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Article(id=1198628603614298210, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1198628599835227075, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2022-1265, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1669219200000, receivedDateStr=2022-11-24, revisedDate=1671724800000, revisedDateStr=2022-12-23, acceptedDate=null, acceptedDateStr=null, onlineDate=1763704928544, onlineDateStr=2025-11-21, pubDate=1686499200000, pubDateStr=2023-06-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1763704928544, onlineIssueDateStr=2025-11-21, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1763704928544, creator=13701087609, updateTime=1763704928544, updator=13701087609, issue=Issue{id=1198628599835227075, tenantId=1146029695717560320, journalId=1189982191388893191, year='2023', volume='58', issue='6', pageStart='0', pageEnd='1724', issueExtLink='null', onlineDate='null', pubDate='1686499200000', pubDateStr='2023-06-12', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1763704927643, creator='13701087609', updateTime=1766137690373, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1208832346359468483, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1198628599835227075, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1208832346359468484, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1198628599835227075, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=1557, endPage=1565, ext={EN=ArticleExt(id=1198628603979202675, articleId=1198628603614298210, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Research progress of active probes targeting specific aminoacids, columnId=1190335348648547107, journalTitle=Acta Pharmaceutica Sinica, columnName=Reviews, runingTitle=null, highlight=null, articleAbstract=

