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Article(id=1199783104631108324, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1199783099115598386, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2024-0418, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1714406400000, receivedDateStr=2024-04-30, revisedDate=1723651200000, revisedDateStr=2024-08-15, acceptedDate=null, acceptedDateStr=null, onlineDate=1763980183035, onlineDateStr=2025-11-24, pubDate=1731340800000, pubDateStr=2024-11-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1763980183035, onlineIssueDateStr=2025-11-24, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1763980183035, creator=13701087609, updateTime=1763980183035, updator=13701087609, issue=Issue{id=1199783099115598386, tenantId=1146029695717560320, journalId=1189982191388893191, year='2024', volume='59', issue='11', pageStart='2897', pageEnd='3178', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1763980181720, creator=13701087609, updateTime=1764225007568, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1200809973203726680, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1199783099115598386, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1200809973203726681, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1199783099115598386, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=2953, endPage=2961, ext={EN=ArticleExt(id=1199783104937292535, articleId=1199783104631108324, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Chemically mediated 14-3-3 protein post-translational modification interference: design of molecular glue and the application in cancer treatment, columnId=null, journalTitle=Acta Pharmaceutica Sinica, columnName=null, runingTitle=null, highlight=null, articleAbstract=

Protein-protein interactions (PPIs) are not only crucial for the assembly of protein complexes but also fundamental for maintaining normal biological functions. These interactions are vital for protein structure and biological functionality and play a central role in cellular signaling, metabolic pathways, and regulatory networks. The 14-3-3 protein, highly conserved and widely expressed in eukaryotes, primarily recognizes and binds to its partner proteins to participate in essential life processes such as cell cycle control, signal transduction, and energy metabolism. This review discusses the role of dysregulated PPIs between 14-3-3 proteins and their partner proteins such as estrogen receptor α (estrogen receptor α, ERα), RAF proto-oncogene serine/threonine-protein kinase (C-RAF/RAF-1), and p53 in the onset and progression of tumors, focusing on the research progress of 14-3-3/ERα, 14-3-3/C-RAF, and 14-3-3/p53 molecular glues. These molecular glues, by mimicking or enhancing the phosphorylation sites of serine on partner proteins, form covalent bonds, salt bridges, and hydrogen bonds with 14-3-3 proteins, thereby enhancing the stability of PPIs and effectively intervening in protein activity and signaling under pathological conditions. Additionally, this article explores the potential of this chemical intervention strategy in clinically suppressing tumor progression, providing a theoretical foundation and practical guidance for future research directions.

, correspAuthors=Jin-lei BIAN, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2024 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, authorCompany=null, fund=null, authors=null, authorsList=Liu-yi WU, Long-jing LI, Yu-cheng TIAN, Qian-qian XU, Wei WEI, Zhi-yu LI, Jin-lei BIAN), CN=ArticleExt(id=1199783107453875046, articleId=1199783104631108324, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=化学介导的14-3-3蛋白翻译后修饰干预: 分子胶设计及其在肿瘤治疗中的应用, columnId=1199783099958653494, journalTitle=药学学报, columnName=专题报道: 蛋白成熟与翻译后修饰的化学干预, runingTitle=null, highlight=null, articleAbstract=

