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Bicyclic stapled peptides based on p53 as dual inhibitors for the interactions of p53 with MDM2 and mdmx

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Chinese Chemical Letters 2022年第3期33卷 1254-1258页

作者： Hongjin Li Xiangyan Chen Minghao Wu Panpan Song Xia Zhao Key Laboratory of Marine Drugs Ministry of EducationSchool of Medicine and PharmacyOcean University of ChinaQingdao 266003China Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology Qingdao 266237China

In recent years, the strategy of inhibiting the interactions of p53 with murine double minute 2(MDM2)and murine double minute X(mdmx) has been proved to be a promising approach for tumor therapy.However, the poor proteolytical stability and low intracellular delivery efficiency of peptide inhibitors limit their clinical application. Here, we designed and synthesized the bicyclic stapled peptides based on p53 by combining all-hydrocarbon stapling and lactam stapling strategies. We demonstrated that bicyclic stapled peptide p53-16 significantly improved α-helicity and proteolytic stability. Especially, p53-16showed nanomolar binding affinity for MDM2 and mdmx. In addition, p53-16 could penetrate the cell membrane, and selectively inhibited the activity of tumor cells via activating p53 pathway in vitro. Our data suggest that p53-16 is a potential dual inhibitor of MDM2 and mdmx interactions. The bicyclic stapling strategy is a promising drug design strategy for protein–protein interactions inhibitors.

关键词： p53 MDM2 mdmx All-hydrocarbon stapling strategy Lactam stapling strategy Bicyclic stapling strategy

mdmx phosphorylation-dependent p53 downregulation contributes to an immunosuppressive tumor microenvironment

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Journal of Molecular Cell Biology 2020年第9期12卷 713-722页

作者： Bing Wang Chuan-Bian Lim Jiawei Yan Lizhen Li Jufang Wang John B.Little Zhi-Min Yuan Key Laboratory of Space Radiobiology of Gansu Province&Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences Institute of Modern PhysicsChinese Academy of SciencesLanzhouChina University of Chinese Academy of Sciences BeijingChina John B.Little Center for Radiation Sciences Harvard T.H.Chan School of Public HealthBostonMAUSA Present address:School of Life Sciences and Technology ShanghaiTech UniversityShanghaiChina

A role of tumor-suppressive activity of p53 in the tumor microenvironment(TME)has been implicated but remains fairly understudied.To address this knowledge gap,we leveraged our mdmxS314A mice as recipients to investigate how implanted tumor cells incapacitate host p53 creating a conducive TME for tumor progression.We found that tumor cell-associated stress induced p53 downregulation in peritumor cells via an mdmx-Ser314 phosphorylation-dependent manner.As a result,an immunosuppressive TME was developed,as reflected by diminished immune cell infiltration into tumors and compromised macrophage M1 polarization.Remarkably,ablation of mdmx-Ser314 phosphorylation attenuated p53 decline in peritumor cells,which was associated with mitigation of immunosuppression and significant tumor growth delay.Our data collectively uncover a novel role of p53 in regulating the tumor immune microenvironment,suggesting that p53 restoration in the TME can be exploited as a potential strategy of anticancer therapy.

关键词： p53 mdmx tumor microenvironment immune cell infiltration macrophage polarization

Design of ultrahigh-affinity and dual-specificity peptide antagonists of MDM2 and mdmx for P53 activation and tumor suppression

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Acta Pharmaceutica Sinica B 2021年第9期11卷 2655-2669页

作者： Xiang Li Neelakshi Gohain Si Chen Yinghua Li Xiaoyuan Zhao Bo Li William D.Tolbert Wangxiao He Marzena Pazgier Honggang Hu Wuyuan Lu School of Pharmacy Second Military Medical UniversityShanghai 200433China Institute of Human Virology and Department of Biochemistry and Molecular Biology University of Maryland School of MedicineBaltimoreMD 21201USA School of Medicine Shanghai UniversityShanghai 200444China Institute of Translational Medicine Shanghai UniversityShanghai 200444China State Key Laboratory of Rare Earth Resource Utilization Changchun Institute of Applied ChemistryChinese Academy of SciencesChangchun 130022China Department of Talent Highland the First Affiliated Hospital of Xi’an Jiaotong UniversityXi’an 710061China Key Laboratory of Medical Molecular Virology(MOE/NHC/CAMS)of School of Basic Medical Sciences and Shanghai Institute of Infectious Disease and Biosecurity of School of Public Health Fudan UniversityShanghai 200032China