Activity-based protein (proteomic) profiling (ABPP) has emerged as a key component of the broad field of chemical techniques capable of directly analyzing enzyme activity in living systems. With the deepening of research on electrophilic warheads and nucleophilic amino acids, and the continuous proposal and improvement of effective development strategies, the application of amino acid-targeting active probes in various biological systems has facilitated the identification, development of new targets in various disease contexts and discovery of inhibitors. The purpose of this review is to summarize the latest progress in the design and application of active probes targeting specific amino acids, in order to provide support for the further development of amino acid-targeted covalent inhibitordrugs.

, authors=null, authorsList=Hui-lan LI, Zun-hua YANG, Yu-qi YING, Yuan-ying FANG, authorCompany=null, correspAuthors=Yuan-ying FANG, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2023 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, fund=null), CN=ArticleExt(id=1198628607103959325, articleId=1198628603614298210, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=靶向特定氨基酸的活性探针研究进展, columnId=1190335349655180086, journalTitle=药学学报, columnName=综述, runingTitle=null, highlight=null, articleAbstract=

基于活性的蛋白质(蛋白质组) 分析(ABPP) 因为能够直接分析生命系统中酶活性, 这个化学技术成为了这一广泛领域的关键组成部分。随着对亲电弹头和亲核氨基酸研究的不断深入, 靶向氨基酸的活性探针在各种生物系统中的应用促进了各种疾病背景下新靶点的识别和抑制剂的发现。本文旨在总结和归纳靶向特定氨基酸的活性探针的设计和应用的最新进展, 以期为进一步开发靶向特定氨基酸的共价抑制剂药物提供支持。

, authors=null, authorsList=李惠兰, 杨尊华, 应宇琦, 房元英, authorCompany=null, correspAuthors=房元英, authorNote=null, correspAuthorsNote=
*房元英, Tel: 86-791-87119652, E-mail:
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靶向特定氨基酸的活性探针研究进展
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李惠兰 1 , 杨尊华 2 , 应宇琦 2 , 房元英 1, *
药学学报 | 综述 2023,58(6): 1557-1565
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药学学报 |综述 2023 , 58 (6) : 1557 -1565
靶向特定氨基酸的活性探针研究进展
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李惠兰1, 杨尊华2, 应宇琦2, 房元英1, *
作者信息
  • 1.江西中医药大学中药固体制剂制造技术国家工程研究中心, 江西 南昌 330004
  • 2.江西中医药大学药学院, 江西 南昌 330004
通讯作者:
*房元英, Tel: 86-791-87119652, E-mail:
Research progress of active probes targeting specific aminoacids