蛋白-蛋白相互作用(protein-protein interactions, PPIs) 不仅是构建蛋白质复合体的关键途径, 也是维护正常生物功能的基础。这些相互作用对于蛋白质结构及其生物学功能至关重要, 并在细胞的信号传导、代谢途径和调控网络中扮演核心角色。14-3-3蛋白是一种在真核生物中广泛表达的高度保守的功能性蛋白, 主要通过识别并结合其伴侣蛋白参与细胞周期控制、信号转导和能量代谢等关键生命过程。本文综述了14-3-3蛋白与其伴侣蛋白如雌激素受体α (estrogen receptor α, ERα)、RAF原癌基因丝氨酸/苏氨酸蛋白激酶(RAF proto-oncogene serine/threonine-protein kinase, C-RAF/RAF-1) 和p53的PPIs失调在肿瘤的发生和发展中的角色, 并集中讨论了14-3-3/ERα、14-3-3/C-RAF和14-3-3/p53分子胶的研究进展。这些分子胶通过模拟或增强伴侣蛋白的磷酸化丝氨酸位点, 形成与14-3-3蛋白的共价键、盐桥和氢键, 从而提高了PPIs的稳定性, 并有效地干预了病理状态下的蛋白活性与信号传递。此外, 本文还探讨了这种化学干预策略在临床上抑制肿瘤发展的潜力, 为未来的研究方向提供了理论基础和实践指南。

, correspAuthors=卞金磊, authorNote=null, correspAuthorsNote=
*卞金磊, E-mail:
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化学介导的14-3-3蛋白翻译后修饰干预: 分子胶设计及其在肿瘤治疗中的应用
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吴柳燚 , 李龙静 , 田于成 , 徐倩倩 , 韦伟 , 李志裕 , 卞金磊 *
药学学报 | 专题报道: 蛋白成熟与翻译后修饰的化学干预 2024,59(11): 2953-2961
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药学学报 | 专题报道: 蛋白成熟与翻译后修饰的化学干预 2024, 59(11): 2953-2961
化学介导的14-3-3蛋白翻译后修饰干预: 分子胶设计及其在肿瘤治疗中的应用
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吴柳燚, 李龙静, 田于成, 徐倩倩, 韦伟, 李志裕, 卞金磊*
作者信息
  • 中国药科大学药学院, 江苏 南京 211112

通讯作者:

*卞金磊, E-mail:
Chemically mediated 14-3-3 protein post-translational modification interference: design of molecular glue and the application in cancer treatment
Liu-yi WU, Long-jing LI, Yu-cheng TIAN, Qian-qian XU, Wei WEI, Zhi-yu LI, Jin-lei BIAN*
Affiliations
  • School of Pharmacy, China Pharmaceutical University, Nanjing 211112, China
出版时间: 2024-11-12 doi: 10.16438/j.0513-4870.2024-0418
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摘要
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蛋白-蛋白相互作用(protein-protein interactions, PPIs) 不仅是构建蛋白质复合体的关键途径, 也是维护正常生物功能的基础。这些相互作用对于蛋白质结构及其生物学功能至关重要, 并在细胞的信号传导、代谢途径和调控网络中扮演核心角色。14-3-3蛋白是一种在真核生物中广泛表达的高度保守的功能性蛋白, 主要通过识别并结合其伴侣蛋白参与细胞周期控制、信号转导和能量代谢等关键生命过程。本文综述了14-3-3蛋白与其伴侣蛋白如雌激素受体α (estrogen receptor α, ERα)、RAF原癌基因丝氨酸/苏氨酸蛋白激酶(RAF proto-oncogene serine/threonine-protein kinase, C-RAF/RAF-1) 和p53的PPIs失调在肿瘤的发生和发展中的角色, 并集中讨论了14-3-3/ERα、14-3-3/C-RAF和14-3-3/p53分子胶的研究进展。这些分子胶通过模拟或增强伴侣蛋白的磷酸化丝氨酸位点, 形成与14-3-3蛋白的共价键、盐桥和氢键, 从而提高了PPIs的稳定性, 并有效地干预了病理状态下的蛋白活性与信号传递。此外, 本文还探讨了这种化学干预策略在临床上抑制肿瘤发展的潜力, 为未来的研究方向提供了理论基础和实践指南。

14-3-3分子胶  /  蛋白-蛋白相互作用  /  RAF原癌基因丝氨酸/苏氨酸蛋白激酶  /  雌激素受体α  /  p53

Protein-protein interactions (PPIs) are not only crucial for the assembly of protein complexes but also fundamental for maintaining normal biological functions. These interactions are vital for protein structure and biological functionality and play a central role in cellular signaling, metabolic pathways, and regulatory networks. The 14-3-3 protein, highly conserved and widely expressed in eukaryotes, primarily recognizes and binds to its partner proteins to participate in essential life processes such as cell cycle control, signal transduction, and energy metabolism. This review discusses the role of dysregulated PPIs between 14-3-3 proteins and their partner proteins such as estrogen receptor α (estrogen receptor α, ERα), RAF proto-oncogene serine/threonine-protein kinase (C-RAF/RAF-1), and p53 in the onset and progression of tumors, focusing on the research progress of 14-3-3/ERα, 14-3-3/C-RAF, and 14-3-3/p53 molecular glues. These molecular glues, by mimicking or enhancing the phosphorylation sites of serine on partner proteins, form covalent bonds, salt bridges, and hydrogen bonds with 14-3-3 proteins, thereby enhancing the stability of PPIs and effectively intervening in protein activity and signaling under pathological conditions. Additionally, this article explores the potential of this chemical intervention strategy in clinically suppressing tumor progression, providing a theoretical foundation and practical guidance for future research directions.