Peptide inhibition of the interactions of the tumor suppressor protein P53 with its negative regulators MDM2 and mdmx activates P53 in vitro and in vivo,representing a viable therapeutic strategy for cancer treatment.Using phage display techniques,we previously identified a potent peptide activator of P53,termed PMI(TSFAEYWNLLSP),with binding affinities for both MDM2 and mdmx in the low nanomolar concentration range.Here we report an ultrahigh affinity,dual-specificity peptide antagonist of MDM2 and mdmx obtained through systematic mutational analysis and additivitybased molecular design.Functional assays of over 100 peptide analogs of PMI using surface plasmon resonance and fluorescence polarization techniques yielded a dodecameric peptide termed PMI-M3(LTFLEYWAQLMQ)that bound to MDM2 and mdmx with K_(d)values in the low picomolar concentration range as verified by isothermal titration calorimetry.Co-crystal structures of MDM2 and of mdmx in complex with PMI-M3 were solved at 1.65 and 3.0 A resolution,respectively.Similar to PMI,PMI-M3 occupied the P53-binding pocket of MDM2/mdmx,which was dominated energetically by intermolecular interactions involving Phe3,Tyr6,Trp7,and Leu 10.Notable differences in binding between PMI-M3 and PMI were observed at other positions such as Leu4 and Met11 with MDM2,and Leu1 and Met11 with mdmx,collectively contributing to a significantly enhanced binding affinity of PMI-M3 for both proteins.By adding lysine residues to both ends of PMI and PMI-M3 to improve their cellular uptake,we obtained modified peptides termed PMI-2K(KTSFAEYWNLLSPK)and M3-2K(KLTFLEYWAQLMQK).Compared with PMI-2K,M3-2K exhibited significantly improved antitumor activities in vitro and in vivo in a P53-dependent manner.This super-strong peptide inhibitor of the P53-MDM2/mdmx interactions may become,in its own right,a powerful lead compound for anticancer drug development,and can aid molecular design of other classes of P53 activators as well for anticancer therapy.

关键词： MDM2 mdmx P53 Antitumor peptide Systematic mutational analysis

Mouse modelling of the MDM2/mdmx-p53 signalling axis

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Journal of Molecular Cell Biology 2017年第1期9卷 34-44页

作者： Nicole R. Tackmann Yanping Zhang Department of Radiation Oncology Lineberger Comprehensive Cancer Center University of North Carolina at Chapel Hill Chapel Hill NC 27514 USA Curriculum in Genetics and MoLecular Biology School of Medicine University of North Carolina at Chapel HiLl Chapel HILL NC 27514 USA Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy Cancer Institute Xuzhou Medical College Xuzhou 221002 China

It is evident that p53 activity is critical for tumour prevention and stress response through its transcriptional activation of genes affecting cellular senescence, apoptosis, cellular metabolism, and DNA repair. The regulation of p53 is highly complex, and MDM2 and mdmx are thought to be critical for deciding the fate of p53, both through inhibitory binding and post-translational modification. Many mouse models have been generated to study the regulation of p53 in vivo, and they have altered our interpretations of how p53 is regulated by MDM2 and mdmx. Although MDM2 is absolutely required for p53 regulation, certain functions are dispensable under unstressed conditions, including the ability of MDM2 to degrade p53. mdmx, on the other hand, may only be required in select situations, like embryogenesis. These models have also clarified how cellular stress signals modify the p53-inhibiting activities of MDM2 and mdmx in vivo. It is clear that more work will need to be performed to further understand the contexts for each of these signals and the requirements of various MDM2 and mdmx functions. Here, we will discuss what we have learned from mouse modelling of MDM2 and mdmx and underscore the ways in which these models could inform future therapies.