Hui-lan LI1, Zun-hua YANG2, Yu-qi YING2, Yuan-ying FANG1, *
Affiliations
  • 1. National Engineering Research Center for Manufacturing Technology of TCM Solid Preparation, Jiangxi University of Chinese Medicine, Nanchang 330004, China
  • 2. College of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang 330004, China
出版时间: 2023-06-12 doi: 10.16438/j.0513-4870.2022-1265
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摘要
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基于活性的蛋白质(蛋白质组) 分析(ABPP) 因为能够直接分析生命系统中酶活性, 这个化学技术成为了这一广泛领域的关键组成部分。随着对亲电弹头和亲核氨基酸研究的不断深入, 靶向氨基酸的活性探针在各种生物系统中的应用促进了各种疾病背景下新靶点的识别和抑制剂的发现。本文旨在总结和归纳靶向特定氨基酸的活性探针的设计和应用的最新进展, 以期为进一步开发靶向特定氨基酸的共价抑制剂药物提供支持。

氨基酸  /  靶向  /  活性探针  /  活性蛋白质分析

Activity-based protein (proteomic) profiling (ABPP) has emerged as a key component of the broad field of chemical techniques capable of directly analyzing enzyme activity in living systems. With the deepening of research on electrophilic warheads and nucleophilic amino acids, and the continuous proposal and improvement of effective development strategies, the application of amino acid-targeting active probes in various biological systems has facilitated the identification, development of new targets in various disease contexts and discovery of inhibitors. The purpose of this review is to summarize the latest progress in the design and application of active probes targeting specific amino acids, in order to provide support for the further development of amino acid-targeted covalent inhibitordrugs.

amino acid  /  targeting  /  active probe  /  activity-based protein (proteomic) profiling
李惠兰, 杨尊华, 应宇琦, 房元英. 靶向特定氨基酸的活性探针研究进展. 药学学报, 2023 , 58 (6) : 1557 -1565 . DOI: 10.16438/j.0513-4870.2022-1265
Hui-lan LI, Zun-hua YANG, Yu-qi YING, Yuan-ying FANG. Research progress of active probes targeting specific aminoacids[J]. Acta Pharmaceutica Sinica, 2023 , 58 (6) : 1557 -1565 . DOI: 10.16438/j.0513-4870.2022-1265
正文