14-3-3 molecular glue  /  protein-protein interaction  /  RAF proto-oncogene serine/threonine-protein kinase  /  estrogen receptor α  /  p53
吴柳燚, 李龙静, 田于成, 徐倩倩, 韦伟, 李志裕, 卞金磊. 化学介导的14-3-3蛋白翻译后修饰干预: 分子胶设计及其在肿瘤治疗中的应用. 药学学报, 2024 , 59 (11) : 2953 -2961 . DOI: 10.16438/j.0513-4870.2024-0418
Liu-yi WU, Long-jing LI, Yu-cheng TIAN, Qian-qian XU, Wei WEI, Zhi-yu LI, Jin-lei BIAN. Chemically mediated 14-3-3 protein post-translational modification interference: design of molecular glue and the application in cancer treatment[J]. Acta Pharmaceutica Sinica, 2024 , 59 (11) : 2953 -2961 . DOI: 10.16438/j.0513-4870.2024-0418
正文
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蛋白-蛋白相互作用(protein-protein interactions, PPIs) 构成了细胞生命活动的基础, 涵盖细胞信号转导、结构组装等关键生理过程。14-3-3蛋白能识别近千种结构各异的伴侣蛋白, 作为信号网络的关键调节中枢, 其功能的任何异常变化均可能触发多种疾病。长期以来, 科研人员主要集中于开发针对功能性蛋白的抑制剂, 但由于人体内大约85%~90%的蛋白质靶点难以药用或不可药用, 传统的分子干预策略往往难以达到预期效果。分子胶可作用于两种蛋白质的结合界面, 增强两者之间蛋白-蛋白相互作用, 进而调节相关生物学功能。根据分子的作用机制, 可以将其分为降解型分子胶和非降解型分子胶两类。目前, 以沙利度胺为代表的降解型分子胶研发相对较快, 该类分子可以诱导或稳定泛素连接酶和靶蛋白(底物) 之间的PPIs, 促进靶蛋白参与蛋白酶体系统, 发生泛素依赖性降解。非降解型分子胶则通过结合靶蛋白与伴侣蛋白, 形成三元复合物, 调控靶蛋白及其下游蛋白的生物活性。特别是对于无序蛋白, 由于其本身构象的不稳定性, 其活性状态的维持往往依赖于其他蛋白或底物复合物的互作; 这种依赖关系, 加之卡位效应的存在, 使得与其他底物的PPIs被阻断, 从而为开发具有高选择性的分子胶提供了理想的机制基础。作为一种创新的治疗策略, 针对14-3-3蛋白的分子胶研发虽仍处于初期阶段且尚未经过临床验证, 但其潜在的有效性和特异性是值得进一步探索的。本文重点综述了与肿瘤治疗相关的14-3-3/ERα、14-3-3/C-RAF和14-3-3/p53分子胶的研究进展, 旨在推动14-3-3分子胶在肿瘤治疗领域的应用前景。
1 14-3-3蛋白与癌症
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1967年, Moore等[1]发现了广泛存在于脑组织中的酸性蛋白14-3-3, 其名字是依据层析编号及电泳移动位置进行定义, 因其能够调节酪氨酸与色氨酸羟化酶活性, 又被称为YWHA。随着研究的深入, 学者发现14-3-3蛋白在真核生物的各个组织中普遍表达, 其中细胞质的14-3-3蛋白含量最为丰富。目前在人类体内共发现了7种14-3-3亚型蛋白β、γ、ε、η、σ、τ和ζ[2], 各亚型的蛋白高度保守, 同源性高达44%[3]。因此大部分伴侣蛋白(如Raf-1、BAD和Cbl), 会表现出与各亚型14-3-3蛋白相近的亲和力, 这种相似性为其他亚型蛋白补偿一种亚型蛋白损失提供可能[4]。但由于亚细胞定位和组织表达量的差异, 14-3-3的各亚型蛋白依旧存在功能的特异性, 且与人类疾病密切相关。