关键词： E3 ubiquitin ligase MDM2 mdmx cancer p53

Role of Mdm2 and mdmx in DNA repair

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Journal of Molecular Cell Biology 2017年第1期9卷 69-73页

作者： Christine M. Eischen Department of Cancer Biology Sidney Kimmel Cancer Center Thomas Jefferson University Philadelphia PA 19107 USA

Mdm2 和 mdmx 是 p53 瘤 suppressor 的批评管理者并且是在许多人的恶意的 overexpressed。在最近的年里，然而，他们染色体不稳定性上的影响被显示是至少，部分地独立于 p53。Mdm2 和 mdmx 与 Mre11/Rad50/Nbs1 DNA 修理建筑群通过他... 详细信息

Mdm2 和 mdmx 是 p53 瘤 suppressor 的批评管理者并且是在许多人的恶意的 overexpressed。在最近的年里，然而，他们染色体不稳定性上的影响被显示是至少，部分地独立于 p53。Mdm2 和 mdmx 与 Mre11/Rad50/Nbs1 DNA 修理建筑群通过他们的协会禁止 DNA 裂缝修理。最近的证据在癌症房间显示那利用 Mdm2 或 DNA 裂缝修理的调停 mdmx 的抑制能提供一个治疗学的机会，特别地为失去了功能的 p53 的那些恶意。

关键词： Mdm2 mdmx Nbs1 DNA 修理

The long and the short of it:the MDM4 tail so far

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Journal of Molecular Cell Biology 2019年第3期11卷 231-244页

作者： Sue Haupt Javier Octavio Mejia-Hernandez Reshma Vijayakumaran Simon P.Keam Ygal Haupt Tumor Suppression Laboratory Peter MacCallum Cancer Centre305 Grattan StreetMelbourneVictoria 3000Australia Department of Clinical Pathology The University of MelbourneParkvilleVictoria 3010Australia Department of Biochemistry and Molecular Biology Monash UniversityClayton CampusVictoria 3800Australia Sir Peter MacCallum Department of Oncology The University of MelbourneParkvilleVictoria 3010Australia

The mouse double minute 4(MDM4)is emerging from the shadow of its more famous relative MDM2 and is starting to steal the limelight,largely due to its therapeutic possibilities.MDM4 is a vital regulator of the tumor suppressor p53?It restricts p53 transcriptional activity and also,at least in development,facilitates MDM2's E3 ligase activity toward p53.These functions of MDM4 are critical for normal cell function and a proper response to stress.Their importance for proper cell maintenance and proliferation identifies them as a risk for deregulation associated with the uncontrolled growth of cancer.MDM4 tails are vital for its function,where its N-terminus transactivation domain engages p53 and its C-terminus RING domain binds to MDM2.In this review,we highlight recently identified cellular functions of MDM4 and survey emerging therapies directed to correcting its dys regulation in disease.

关键词： MDMA mdmx MDM4-FL MDM4-S p53 MDM2 cancer

Structural effects and competition mechanisms targeting the interactions between p53 and MDM2 for cancer therapy

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Frontiers of physics 2017年第3期12卷 107-116页

作者： Shu-Xia Liu Yi-Zhao Geng Shi-Wei Yan College of Nuclear Science and Technology Beijing Normal University Beijing 100875 China School of Science Hebei University of Technology Tianjin 300401China Beijing Radiation Center Beijing 100875 China

Approximately half of all human cancers show normal TP53 gene expression but aberrant overexpres- sion of MDM2 and/or mdmx. This fact suggests a promising cancer therapeutic strategy in targeting the interactions between p53 and MDM2/mdmx. To help realize the goal of developing effective in- hibitors to disrupt the p53-MDM2/mdmx interaction, we systematically investigated the structural and interaction characteristics of p53 with inhibitors of its interactions with MDM2 and mdmx from an atomistic perspective using stochastic molecular dynamics simulations. We found that some spe- cific a helices in the structures of MDM2 and mdmx play key roles in their binding to inhibitors, and that the hydrogen bond formed by the Trp23 residue of p53 with its counterpart in MDM2 or mdmx determines the dynamic competition processes of the disruption of the MDM2-p53 interaction and replacement of p53 from the MDM2-p53 complex in vivo. The results reported in this paper are expected to provide basic information for designing functional inhibitors and realizing new strategies of cancer gene therapy.

关键词： p53 mdmx MDM2 molecular dynamics simulation inhibitors cancer therapy

mdmx转录抑制剂抗恶性脑胶质瘤的药效学评价及机制研究

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MDMX转录抑制剂抗恶性脑胶质瘤的药效学评价及机制研究

作者：汪英杰烟台大学

学位级别：硕士

背景与目的:恶性脑胶质瘤(Glioblastoma,GBM)是神经胶质瘤中恶性程度最高的一类亚型,发病率约占颅内原发肿瘤的40%且呈逐年升高趋势,具有死亡率高、预后差等特征,严重威胁人类的健康。现有GBM治疗方式局限于手术及放化疗,难以治愈。针... 详细信息