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随着以质谱(MS) 为基础的蛋白质组学的快速发展, 大规模的表征和定量研究取得了显著进展, 提供了包括蛋白质表达、空间分布、动态和相互作用等丰富的信息。虽然许多蛋白质已经被报道与各种疾病相关, 蛋白质翻译后修饰(PTMs) 包括糖基化、磷酸化和泛素化也受到广泛关注, 并且在系统范围内可有效地用于研究蛋白质的生物学功能。但开发针对这些蛋白质的药物仍然具有挑战性。因为大多数蛋白质缺乏明确的可以在功能上被小分子靶向的结合口袋, 所以被认为是不可成药的蛋白质。
针对具有重要临床意义的不可成药蛋白靶点的目标药物研究, 需要开发使用新技术和新方法。氨基酸序列和蛋白质折叠创造了一个特定的微环境, 并在决定蛋白质的功能活性方面起着关键作用。相同的氨基酸残基在不同的局部环境中可能具有不同的反应活性。因此, 对氨基酸残基反应性的大规模分析不但可以揭示蛋白质的生物功能, 还有助于发现可被共价配体靶向的蛋白质作为药物靶点以及发现治疗性调节剂。
近年来, 基于活性探针(activity-based profiling, ABP) 寻址的氨基酸种类和技术有了极大的发展。随着对亲电弹头和亲核氨基酸的研究不断深入以及有效开发策略不断的提出与改进, 靶向特定氨基酸探针在各种生物系统中的应用促进了各种疾病背景下新靶点的识别和抑制剂的发现, 且为下一代治疗药物的合理设计奠定了坚实的基础。此综述总结和归纳了靶向特定氨基酸ABPs的设计和应用的最新进展, 以期为进一步开发靶向特定氨基酸的药物提供支持。
1 半胱氨酸
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在编码蛋白质的氨基酸中, 半胱氨酸是最具有内在活性的氨基酸, 它的侧链含有一个可以去质子化的巯基。当巯基去质子化时, 硫原子上裸露的孤对电子具有极强的亲核反应性。除此之外, 半胱氨酸还具有较强的还原敏感性[1]。因此, 半胱氨酸可作为催化中的活性位点的亲核试剂, 或分解细胞氧化还原缓冲系统中的残基。其次, 半胱氨酸可以通过二硫键和金属配位稳定蛋白质结构。再者, 半胱氨酸通过翻译后修饰(例如氧化、亚硝化和谷胱甘肽化) 可调节蛋白质功能。半胱氨酸在蛋白质功能中发挥关键作用使其成为翻译后修饰和药物开发的理想靶点, 也成为了基于片段的药物发现的主要焦点[2]。为了全面评估活性半胱氨酸蛋白, 开发化学蛋白质组学探针来标记人类细胞中半胱氨酸残基是一个重要的目标。
卤代乙酰胺、马来酰亚胺和α, β-不饱和酮被证明对半胱氨酸残基中的硫醇基具有高度选择性。2010年, Weerapana等[3]以同位素标记的小分子亲电试剂定量反应谱为基础, 以亲电碘乙酰胺(IA) 探针(图 1a) 标记蛋白质中的半胱氨酸残基。炔基通过“点击化学”结合生物素基团, 使用链霉亲和素富集探针标记的蛋白质, 成功标记到蛋白质组中的1 082个半胱氨酸残基。此后, 更多的卤代乙酰胺类标记蛋白质中半胱氨酸残基的亲电探针被开发出来。碘乙酰胺的细胞毒性阻碍了活细胞上瞬时半胱氨酸修饰的有效标记。为此, 2015年, Abo等[4]开发了一种笼状溴甲基酮(BK) 亲电试剂(图 1b), 它显示出较低的细胞毒性, 并被用于监测A431细胞在表皮生长因子(EGF) 刺激释放细胞活性氧后的半胱氨酸反应性变化。通过此探针首次量化了EGF刺激后细胞内的二硫键形成。2017年, Abo等[5]对此探针进行了优化, 设计了CIK4探针(图 1c)。CIK4提供的更广泛的蛋白质组覆盖使其成为直接在活细胞内对半胱氨酸反应性变化和翻译后修饰等生物学研究的有用工具。2015年, Abegg等[6]发现炔基苯碘酰酮(图 1d) 形成的叠氮化物封端的炔基-半胱氨酸加合物很容易被LC-MS/MS检测到, 使用可进行点击反应的含有叠氮基的炔基苯碘酰酮可以通过铜催化叠氮炔环加成(CuAAC) 与四甲基罗丹明或生物素炔烃进一步功能化, 通过此探针研究发现姜黄素共价修饰了细胞信号传导和代谢的几个关键参与者, 最显著的是酪蛋白激酶Iγ。2016年, Cravatt课题组发现, 含氯乙酰胺和丙烯酰胺的亲电小分子可以选择性标记半胱氨酸[7]。2017年, Bateman等[8]通过筛选氯乙酰胺和丙烯酰胺的半胱氨酸反应性配体库, 发现半胱氨酸高反应性配体丙烯酰胺DKM 3-30靶向共价修饰网状蛋白4 (reticulon 4, RTN4) 上的C1101, 显著损害内质网和核包膜形态从而发挥抗结直肠癌的作用, 并将RTN4鉴定为一种新的结直肠癌治疗靶点, 挑战了经典的“不可成药性”蛋白, 使其变成“可成药性”(图 2)。2018年, Yu等[9]报道了用4-取代环戊烯酮(图 1e) 特异性修饰半胱氨酸特异性蛋白, 该反应具有动力学快、产物稳定的特点。更重要的是, 这种修饰可以通过与迈克尔加成体交换而无痕地去除。结合和再生过程不仅对蛋白质的结构或构象变化不大, 而且对其生物功能(如酶活性) 的干扰也不大。