生物技术通报 ›› 2023, Vol. 39 ›› Issue (9): 12-26.doi: 10.13560/j.cnki.biotech.bull.1985.2023-0188
周璐祺1(), 崔婷茹2, 郝楠1, 赵雨薇1, 赵斌1(
), 刘颖超1(
)
收稿日期:
2023-03-03
出版日期:
2023-09-26
发布日期:
2023-10-24
通讯作者:
赵斌,男,博士,副教授,研究方向:新农药作用机理;E-mail: bdzhaobin@126.com;作者简介:
周璐祺,男,硕士研究生,研究方向:井冈霉素调控伏马毒素合成的分子作用机理;E-mail: luqizhou_hbnd@126.com
基金资助:
ZHOU Lu-qi1(), CUI Ting-ru2, HAO Nan1, ZHAO Yu-wei1, ZHAO Bin1(
), LIU Ying-chao1(
)
Received:
2023-03-03
Published:
2023-09-26
Online:
2023-10-24
摘要:
绿色新农药的开发和利用有利于农业的可持续发展,基于天然产物进行活性先导发现及作用机制研究是重要的新农药创制策略,然而其作用靶标和作用机制难以确定,阻碍了其在新农药中的应用。因此发现化合物新靶点对于新农药创制来说是一项既重要又艰巨的任务。化学蛋白质组学作为后基因组时代的新技术,目前已经成为研究药物靶点的重要手段之一。本文对基于化学蛋白组学的化合物作用分子靶点发现方法和典型案例进行探析,介绍这些技术的主要原理、应用以及各自的优点和局限性,旨在阐述基于化学蛋白质组学发现药物作用靶标的最新方法,并为天然产物靶点及新农药创制研究提供参考。
周璐祺, 崔婷茹, 郝楠, 赵雨薇, 赵斌, 刘颖超. 化学蛋白质组学在天然产物分子靶标鉴定中的应用[J]. 生物技术通报, 2023, 39(9): 12-26.
ZHOU Lu-qi, CUI Ting-ru, HAO Nan, ZHAO Yu-wei, ZHAO Bin, LIU Ying-chao. Application of Chemical Proteomics in Identifying the Molecular Targets of Natural Products[J]. Biotechnology Bulletin, 2023, 39(9): 12-26.
图2 基于亲和蛋白质组分析策略 A:与生物素偶联结合;B:基于生物正交反应基团(炔基)的探针;C:基于光亲和基团的生物探针
Fig. 2 Analysis strategies based on affinity proteomic A: Conjugated with biotin. B: Probes based on the bioorthogonal reactive groups(alkynyl). C: Biological probes based on photoaffinity groups
小分子化合物 Small molecule compound | 基于活性的探针结构 ABPs | 靶蛋白 Protein target |
---|---|---|
Thieno[2,3-d]pyrimidine derivatives[ | ![]() | Tubulin |
Ebselen[ | ![]() | β-lactoglobulin A |
Clavulanic acid[ | ![]() | Human serum albumin; Ig gamma-1 chain C region human; Haptoglobin human; Ig kappa chain C region human |
Dihydroartemisinin[ | ![]() | DNA methyltransferase 1 |
1,2,4-Oxadiazole derivatives[ | ![]() | Rpn6 |
Prazosin[ | ![]() | Flagellum Attachment Zone 1 |
表1 生物素探针用于小分子化合物的靶点鉴定实例
Table 1 Examples of biotin probes used for the target identification of small molecular compounds
小分子化合物 Small molecule compound | 基于活性的探针结构 ABPs | 靶蛋白 Protein target |
---|---|---|
Thieno[2,3-d]pyrimidine derivatives[ | ![]() | Tubulin |
Ebselen[ | ![]() | β-lactoglobulin A |
Clavulanic acid[ | ![]() | Human serum albumin; Ig gamma-1 chain C region human; Haptoglobin human; Ig kappa chain C region human |
Dihydroartemisinin[ | ![]() | DNA methyltransferase 1 |
1,2,4-Oxadiazole derivatives[ | ![]() | Rpn6 |
Prazosin[ | ![]() | Flagellum Attachment Zone 1 |
小分子化合物 Small molecule compound | 基于活性的探针结构 ABPs | 靶蛋白 Protein target |
---|---|---|
Catechol estrogens[ | ![]() | Cytochrome c; superoxide dismutase |
Calenduloside E[ | ![]() | Hsp90 |
Swertiamarin[ | ![]() | AKT-PH |
Salinipostin A[ | ![]() | Lysophospholipase; exported lipase 2; esterase; a/β hydrolase; BEM4 6-like protein |
Nitro-fatty acids[ | ![]() | Extended synaptotagmin 2; signal transducer and activator of transcription 3; toll-like receptor 2; retinoid X receptor alpha; glucocorticoid receptor |
Natural product: BE-43547A2[ | ![]() | Eukaryotic translation elongation factor 1 |
表2 生物正交化学反应用于小分子化合物的靶点鉴定实例
Table 2 Examples of bioorthogonal chemistry for target identification of small molecular compounds
小分子化合物 Small molecule compound | 基于活性的探针结构 ABPs | 靶蛋白 Protein target |
---|---|---|
Catechol estrogens[ | ![]() | Cytochrome c; superoxide dismutase |
Calenduloside E[ | ![]() | Hsp90 |
Swertiamarin[ | ![]() | AKT-PH |
Salinipostin A[ | ![]() | Lysophospholipase; exported lipase 2; esterase; a/β hydrolase; BEM4 6-like protein |
Nitro-fatty acids[ | ![]() | Extended synaptotagmin 2; signal transducer and activator of transcription 3; toll-like receptor 2; retinoid X receptor alpha; glucocorticoid receptor |
Natural product: BE-43547A2[ | ![]() | Eukaryotic translation elongation factor 1 |
小分子化合物Small molecule compound | 探针结构ABPs | 靶蛋白Protein target |
---|---|---|
Anticancer pyrroloquinazoline: LBL1[ | Nuclear lamins | |
Benzoxepane Derivatives[ | PKM2 | |
7-oxocallitrisic acid[ | Carnitine palmitoyltransferase 1A | |
MCC950[ | Carbonic Anhydrase 2 | |
Protopanaxadiol[ | Retinoblastoma Binding Protein 4 |
表3 光亲和探针用于小分子化合物的靶点鉴定实例
Table 3 Photoaffinity probe for the target identification of small molecular compounds
小分子化合物Small molecule compound | 探针结构ABPs | 靶蛋白Protein target |
---|---|---|
Anticancer pyrroloquinazoline: LBL1[ | Nuclear lamins | |
Benzoxepane Derivatives[ | PKM2 | |
7-oxocallitrisic acid[ | Carnitine palmitoyltransferase 1A | |
MCC950[ | Carbonic Anhydrase 2 | |
Protopanaxadiol[ | Retinoblastoma Binding Protein 4 |
图4 非标记法识别药物靶标蛋白策略 A:药物亲和反应的靶点稳定性;B:蛋白质热稳定性分析;C:热蛋白质组分析;D:氧化蛋白稳定性
Fig. 4 Schematics of label-free target identification methods A: Drug affinity responsive target stability(DARTS). B: Cellular thermal shift assay(CETSA). C: Thermal proteome profiling(TPP). D: Stability of proteins from rates of oxidation(SPROX)
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