背景与目的:恶性脑胶质瘤(Glioblastoma,GBM)是神经胶质瘤中恶性程度最高的一类亚型,发病率约占颅内原发肿瘤的40%且呈逐年升高趋势,具有死亡率高、预后差等特征,严重威胁人类的健康。现有GBM治疗方式局限于手术及放化疗,难以治愈。针对其特异性靶标的发现及活性分子的开发对于靶向GBM药物的研发至关重要。鼠双微体X(Murine Double Minute X,mdmx)是驱动肿瘤恶性化的重要因子,在GBM细胞普遍高表达,化学靶向mdmx在脑胶质瘤中的潜在抗肿瘤活性尚不明确。烟酰胺N-甲基转移酶(Nicotinamide-N-Methyltransferase,NNMT)是调控肿瘤细胞中基因表达的关键因子,同样在GBM细胞中高表达并促进其恶性化加剧,是GBM临床诊断和治疗的潜在靶标,但相关作用机制尚未阐明。本研究前期发现mdmx转录抑制剂XI-011,通过抑制mdmx转录活性激活p53的活性,从而发挥抗肿瘤活性,为以mdmx为治疗靶点并以此开发新型有效的抗恶性脑胶质瘤药物提供前期依据。方法和结果:1、XI-011抗恶性脑胶质瘤细胞水平的活性评价本研究自主合成化合物XI-011,通过MTT实验、细胞生长曲线实验、集落形成实验和WB实验证实XI-011能够抑制恶性脑胶质瘤细胞的增殖、抑制GBM细胞内mdmx蛋白的表达并激活野生型p53蛋白的表达。2、XI-011体内抗恶性胶质瘤细胞活性评价取健康C57BL/6小鼠腹腔注射给予10 mg/kg的XI-011,分别于不同时间节点采集血样和组织样本,通过LC-MS检测显示XI-011腹腔给药可快速吸收进入循环,并能透过血脑屏障进入脑组织。建立BALB/c裸鼠体内异位移植瘤模型,随机分为Control组、替莫唑胺组(50mg/kg)、XI-011组(10 mg/kg)、XI-011联合替莫唑胺组。实验结果显示XI-011单用可有效抑制体内恶性脑胶质瘤细胞生长,联合替莫唑胺可增强其抗肿瘤活性。3、XI-011抗恶性脑胶质瘤相关机制研究本研究通过分子对接、生物膜干涉技术、基因沉默技术、q RT-PCR、WB及双荧光素酶报告基因技术发现并鉴定NNMT是mdmx蛋白的上游转录因子并促进GBM细胞内mdmx蛋白的表达。通过Pull-down、基因沉默、WB、q RT-PCR、双荧光素酶报告基因及技术发现并鉴定了NNMT调控mdmx蛋白表达的中间转录因子MYH9,机制研究表明NNMT蛋白通过转录因子间接调控mdmx蛋白的表达而发挥抗恶性脑胶质瘤的作用。研究结论:本研究自行合成化合物XI-011,药效学评价发现该化合物XI-011体内外具有良好的抗恶性脑胶质瘤活性;药代动力学研究发现化合物XI-011能有效的透过血脑屏障;机制研究发现化合物XI-011结合NNMT蛋白,通过转录因子间接影响mdmx的转录,从而发挥抗恶性脑胶质瘤作用。

关键词： mdmx 转录调控抑制剂 NNMT 恶性脑胶质瘤

马鞭草苷调节mdmx/PPARα介导的铁死亡减轻酒精性脂肪性肝炎的作用研究

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马鞭草苷调节MDMX/PPARα介导的铁死亡减轻酒精性脂肪性肝炎的作...

作者：董佳慧安徽医科大学

学位级别：硕士

酒精是引起全球肝脏相关疾病发病率和死亡率的主要原因之一。酒精性脂肪性肝炎(ASH)严重危害人类的健康,若不加以治疗,会造成更加严重的肝脏损伤,肝纤维化,肝硬化甚至是肝癌。然而,酒精性脂肪性肝炎仍然缺乏有效的治疗方法。值得注意的... 详细信息