14-3-3σ主要在上皮细胞中特异性表达, 14-3-3σ亚型蛋白的功能障碍与许多上皮组织肿瘤(如卵巢上皮癌) 的发生有关[5]。此外, 受到各亚型蛋白的序列差异影响, 依旧有部分伴侣蛋白表现出对某个单一亚型14-3-3的亲和偏好。如Cdc25C与14-3-3ζ、ɛ和γ结合, 但不与σ结合[6]。14-3-3蛋白大多以二聚体形式存在, 每个单体蛋白由9个反向平行α-螺旋(α1~α9) 组成, 含有1个磷酸肽结合位点, α1螺旋折叠呈凹槽形并且与α3螺旋和α4螺旋结合(图 1)。所有的14-3-3亚型蛋白均包含产生PPIs所必需的两亲性凹槽, 可以识别特异的磷酸化丝氨酸/苏氨酸位点, 根据结合序列特征, 其伴侣蛋白可以分为三类: ① R[S/Φ][+](pS/pT)XP; ② RX[Φ/S][+](pS/pT)XP; ③ (pS/pT)X1–2-COOH[7-10]。其中, pS/pT是磷酸化丝氨酸或苏氨酸, Φ是芳香性氨基酸残基, +是碱性氨基酸残基, X是任意氨基酸类型的残基(通常是亮氨酸、谷氨酸、丙氨酸和甲硫氨酸)。
随着研究的深入, 学者陆续证实14-3-3蛋白调节功能的失衡, 可以促进乳腺癌[11]、肺癌[12]、前列腺癌[13]、胃癌[14]、头颈癌[15]、骨髓瘤[16]和胶质母细胞瘤[17]等多类恶性肿瘤的发生与发展, 并与患者的化疗耐药和不良预后相关。由于1‍4‍-‍3‍-‍3与配体的PPIs是由特定磷酸肽基序所介导, 因此通过化学干预, 竞争性占据底物结合口袋并抑制14-3-3的调控活性, 可以恢复其异常的生理功能。例如, 一种磷酸化R18短肽, 能作用于带正电的14-3-3配体结合槽, 抑制其与伴侣蛋白的PPIs, 增加顺铂对肿瘤细胞的杀伤能力[18-20]。截至目前, 干预14-3-3 PPIs的抑制剂种类繁多, 但由于各亚型蛋白高度同源, 导致选择性抑制剂的开发十分困难。14-3-3蛋白作为一种信号传导网络的核心蛋白, 其调控活性的广泛抑制, 可能导致潜在的毒副作用。与传统的抑制剂相比, 14-3-3分子胶受到PPIs界面的可变性和特异性影响, 使得分子的选择性设计更易实现, 这些分子胶的发现促进了14-3-3 PPIs机制的深入研究, 也为相关疾病的治疗作出了积极贡献[21]。
2 14-3-3 PPI分子胶
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2.1 14-3-3/ERα分子胶
目前, 乳腺癌的治疗药物主要包含雌激素受体阻断剂、芳香化酶抑制剂等[22], 它们可以阻止雌激素的产生或竞争性结合雌激素受体α (estrogen receptor α, ERα), 抑制ERα转录活性。但随着抗雌激素治疗的深入, 患者常表现出耐药现象[23], 因此寻找新的治疗靶点并以此为基础开展化学干预, 具有较高的应用价值。14-3-3蛋白通过识别ERα的倒数第二位的磷酸化苏氨酸(Thr594), 可以与ERα的C端结合, 进而抑制ERα的转录活性(图 2A) 和乳腺癌细胞的增殖[24]。
天然产物fusicoccanes (FCs) 是真菌Phomopsis amygdali的提取物, 这类分子都具有以5-8-5环为核心的化学结构, 大部分FCs能打开气孔导致引起叶子枯萎并导致植物死亡[25], 因此最初FCs是植物学领域的研究热点。随着研究的深入, 与其他FCs相比, fusicoccin A (FC-A, 1, 图 2B) 表现出了良好的抗肿瘤活性。De Vries-van Leeuwen等[24]证实FC-A能够增强14-3-3σ/ERα相互作用, 抑制ERα二聚化, 降低ERα下游基因的转录活性, 如RAPα、PGR、GREB1, 进一步诱导乳腺癌细胞的凋亡(图 2A)。FC-A填补了14-3-3和ERα结合界面的空间(图 2A), 熵效应和形状互补使14-3-3和ERα结合作用增强(图 2C)。浓度为10 μmol·L-1的FC-A将ERα与14-3-3σ的结合亲和力提高了25倍(Kd-app = 6.7 nmol·L-1, Kd-DMSO = 169.0 nmol·L-1)[26]。利用14-3-3/ERα分子胶, 开展针对ERα阳性乳腺癌的化学干预, 有望成为乳腺癌治疗的新兴疗法。目前FC-A已成为研究靶向14-3-3 PPIs的重要工具, 为研发靶向14-3-3分子胶的设计开发及作用机制研究提供大量信息。然而, FC-A对于14-3-3/p53[27]、14-3-3/CFTR[28]等靶点的非选择性, 以及天然产物在合成和纯化中的难度, 限制了该类分子的进一步发展。
