (RAB1A)	[40]
iTRAQ- SPROX SILAC-SPROX PAB-SPROX	Tamoxifen (TAM) N-desmethyl tamoxifen (NDT)	Y-box binding protein 1 (YBX1)	[41]
氢氘交换质谱(HDX-MS)	GSK2830371	Protein phosphatase, Mg²⁺/Mn²⁺ dependent 1D (PPM1D)	[42]
氢氘交换质谱(HDX-MS)	AZ1-4	Phosphatidylinositide 3-kinase γ (PI3Kγ)	[43]
表面等离子共振法(SPR)	GA-1	Protein disulfide isomerase family a member 3 (PDIA3)	[44]
表面等离子共振法(SPR)	Tanshinone I (tan i)	Enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2)	[45]
生物膜干涉技术(BLI)	LFS-1107	Chromosome region maintenance 1 (CRM1)	[46]
生物膜干涉技术(BLI)	AVG-233	RNA-dependent RNA polymerase RdRp (RdRP)	[47]
圆二色谱法(CD)	PGA-g-Chol	Human serum albumin (HAS)	[48]
圆二色谱法(CD)	Glycyrrhetinic acid (GA)	HRas proto-oncogene, GTPase (HRAS)	[49]
饱和转移差核磁共振分析(STD NMR)	NSC622608	V-domain Ig suppressor of T-cell activation (VISTA)	[50]
饱和转移差核磁共振分析(STD NMR)	Gold-1 a	Heat shock protein 60 (HSP60)	[51]

方法	化合物	靶点蛋白	参考文献
药物亲和力反应靶点稳定性(DARTS)	Bruceine D (BD)	Inhibitor of β-catenin/T-cell factor (ICAT)	[38]
DIA-DARTS	Azelastine	ADP ribosylation factor 1 (ARF1)	[39]
氧化速率蛋白稳定性(SPROX)	NAB5	RAB1A, member RAS oncogene family (RAB1A)	[40]
iTRAQ- SPROX SILAC-SPROX PAB-SPROX	Tamoxifen (TAM) N-desmethyl tamoxifen (NDT)	Y-box binding protein 1 (YBX1)	[41]
氢氘交换质谱(HDX-MS)	GSK2830371	Protein phosphatase, Mg²⁺/Mn²⁺ dependent 1D (PPM1D)	[42]
氢氘交换质谱(HDX-MS)	AZ1-4	Phosphatidylinositide 3-kinase γ (PI3Kγ)	[43]
表面等离子共振法(SPR)	GA-1	Protein disulfide isomerase family a member 3 (PDIA3)	[44]
表面等离子共振法(SPR)	Tanshinone I (tan i)	Enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2)	[45]
生物膜干涉技术(BLI)	LFS-1107	Chromosome region maintenance 1 (CRM1)	[46]
生物膜干涉技术(BLI)	AVG-233	RNA-dependent RNA polymerase RdRp (RdRP)	[47]
圆二色谱法(CD)	PGA-g-Chol	Human serum albumin (HAS)	[48]
圆二色谱法(CD)	Glycyrrhetinic acid (GA)	HRas proto-oncogene, GTPase (HRAS)	[49]
饱和转移差核磁共振分析(STD NMR)	NSC622608	V-domain Ig suppressor of T-cell activation (VISTA)	[50]
饱和转移差核磁共振分析(STD NMR)	Gold-1 a	Heat shock protein 60 (HSP60)	[51]