2021年, Kuljanin等[10]基于脱硫生物素的碘乙酰胺(desthiobiotin iodoacetamide, DBIA) 探针(图 1f), 重新设计了靶向半胱氨酸残基的基于活性蛋白质分析的工作流程, 提出了一种使用质谱分析反应性半胱氨酸位点(streamlined cysteine activity-based protein profiling, SLC-ABPP) 的优化分析, 与基于蛋白质水解活性的同位素串联正交蛋白图谱(isotopic tandem orthogonal proteolysis-activity-based protein profiling, isoTOP-ABPP) 相比, 大限度地减少筛选每个片段所需的仪器时间和样品输入, 并用以识别突变型克尔斯滕大鼠肉瘤和布鲁顿酪氨酸激酶的共价抑制剂的蛋白质组。
2 赖氨酸
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赖氨酸在蛋白质表面的天然丰度很高(占人类蛋白质所有位点的5.9%), 是蛋白质组中最普遍的氨基酸之一。约650 000个赖氨酸残基分布在约20 000种人类蛋白质中(相比之下半胱氨酸只有约260 000个), 参与二硫键形成[11]。
2014年, Shannon等[12]通过研究芳基卤化物与蛋白质组的反应性和选择性, 发现其对氨基酸选择性并不是一致的。研究发现通过修饰芳基环体系的空间和电子性质, 可以使其反应性符合所需的应用, 并发现二氯三嗪(图 3a) 优先与赖氨酸残基反应。2017年, Cravatt团队发展了苯磺酸钠基团作为特异性的赖氨酸修饰基团, 利用这个基团结合ABPP技术从人类细胞组中识别了超过9 000个赖氨酸残基[13]。初步开发和应用磺酰四氟苯基(sulfotetrafluorophenyl, STP) 探针(图 3b) 用于分析人类蛋白质组中反应性和配体赖氨酸, 确定了胺片段-赖氨酸相互作用, 并发现STP抑制几个致癌基因的酶活性, 表明以赖氨酸为靶标用于癌症药物的开发是一个可行的策略。2021年, Cravatt团队报告了超过30种未知的亲氨化学结构类型并对其深入分析, 极大地扩展了人类蛋白质中可配体赖氨酸的量[14]。研究发现氰甲基酰基磺酰胺化合物可作为细胞活性探针(图 3c), 通过靶向保守的赖氨酸残基来干扰IFIT家族先天免疫蛋白的RNA结合相互作用。2020年, Adusumalli等[15]报告了一种能够对天然蛋白质中的高频赖氨酸残基进行单点标记的方法。研究发现赖氨酸定向修饰使抗体-药物偶联物(antibody-drug conjugate, ADC) 曲妥珠单抗-伊美坦辛通过酰胺键连接在赖氨酸残基(K169和K395) 上, 并发现ADC对HER-2细胞的表达具有显著的抗增殖活性和选择性。这种方法的原理是使试剂与多种溶剂可及的赖氨酸残基化学选择性地形成稳定的亚胺, 以调节第二个赖氨酸选择性亲电体的位置连接间隔。因此能够对赖氨酸残基进行不可逆的单位点标记, 而与其在反应顺序中的位置无关。2022年, King等[16]利用CO2类似物异氰酸HNCO对天然的Lys-CO2位点具有选择性, 产生了类似于Lys-CO2的稳定电子等排加合物来表征位点功能, 开发了一种定量方法来识别蛋白质的CO2羧化赖氨酸残基, 使得CO2通过赖氨酸残基的胺基羧化调节蛋白质生物化学的分子控制机制得以阐明。
3 酪氨酸
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酪氨酸具有电离的芳香环侧链, 呈亲水性, 在人及动物体内由苯丙氨酸羟化而产生。
2015年, Hett等[17]首次描述了小分子共价探针合理靶向蛋白质结合位点中的酪氨酸残基。通过使用磺酰氟共价抑制剂(图 4a) 修饰了mRNA脱壳清除酶DcpS活性位点中的特定酪氨酸残基, 验证了DcpS作为人原代细胞中二氨基喹唑啉运动神经元存活基因调节剂的真正靶点, 并说明了化学蛋白质组学对转化药理学研究的价值。2016年, Chen等[18]报道了结构简单的芳基氟代硫酸盐(图 4b) 与一些细胞内脂质结合蛋白(intracellular lipid binding protein, iLBP) 有效地反应, 能够催化硫-氟化物交换(sulfur fluoride exchange, SuFEx) 与结合位点的酪氨酸残基反应。iLBP将疏水性小分子传递给核激素受体, 激活它们的转录因子功能。研究发现, 芳基氟磺酸盐的蛋白质反应性低于相应的芳基磺酰氟化合物, 是较好的蛋白质组反应性表征。2018年, Mortenson等[19]通过研究“逆向药物发现”策略作为一种探索潜在亲电试剂的方法, 用于探索潜在或“激活”反应性的官能团, 和/或其反应性尚未在细胞环境中被探索的官能团。