2019年, Sijbesma等[29]采用针对半胱氨酸的定向筛选技术, 发现了一类可以作用于14-3-3σ/ERα的共价分子胶。为了提高筛选灵敏性, 研究人员将14-3-3σ的42位突变为半胱氨酸, 得到C42突变体, 100 μmol·L-1化合物2 (图 2B) 将ERα与14-3-3σ (C42) 的结合亲和力提高了40倍(Kd-app = 32.0 nmol·L-1, Kd-‍DMSO = 1.3 μmol·L-1), 然而该分子并未关注对C-RAF的选择性问题。晶体结构示意图显示化合物2的硫原子连接到14-3-3突变体的C42, 芳香环指向14-3-3口袋末端, 与ERα-pp的C端形成疏水相互作用, 增强了14-3-3σ/ERα相互作用(图 2D)。2023年, 该团队改用14-3-3σ (WT) 进一步筛选, 发现了可以作用于14-3-3σ/ERα非选择性共价分子胶的化合物3 (图 2B), 浓度为1 mmol·L-1的化合物3对C-RAF与14-3-3σ的结合亲和力提高了81倍(Kd-app = 106.0 nmol·L-1, Kd-DMSO = 8.5 μmol·L-1), ERα与14-3-3σ亲和力提高了19倍(Kd-app = 21.0 nmol·L-‍1, Kd-DMSO = 360.0 nmol·L-1), 14-3-3σ/USP8的亲和力提高了4倍(Kd-app = 1.1 μmol·L-‍1, Kd-DMSO = 4.5 μmol·L-1) [30]。化合物3与14-3-3σ/ERα结合模式与化合物2相似, 其末端的氯代苯基结构朝向了ERα的磷酸化短肽(图 2E)。鉴于化合物3具有较低的底物选择性, Konstantinidou等[31]对化合物3开展了系列优化: 一方面, 将谐二甲基替换为大位阻的取代基团, 增加分子末端苯环的位阻, 提高对C-RAF的选择; 另一方面, 将靶向14-3-3σ C38的二硫键共价弹头替换为氯乙酰胺弹头, 增加连接体的刚性, “锁定”化合物的构象, 进一步增强对ERα的活性。设计出兼具选择性和活性的化合物4 (图 2B), 100 μmol·L-1化合物4对14-3-3σ/C-RAF稳定作用比化合物3降低了42%, 对14-3-3σ/ERα稳定作用比化合物3提高了29倍, 与FC-A相近(Kd-app = 13.0 nmol·L-1, Kd-DMSO = 2.2 μmol·L-1), 稳定作用总共为116倍(Kd-app = 18.0 nmol·L-1, Kd-DMSO = 2.1 μmol·L-1)。在晶体结构中(图 2F), 连接环系的改变影响了弹头的定向方式, 使化合物4与14-3-3的极性氨基酸形成氢键增强稳定作用。
Visser等[32]结合已发现的两类分子碎片, 分析其与ERα/14-3-3复合物的结合模式, 将两个作用于邻近位点的分子碎片fragment class Ⅰ (化合物2) 和fragment class Ⅱ进行拼接和结构优化(图 3A), 最终发现了非共价类分子胶5 (图 3B)。500 μmol·L-1的化合物5将14-3-3γ/ERα PPIs增加了25倍。Fragment class Ⅰ与14-‍3-3σ (C42) 的C42共价形成二硫键, 氯代苯环延伸到14-3-3口袋末端, 通过与ERα磷酸肽C端缬氨酸的疏水作用发挥作用(图 3C)。Fragment class Ⅱ的氨基通过与14-3-3的E14羧基形成盐桥发挥作用(图 3D)。化合物5则是拼接了两个分子碎片的有效部分进行优化, 增强与ERα磷酸肽C端的疏水作用同时还与14-3-3的E14羧基形成盐桥进一步增强了5对14-3-3γ/ERα的稳定作用(图 3E)。这种通过识别分子作用位点以及结合模式的化学生物学策略, 给一些形状和距离匹配不佳的分子提供改造空间, 更有利于识别蛋白质间的相互作用。