方法	化合物	靶点蛋白	参考文献
细胞热漂移测定(CETSA)	Elaiophylin	Src homology 2-containing protein tyrosine phosphatase 2 (SHP2)	[67]
细胞热漂移测定(CETSA)	MEHP	Hydroxyacyl-CoA dehydrogenase (HADH) Hydroxysteroid 17-beta dehydrogenase 10 (HSD17B10)	[68]
热蛋白质组分析(TPP)	Kurarinone	Soluble epoxide hydrolase (sEH)	[69]
热蛋白质组分析(TPP)	Napabucasin	Sirtuin 1 (SIRT1) Chromobox 5 (CBX5) Bardet-Biedl syndrome 7 (BBS7)	[70]
微量热泳动(MST)	4,4'-Diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS)	Voltage dependent anion channel 1 (VDAC1)	[71]
微量热泳动(MST)	Ruscogenin (Rus)	Myosin heavy-chain IIA (NMMHC IIA)	[72]
等温滴定量热法(ITC)	Naringia	14-3-3e	[73]
等温滴定量热法(ITC)	Lumefantrine	Fli-1 proto-oncogene, ETS transcription factor (FLI1)	[74]
微量差示扫描荧光法(NanoDSF)	F2050 F1787	Tetrameric lactate dehydrogenases (LDHs)	[75]
	Auranofin Tenatoprazole Omapatrilat	Glutathione peroxidase 1 (GPX1)	[76]
	VU0661013	Glutathione peroxidase 4 (GPX4)	[76]

方法	化合物	靶点蛋白	参考文献
细胞热漂移测定(CETSA)	Elaiophylin	Src homology 2-containing protein tyrosine phosphatase 2 (SHP2)	[67]
细胞热漂移测定(CETSA)	MEHP	Hydroxyacyl-CoA dehydrogenase (HADH) Hydroxysteroid 17-beta dehydrogenase 10 (HSD17B10)	[68]
热蛋白质组分析(TPP)	Kurarinone	Soluble epoxide hydrolase (sEH)	[69]
热蛋白质组分析(TPP)	Napabucasin	Sirtuin 1 (SIRT1) Chromobox 5 (CBX5) Bardet-Biedl syndrome 7 (BBS7)	[70]
微量热泳动(MST)	4,4'-Diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS)	Voltage dependent anion channel 1 (VDAC1)	[71]
微量热泳动(MST)	Ruscogenin (Rus)	Myosin heavy-chain IIA (NMMHC IIA)	[72]
等温滴定量热法(ITC)	Naringia	14-3-3e	[73]
等温滴定量热法(ITC)	Lumefantrine	Fli-1 proto-oncogene, ETS transcription factor (FLI1)	[74]
微量差示扫描荧光法(NanoDSF)	F2050 F1787	Tetrameric lactate dehydrogenases (LDHs)	[75]
	Auranofin Tenatoprazole Omapatrilat	Glutathione peroxidase 1 (GPX1)	[76]
	VU0661013	Glutathione peroxidase 4 (GPX4)	[76]

方法	化合物	靶点蛋白	参考文献
荧光关联光谱/荧光互相关光谱 (FCS/FCCS)	RGG sequence	G4s	[92]
荧光关联光谱/荧光互相关光谱 (FCS/FCCS)	c-myc mRNA probe	Coding region determinant-binding protein (CRD-BP)	[93]
荧光偏振技术(FP)	8-N-benzyladenosine compounds 1 and 2	Heat shock protein 72 (HSP72)	[94]
荧光偏振技术(FP)	N-Alkylcyclophellitol aziridines	Glucosylceramidase Beta 2 (GBA2)	[95]
基于相分离的蛋白质相互作用报告 (SPPIER)/蛋白水解酶活性报告的相分离(SPARK)	Isoprenaline H89	Protein kinase A (PKA) Forkhead-associated domain 1 (FHA1)	[96]
基于相分离的蛋白质相互作用报告 (SPPIER)/蛋白水解酶活性报告的相分离(SPARK)	Neocarzinostatin (NCS) SS-55933	FHA1	[97]
人类蛋白质微阵列 (human proteome microarrays)	Celastrol	Peroxiredoxin 2 (PRDX2)	[98]
人类蛋白质微阵列 (human proteome microarrays)	Icarin (ICA)	Peroxiredoxin 3 (PRDX3)	[99]

适用于活性化合物靶点鉴定的无标记蛋白质分析方法

Label-free Protein Analysis Methods for Active Compound Targets Identification

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