以芳基氟代硫酸酯(图 4c) 为例, 验证了芳基磺酰氟与芳基氟代硫酸盐靶向酪氨酸残基反应, 为实现高选择性蛋白质偶联形成所需的蛋白质结构特征提供了方法。2020年, Hahm等[20]发现SuFEx的反应性主要是通过在共价反应过程中稳定蛋白质位点的氟离去基团(leaving group, LG) 来驱动。对氟的依赖虽然是激活SuFEx化学的关键, 但LG的修饰可以修改整个蛋白质组中蛋白质位点的反应性、特异性和结合亲和力。基于以往研究三氮唑可激活尿素进行共价蛋白修饰具有可调节性的显著优势。相比之下, 氟原子作为LG是不可能实现这一点。他们用硫-三唑交换(sulfur-triazole exchange, SuTEx) 化学方法开发含酚共价探针的方法, 通过对三氮唑离去基进行修饰, 使探针对酪氨酸的化学选择性比其他亲核氨基酸提高了5倍(图 4d), 并首次对裂解物和活细胞中的10 000多个酪氨酸位点进行了研究。通过使用一系列探针在癌细胞蛋白质组中描绘酪氨酸反应性和磷酸化, 并发现和确定了几个有吸引力的位点酪氨酸定向配体。2021年, Huang等[21]合成了一系列5-羟色胺受体拮抗剂利坦色林的疏水片段功能化SuTEx探针(图 4e), 用于发现活细胞中蛋白质和代谢激酶的催化和调节域中存在的可配体酪氨酸。研究发现人蛋白激酶(protein kinase C-a, PKC-a) C2结构域修饰对PKC-a水平和功能非常重要。
4 蛋氨酸
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蛋氨酸是两种天然存在的含硫氨基酸和最具疏水性的氨基酸之一, 很容易被活性氧、活性氯或氧化酶氧化。一旦蛋氨酸被氧化, 疏水性蛋氨酸就会转化为高度亲水性的甲硫氨酸亚砜[22]。甲硫氨酸亚砜对蛋白质内的相邻芳香族残基具有很强的结合亲和力。然而, 蛋氨酸氧化反应可能改变目标蛋白的功能, 且在生命系统中在甲硫氨酸亚砜还原酶的存在下是可逆的。通过敲除蛋氨酸亚砜还原酶可破坏蛋氨酸的氧化反应, 可导致蛋氨酸亚砜在细胞中积累[23]。蛋氨酸侧链具有弱亲核性, 在其他具有更强亲核性的氨基酸存在的情况下, 很难找到合适的蛋氨酸特异性亲电体伙伴。生物偶联为破解蛋氨酸的生物学功能提供了一种新策略。最近开发的以残基选择性方式进行蛋氨酸生物偶联的试剂, 包括烷基试剂、噁氮丙啶试剂和高价碘试剂。
蛋氨酸在中性pH下是一种弱亲核试剂, 然而在酸性条件下是一种强亲核试剂。蛋氨酸是唯一可以在酸性条件下烷基化的蛋白质氨基酸, 产生相对稳定的甲硫氨酸锍盐。Kramer等[24]发现卤代烷和三氟甲磺酸烷基酯是甲酸水溶液中选择性和高效的蛋氨酸生物偶联的良好试剂。此外, 烯烃、炔烃、叠氮化物、硼酸和糖等多种官能团可以通过烷基化以优异的收率引入, 以进一步扩大其应用范围。他们通过进一步研究发现甲硫氨酸锍盐可以被脱烷基化试剂(例如硫脲) 裂解, 从而获得可逆的化学选择性功能化的含蛋氨酸肽[25]。然而, 酸碱偶联策略需要酸性环境, 在该环境中大多数蛋白质会失活或聚集。此外, 当修饰位置与亲核氨基酸相邻时, 甲硫氨酸锍盐的缓慢反应速率和稳定性存在相当大的问题。
2017年, Lin等[26]使用氧化还原活化化学标记(redoxactivated chemical tagging, ReACT) 策略, 对蛋白质进行化学选择性蛋氨酸生物偶联, 并从多种硫酰亚胺化试剂中发现噁氮丙啶化合物(图 5a) 是理想的在生物相容性条件下可用于蛋氨酸生物偶联的试剂。ReACT的一个关键问题是所需的氮转移反应产物(N-transfer product, NTP) 甲硫氨酸硫亚胺和不需要的副产物(O-transfer product, OTP) 甲硫氨酸亚砜之间的选择性。在调整了噁氮丙啶试剂的电子效应和空间效应后, 例如将探针的连接从氨基甲酸酯改变为弱吸电子基团的尿素, 增加溶剂介质中水的百分比, 蛋氨酸可以有效地转化和化学选择性标记蛋氨酸硫亚胺, 实现高选择性(NTP∶OTP = 25∶1)、快速(10 min) 和稳健的蛋氨酸标记。2019年, Christian等[27]应用了物理有机方法, 发现二乙基、哌啶和吡咯烷衍生的噁氮丙啶试剂(图 5b) 可产生更稳定的蛋氨酸硫亚胺产物。增加尿素部分的电子密度可以增加改性蛋氨酸的稳定性。双-甲硫氨酸肽可以被双-噁氮丙啶化合物有效地大环化(高达94%的产率)。噁氮丙啶试剂对蛋白质上的甲硫氨酸具有更好的反应性和化学选择性。2018年, Taylor等[28]通过利用定制的高价碘试剂λ-3-碘烷(λ-3-iodanes) (图 5c) 的亲电反应性, 可以靶向甲硫氨酸侧链中的S-Me基团。通过调整碘(Ⅲ) 原子上的取代基和反离子, 可以调整可极化的I (Ⅲ) 节点中心的反应性, 使其与硫醚的孤对电子相吻合, 并通过调节直接附在阳离子硫基序上的基团的电子特征, 从而调节由此产生的硫共轭物的稳定性。生物偶联反应快速、选择性、在低微摩尔浓度下进行, 是对现有生物偶联策略的补充。