2020年, 研究人员[33]发现了一种外消旋的吡咯烷酮类结构6 (图 4A), 其对14-3-3/ERα有较弱的分子胶活性, 通过化学合成和手性拆分拆分, 发现R构象的分子6为其活性形式, 利用共晶衍射揭露出(R)-6与14-3-3/ERα的三元复合物模型, 并发现该分子在晶体结构中与Mg2+形成螯合物。为了验证金属螯合特征对分子活性产生的影响, 研究人员在荧光偏振测试体系中额外增加高浓度的金属离子, 发现(R)-6的分子活性与金属离子浓度呈正比。因此作者推测金属离子的螯合作用可能是影响分子构象的关键。为了对该假设进行探索, 研究人员采用环化策略以及分子内氢键模拟策略, 设计合成了一系列化合物, 其中R构象的化合物7 (图 4A) 表现出了更强的分子胶活性(图 4B)。
此外, Gigante等[34]报道了一类含有对称结构的精氨酸模拟物, 该类分子多含有三个或四个结构相同的多肽臂, 浓度为150 μmol·L-1的化合物8能使1‍4‍-‍3‍-‍3ζ/ERα亲和力提高80倍(Kd-app = 29.0 nmol·L-1, Kd-DMSO = 2.321 μmol·L-1)。而20 μmol·L-1化合物8与FC-A联用时能使14-3-3ζ/ERα结合亲和力提高203倍(Kd-app = 11.0 nmol·L-1, Kd-DMSO = 2.238 μmol·L-1), 证实了化合物8可以与FC-A以协同方式, 增强二者的分子胶活性(图 4A)。化合物9是采用结构衍生化得到的一个14-3-3/ERα分子胶[35] (图 4A), 尽管其活性较弱, 500 μmol·L-1化合物9对14-3-3/ERα稳定作用仅增加6.2倍(Kd-app = 1.1 μmol·L-1, Kd-DMSO = 6.9 μmol·L-1), 但其选择性较强。化合物10则是一类新型的非共价类分子胶(图 4A), 该分子可以稳定14-3-3的二聚体形式, 并与FC-A协同增强14-3-3与ERα的稳定活性[36]。
2.2 14-3-3/C-RAF分子胶
RAF原癌基因丝氨酸/苏氨酸蛋白激酶(RAF proto-oncogene serine/threonine-protein kinase, C-RAF/RAF-1) 是快速加速纤维肉瘤(rapidly accelerated fibrosarcoma, RAF) 蛋白家族成员之一, 它参与了膜蛋白RAS下游的MAPK信号转导。根据蛋白的三级结构, C-RAF从C端到N端可分为三部分: 催化结构域(CAD)、RAS结合域(RBD) 和富含半胱氨酸结构域(CRD)。当激素、生长因子(如EGF) 等信号因子, 与细胞表面受体结合时, 细胞中的RAS-GTP增加, 进而激活RAS; RAS的激活会引发RAS-GTP与C-RAF直接结合, 从而将细胞浆中的C-RAF二聚体募集到细胞膜上[37]。募集到膜上的C-RAF发生磷酸化而激活, 促RAS-RAF-MEK-ERK通路激活, 从而参与细胞的增殖、分化和迁移等相关生理活动。C-RAF活化的关键是14-3-3介导的C-RAF激酶结构域二聚化, 14-3-3二聚体能同时结合两个C-RAF分子并稳定C-RAF二聚体构象。C-RAF蛋白中共有三个14-3-3蛋白结合位点(S233、S259和S621), 14-3-3与C-RAF的S233和S259结合会阻止Ras介导的质膜募集和C-RAF的激活, 而14-3-3与C-RAF的Ser621的结合可激活C-RAF[38] (图 5A)。
真菌提取物cotylenin A (CN-A, 图 5B), 是一种与FC-A结构相似的天然产物。Molzan等[39]发现CN-A在增强C-RAF与14-3-3ζ蛋白相互作用时, 选择性稳定了作用于pSer233和pSer259位点, 但不结合活化C-RAF的pSer621位点。500 μmol·L-1 CN-A使14-3-3ζ/C-RAF (pSer233, pSer259) 结合亲和力增强了17倍(Kd-app = 20.0 nmol·L-1, Kd-DMSO = 346.0 nmol·L-1)。CN-A处于14-3-3和C-‍RAF (pSer233, pSer259) 结合界面中(图 5C), CN-A高度位点选择性的产生, 是由C-RAF的E622与CN-A母环之间严重的立体空间和静电冲突所导致。