摘要
原创药物的研制得益于蛋白质新靶标的发现,而新靶标的发现依赖于高可信度、高通量的药物-蛋白质相互作用分析方法。蛋白质作为生命功能的执行者,其表达量、空间定位与结构差异直接影响药效的发挥。目前,超过85%的蛋白质尚被认为是无法成药的,主要原因是缺少药物分子靶向的空腔以及相应的反应活性位点。因此,基于蛋白质组学层次实现对氨基酸反应活性位点的表征成为原创共价靶向药物设计的关键,也是克服难以成药靶标蛋白问题的关键。近年来,质谱技术的飞速发展极大地推动了基于蛋白质组学技术的药物-靶蛋白相互作用研究。其中基于活性的蛋白质组分析(ABPP)策略是利用活性位点导向的化学探针分子在复杂样品中实现功能状态酶和药物靶标等蛋白质的检测。基于化学探针的开发和质谱定量技术的发展,ABPP技术在氨基酸反应活性表征研究中展现出重要的应用潜力,将助力于药物新靶标的发现和药物先导化合物的开发。ABPP策略主要基于蛋白质的活性特征进行富集,活性探针作为ABPP策略的核心,近年来取得了飞速进展。该文回顾了ABPP策略的发展历程,重点介绍基于广谱活性探针的ABPP技术在多种氨基酸反应活性筛选领域的研究进展,并对其在药物靶点发现中的应用前景进行展望。
The discovery of novel drug targets enhances the development of novel drugs, and the discovery of novel target proteins depends on highly accurate high-throughput methods of analyzing drug-protein interactions. Protein expression levels, spatial localization, and structural differences directly affect pharmacodynamics. To date, >20 000 proteins have been discovered in the human proteome by the genome and proteome projects via gene and protein sequencing. Understanding the biological functions of proteins is critical in identifying and regulating biological processes, with most remaining unidentified. Until recently, >85% of proteins were considered undruggable, mainly because of the lack of binding pockets and active sites targeted by small molecules. Therefore, characterization of the reactive sites of amino acids based on proteomic hierarchy is the key to novel drug design. Recently, with the rapid development of mass spectrometry(MS), the study of drug-target protein interactions based on proteomics technology has been considerably promoted. Activity-based protein profiling(ABPP) is an active chemical probe-based method of detecting functional enzymes and drug targets in complex samples. Compared with classical proteomics strategies, ABPP is based mainly on protein activity. It has been successfully utilized to characterize the activities of numerous protease families with crucial biological functions, such as serine hydrolases, protein kinases, glycosidases, and metalloenzymes. It has also been used to identify key enzymes that are closely related to diseases and develop covalent inhibitors for use in disease treatment. The technology used in proteome analysis ranges from gel electrophoresis to high-throughput MS due to the progress of MS technology. ABPP strategies combined with chemical probe labeling and quantitative MS enable the characterization of amino acid activity, which may enhance the discovery of novel drug targets and the development of lead compounds. Amino acid residues play critical roles in p
作者
李佳颖
王国胜
叶明亮
秦洪强
LI Jiaying;WANG Guosheng;YE Mingliang;QIN Hongqiang(College of Chemical Engineering,Shenyang University of Chemical Technology,Shenyang 110142,China;CAS Key Laboratory of Separation Science for Analytical Chemistry,Dalian Institute of Chemical Physics,Chinese Academy of Sciences,Dalian 116023,China)
出处
《色谱》
CAS
CSCD
北大核心
2023年第1期14-23,共10页
Chinese Journal of Chromatography
基金
国家重点研发计划项目(2021YFA1302602,2020YFE0202200)
国家自然科学基金项目(21775146,22034007)
中国科学院大连化学物理研究所创新基金(DICP I201919)。