5 天冬氨酸、谷氨酸
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在抗生素领域, 迫切需要确定共价抑制剂的新结合位点, 以有效治疗多重耐药性细菌感染。细菌蛋白质中许多重要的结合口袋缺乏合适的半胱氨酸残基。因此, 靶向其他氨基酸残基的共价抑制剂对于抗生素开发非常的重要。天冬氨酸和谷氨酸在细菌蛋白质组中约占所有残基的12%, 它们最初的亲核特性可以通过合适的活化剂转化为亲电反应性, 可用于抗生素领域的共价抑制剂的新结合位点研究。
2017年, Martín-Gago等[29]研究发现伍德沃德试剂K (Woodward′s reagant K, WRK) 衍生的探针(图 6a) 选择性地靶向结合口袋中的谷氨酸。异噁唑鎓盐通过碱介导的开环形成酮亚胺。酮亚胺亲电子试剂与羧酸反应生成烯酰胺, 可重排为更稳定的烯醇酯, 共价加合物的形成通过烯醇酯的快速形成而发生, 并且即使在强亲核试剂存在下共价键也是稳定的(图 7)。分子对接显示, 将WRK中的苯环替换为由两个或四个亚甲基单元连接的N-甲基异噁唑环可与Glu88共价结合, 结构更加稳定, 标记效率为95%。2020年, Bach和同事[30]开发了一系列可光激活的2, 5-双取代四唑(图 6b), 用于天冬氨酸和谷氨酸的位点特异性标记。其原理是光反应探针在紫外线(ultraviolet rays, UV) 光照射下形成高度反应的自由基, 自由基驱动探针和可逆结合蛋白之间形成共价键[31]。2, 5-双取代四唑光活化后, 通过释放氮产生腈亚胺高反应性中间体, 形成非常稳定的1, 2-二酰基-1芳基肼与羧酸反应, 化学蛋白质组学分析发现其对裂解物中的天冬氨酸和谷氨酸残基具有很高的特异性和高覆盖率。通过将此探针应用于细菌致病菌金葡菌进行羧酸定向配体的竞争性筛选, 强调了肼酰氯是羧酸共价抑制剂的有前途的亲电试剂。
6 组氨酸
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组氨酸残基具有缺电子的芳基咪唑侧链, 在蛋白质中的丰度较低, 约为2.2%。咪唑侧链是一种良好的金属配体, 可以与金属定向共价标记或直接非共价金属-组氨酸络合实现蛋白质修饰。组氨酸既能作为良好的亲核试剂又能作为离去基团, 使其亲电性基团与咪唑侧链形成稳定的化学键变得困难。组氨酸亲核反应需要在高温或强酸碱或亲和定向配体等苛刻的反应条件。因此, 组氨酸的选择性和直接共价标记是一个挑战。
在天然组氨酸磷酸化过程中, 磷酰化钾可选择性地磷酸化组氨酸, 并且硫磷酰氯和硫磷酰化钾可生成硫磷组氨酸类似物并提高其水溶液稳定性。受此启发, 2019年, Jia等[32]发现硫代磷氯化物和硫代磷酸炔烃二氯化物(thiophosphoro alkyne dichloridate, TPAC) (图 8a) 可作为蛋白质组氨酸选择性共价修饰的试剂。通过LC-MS/MS检测表明反应主要发生在表面暴露的组氨酸H48上, 而不是催化中心的组氨酸(H12和H119)。2021年, Nakane等[33]利用亲核小分子(1-甲基-4-芳基脲唑) (图 8b) 在白光LED光下用钌催化剂产生的单线态氧(1O2) 选择性标记组氨酸。2022年, Wan等[34]通过亲电的锍中间体(图 8c), 通过可见光驱动硫缩醛活化反应能够轻松修饰组氨酸残基。首次发现78种含组氨酸的蛋白质具有显著的富集, 大多数在脑相关疾病中通过金属积累发挥作用。
7 其他
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2009年, Antos等[35]报道色氨酸的靶向修饰可用铑卡宾进行化学选择性标记, 但转化率和化学选择性较其他的氨基酸差。2022年, Chen等[36]首次使用光交联剂对色氨酸进行标记, 以色氨酸特异性Ru-TAP复合物作为光交联剂, 亲和结合使探针的Ru-TAP复合物靠近PKA活性位点并与Trp196结合, 具有细胞相容性和高选择性。
精氨酸在底物特异性决定因素和蛋白质-蛋白质和蛋白质-DNA相互作用中起着关键作用。精氨酸修饰包括甲基化、磷酸化、ADPa-核糖基化和瓜氨酸化。蛋白质精氨酸脱氨基酶(protein arginine deiminases, PAD) 水解精氨酸的侧链, 形成瓜氨酸[37]。在瓜氨酸化过程中, 带正电荷的胍被水解为中性尿素, 改变了残留物的电荷和H键电位。瓜氨酸化引起的质量变化很小(+0.98 Da), 使其难以与邻近的天冬酰胺和谷氨酰胺的去酰胺化区分。2019年Mondal等[38]基于苯乙二醛(phenylglyoxal, PG) 在强酸性pH下与瓜氨酸的尿素基具有选择性凝结的能力, 将罗丹明和生物素分别附着在PG上, 开发了瓜氨酸特异性探针罗丹明-PG (Rh-PG) 和生物素-PG。这些探针选择性地修饰含有瓜氨酸的肽和蛋白质, 在皮摩尔范围内具有显著的敏感性。