体外实验发现CN-A可以诱导ERK活化, 其作用机制尚未被完全解析, 可能与14-‍3-‍3和RAF家族成员(A-RAF、B-RAF和C-RAF) 之间复杂的相互作用有关。在RAS突变癌症模型中单独使用CN-A并未表现出显著的治疗效果, 但与抗EGFR抗体西妥昔单抗联合治疗时, 可显著下调ERK活性并增强对肿瘤的杀伤能力, 表明CN-A可以作为ERK通路治疗药物的增敏剂而发挥药理活性。因此靶向C-RAF抑制活化位点pSer233和pSer259, 寻找可以增强其与14-3-3结合作用的分子胶, 并以此为基础开展化学, 将有望成为治疗RAS突变癌症的新策略。
Kenanova等[30]通过将含有pSer259的C-RAF肽段进行荧光标记(FAM-QRST{pS}TPNVHH-CONH2), 构建了针对14-3-3和C-RAF分子胶的筛选模型, 通过荧光偏振检测筛选得到化合物12~14 (图 5B), 浓度为1 mmol·L-1的化合物12和13使14-3-3/C-RAF的结合亲和力分别增加250倍(Kd-app = 92.0 nmol·L-1, Kd-DMSO = 23.0 μmol·L-1) 和420倍(Kd-app = 100.0 nmol·L-1, Kd-DMSO = 42.0 μmol·L-1)。化合物14对14-3-3/C-RAF的结合作用虽只增强了77倍(Kd-‍app = 294.0 nmol·L-1, Kd-DMSO = 23.0 μmol·L-1), 但14对14-3-3其他伴侣蛋白无稳定作用, 对C-RAF选择性良好。虽然12和14的结构不同, 但12的萘环和14的三氟甲基占据相同空腔, 通过与C-RAF的+1 Thr残基作用稳定14-‍3-‍3/C-‍RAF (图 5D、E)。此外, 12和14都能使C-RAF发生了构象变化, 将C-RAF推向14-3-3σ增强14-3-3/C-RAF相互作用。尽管12~14对C-RAF激活位点pSer621的作用尚未被披露, 但相关工作也为14-3-3分子胶的发现及修饰奠定了基础。
2.3 14-3-3/p53分子胶
p53是一种抑瘤因子, 通过调控细胞周期及其凋亡, 防止受损细胞转变为恶性细胞。据统计, 约50% 癌症患者体内, p53存在突变失活现象, 其活性的正常发挥受到翻译后修饰和PPIs的调控[40]。在正常的非应激细胞中, p53会刺激MDM2的表达, 促进MDM2介导的p53降解。但在应激信号作用下, 14-3-3σ可以分别与p53和MDM2-COP1的相互作用, 增强p53稳定性从而抑制p53的降解, 抑制肿瘤细胞的生长[41-43]。目前针对p53的治疗策略主要是恢复野生型p53功能或抑制p53与关键负调控因子MDM2的相互作用(图 6A)。通过稳定p53与正调节因子14-3-3相互作用, 增强p53稳定性, 对于抑制肿瘤生长具有重要意义。
FC-A (图 6B) 除了能够参与调节14-3-3/ERα的PPIs外, 还能占据14-3-3和p53结合界面空腔(图 6C), 使14-3-3/p53结合增强从而稳定p53和抑制p53降解。1 mmol·L-1 FC-A使14-3-3σ/p53稳定倍数增加4倍(Kd-app = 2.1 μmol·L-‍1, Kd-DMSO = 8.1 μmol·L-1)[27]。Andrei等[44]通过将FC-A的C19酰胺衍生化得到FC-‍NAc (15, 图 6D), FC-NAc增加了与14-3-3的D215氢键相互作用, 浓度为400.0 μmol·L-1 FC-NAc对14-3-3/p53的稳定因子为5.1, 相对稳定因子为3.1的FC-A增加了1.6倍。但0.5 μmol·L-1 FC-NAc也对14-3-3/TASK-3稳定作用增强42倍, 对14-3-3/p53选择性较差。
Amifostine (16, 图 6E) 是一种临床批准的前药, 用于减轻与化疗和放疗相关的不良反应。在健康细胞中, 16被碱性磷酸酶(ALP) 去磷酸化, 释放出活性物质氨基硫醇WR-1065 (17, 图 6E)。17主要清除辐射产生的有害活性氧(ROS), 帮助双链断裂(DSB) 的修复, 以保护正常细胞免受辐射诱导的DNA损伤。Falcicchio等[26]通过蛋白质质谱发现17直接与14-3-3σ的Cys38形成共价二硫键, 通过荧光偏振实验证明浓度为1 mmol·L-1的化合物17能增强14-3-3σ/p53稳定作用1.4倍(Kd-app = 5.6 μmol·L-1, Kd-DMSO = 8.1 μmol·L-1), 17和FC-A联用时增强1‍4‍-‍3‍-‍3σ/p53稳定作用5倍(Kd-app = 1.6 μmol·L-1, Kd-DMSO = 8.1 μmol·L-1)。此外, 细胞水平实验进一步证实了17可以与FC-A协同增强p53活性, 从而增加膀胱癌细胞EJp53的杀伤效果。
3 总结与展望
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14-3-3蛋白通过与伴侣蛋白的相互作用参与了细胞凋亡、信号转导和能量代谢等关键生命活动。这些PPIs的失调与多种人类疾病密切相关, 因此, 调节1‍4‍-‍3‍-‍3 PPIs可能是一种有效的药物治疗策略。14-3-3的伴侣蛋白通过三种主要的结合基序与14-3-3蛋白结合, 14-3-3 PPIs抑制剂(如R18和BV101) 可以与伴侣蛋白竞争性结合14-3-3蛋白的两亲性凹槽, 其对伴侣蛋白的特异性差。而稳定1‍4‍-‍3‍-‍3 PPIs的分子胶主要结合于14-3-3蛋白与伴侣蛋白结合界面, 在不同的伴侣蛋白结合模式中, PPIs的作用界面表现出一定的可变性, 因此14-3-3 PPIs分子胶的开发可能具有更高的选择性。14-3-3分子胶的早期研发以FC-A等天然产物为主, 分子发现过程具有很高的随机性, 且受到合成难度和潜在的脱靶效应的制约, 导致相关研究进展缓慢。随着研究深入和高通量筛选技术的应用, 学者利用针对半胱氨酸的共价筛选方法, 发现了一类含有二硫片段或氯代乙酰基片段的分子可以增强14-3-3和伴侣蛋白的结合, 为靶向性分子胶的研发提供了一条新思路。但14-3-3分子胶的研发目前仍面临许多问题, 例如, 现有的药物研发大多局限于1‍4‍-‍3‍-‍3的某个单一亚型, 缺少对其他亚型甚至突变型14-3-3蛋白的探索。此外, 这一调控策略的有效性尚未通过临床试验得到证实, 且对于某些靶点还缺乏充分的细胞水平验证。未来研究需要进一步探索如何分离伴侣蛋白的活性, 并开发出具有精确治疗潜力的特异性分子胶。
作者贡献: 吴柳燚、李龙静和田于成是文章框架的构思者并负责内容的撰写和文献整理; 卞金磊和李志裕指导论文写作; 徐倩倩和韦伟对论文进行了检查和修改。
利益冲突: 所有作者声明不存在利益冲突。
基金
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  • 国家自然科学基金面上项目(82373740)
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2024年第59卷第11期
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doi: 10.16438/j.0513-4870.2024-0418
  • 接收时间：2024-04-30
  • 首发时间：2025-11-24
  • 出版时间：2024-11-12
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  • 收稿日期：2024-04-30
  • 修回日期：2024-08-15
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国家自然科学基金面上项目(82373740)
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    中国药科大学药学院, 江苏 南京 211112

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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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