8 总结与展望
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本文概述分析了复杂蛋白质组中靶向特定氨基酸的活性探针的设计和应用。以活性探针为基础的ABPP为蛋白的分析和药物的开发提供了新的手段和方法。共价抑制作为一种治疗策略具有较长的停留时间和作用持续时间, 可以靶向对非共价配体不敏感的浅结合袋、规避耐药机制和选择性靶向疾病相关突变体。然而, 其不可逆地抑制导致毒性脱靶, 难以对可逆的、非共价结合的目标分析, 以及具有潜在的与免疫相关的异质药物不良反应, 限制了其在化学可达目标的应用[39, 40]。光笼策略可提高探针的靶向性, 减少脱靶的发生, 降低细胞毒性。但其依赖于已验证的保护基团, 目前其只限于分析半胱氨酸的反应性, 且存在探针蛋白结合亲和力和有效细胞分布降低的影响。光激活探针是通过在紫外线的照射下形成高度反应的自由基驱动探针和可逆结合蛋白之间形成共价键, 是ABPs技术的最新进展。光反应探针还可用于研究蛋白质目标的立体选择性, 以及如何使用它来帮助确定目标的优先级, 以解决ABPP确定的潜在目标的优先次序。当目标富集与多个对映体探针相结合时, 立体特异性相互作用只与一对探针相结合。所鉴定的蛋白质靶点可跨越广泛的功能和结构类别。
总之, 化学蛋白质组学在药学领域的应用正在凸现, 其在靶点鉴别、新药开发中的潜力还需要进一步挖掘。随着研究的深入, 更多的高价值不可成药靶标的靶向配体将逐步被发现。新的化学探针, 创新的蛋白质组学方法和质谱技术的改进将有助于进一步建立化学蛋白质组学作为生命科学的基本和不可或缺的工具。
作者贡献: 文献调查和整理由李惠兰、应宇琦完成, 文稿的撰写由李惠兰完成, 整个研究、稿件修改等工作由房元英、杨尊华完成。
利益冲突: 所有作者均无相关利益冲突。
基金
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  • 国家自然科学基金资助项目(82160663)
  • 江西省教育厅科技项目(GJJ201211)
  • 江西省自然科学基金资助项目(20212BAB206015)
  • 江西省自然科学基金资助项目(20212BAB206016)
  • 江西中医药大学校级科技创新团队发展计划项目(CXTD22001)
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2023年第58卷第6期
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doi: 10.16438/j.0513-4870.2022-1265
  • 接收时间：2022-11-24
  • 首发时间：2025-11-21
  • 出版时间：2023-06-12
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  • 收稿日期：2022-11-24
  • 修回日期：2022-12-23
基金
国家自然科学基金资助项目(82160663)
江西省教育厅科技项目(GJJ201211)
江西省自然科学基金资助项目(20212BAB206015)
江西省自然科学基金资助项目(20212BAB206016)
江西中医药大学校级科技创新团队发展计划项目(CXTD22001)
作者信息
    1.江西中医药大学中药固体制剂制造技术国家工程研究中心, 江西 南昌 330004
    2.江西中医药大学药学院, 江西 南昌 330004

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*房元英, Tel: 86-791-87119652, E-mail:
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2种不同金属材料的力学参数
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Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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