酒精是引起全球肝脏相关疾病发病率和死亡率的主要原因之一。酒精性脂肪性肝炎(ASH)严重危害人类的健康,若不加以治疗,会造成更加严重的肝脏损伤,肝纤维化,肝硬化甚至是肝癌。然而,酒精性脂肪性肝炎仍然缺乏有效的治疗方法。值得注意的是,越来越多的证据表明酒精性脂肪性肝炎的损伤与铁死亡有关。铁死亡(ferroptosis)是一种由细胞代谢和铁超载的脂质过氧化引起的细胞死亡过程,与癌症和多种肝脏疾病有关。多项研究表明鼠双微体蛋白X(mdmx)影响铁死亡与细胞中的脂质过氧化有关系,它最初是从小鼠c DNA表达文库中分离出的可以与p53相互作用的蛋白,它可以明显抑制各种癌症模型中的铁死亡。马鞭草苷是马鞭草中的主要化合物L(马鞭草科),被美国食品和药物管理局普遍认为是一种安全食品。马鞭草,首次记录在“名医补充记录”中。马鞭草苷(VE)是其主要活性成分,已被发现具有许多生物学作用,包括抗肥胖,抗炎和抗氧化活性,去除黄疸和治疗疟疾。它可以治疗肿块积聚、痛经、喉咙阻塞、水肿、黄疸和疟疾。研究表明马鞭草苷对棕榈酸(PA)、油酸(OA)、乙醇和对乙酰氨基酚等引起的肝损伤有一定的治疗作用。为进一步探究马鞭草苷在酒精性脂肪性肝炎中机制作用。我们设计了以下五个部分对本课题进行研究:1.马鞭草苷在体内对酒精性脂肪性肝炎的影响我们购买了70只C57BL/6J雄鼠(体重18g-22g),随后分为7组,每组10只将其分为正常组、模型组、模型组加12.5mg/kg,25mg/kg,50mg/kg马鞭草苷组,正常加50mg/kg马鞭草苷组,水飞蓟宾组。模型组小鼠喂养酒精饲料建立酒精性脂肪性肝损伤模型,给药组在造模第一天时开始每天给予灌胃低、中、高剂量的VE,开始喂养酒精饲料时,同时也腹腔注射水飞蓟宾;正常组喂养对照饲料。酒精性脂肪性肝炎小鼠模型成功后,我们对于小鼠禁食24h但是还要给小鼠准备充足的水。将小鼠用水合氯醛麻醉之后,随后用眼球取血的方式收集血浆,解剖小鼠收集肝脏组织。选用HE染色、油红染色、血清ALT,AST和TG等数据和损伤程度来验证其损伤情况。小鼠酒精性脂肪性肝损伤模型成功建立的情况下,实验数据表明马鞭草苷对肝脏损伤具有保护作用。2.马鞭草苷抑制酒精性脂肪性肝损伤中氧化应激诱导的铁死亡首先我们通过对血清及组织中ROS,4-HNE,MDA,GSH,SOD等一系列指标的检测,结果表明VE对酒精性脂肪性肝损伤中氧化应激有一定的抑制作用。接着对于AML-12细胞来说,我们选用CCK8法筛选出马鞭草苷的最适浓度。同时我们对细胞中ROS,4-HNE,MDA,GSH,SOD等一系列氧化应激指标进行检测,结果表明VE对酒精引起的小鼠肝细胞的损伤有一定的保护作用。另外,透射电镜结果表明VE对线粒体功能障碍有一定的减轻作用。同时,Fe含量的检测表明VE可减轻酒精性脂肪性肝炎中的Fe的释放。以上实验结果表明,VE抑制酒精性脂肪性肝炎中氧化应激诱导的铁死亡。3.马鞭草苷通过靶向mdmx对铁死亡的影响网络药理学结果表明,马鞭草苷可以靶向mdmx。随后我们使用mdmx活性试剂盒,为的是测定马鞭草苷对mdmx活性是否有影响,进一步验证马鞭草苷靶向mdmx。实验结果表明,VE可以与mdmx结合,并减轻肝损伤中mdmx的活性。同时进行热稳定性实验,结果表明VE提高了mdmx的耐热性。接着,我们对于AML-12细胞给予mdmx抑制剂(NCS207895)对mdmx进行抑制,同时给予Ethanol(200m M)处理24h,对ROS,4-HNE,MDA,GSH,SOD等一系列指标的检测显示VE对AML-12细胞氧化应激有一定的抑制作用。另外,采用透射电镜检测线粒体以及Fe含量检测验证马鞭草苷对铁死亡的影响。实验结果表明,VE能够抑制mdmx的表达,而在mdmx被抑制给予VE处理时,发现VE能通过影响mdmx抑制铁死亡。接着,在AML-12细胞上将mdmx过表达,随后接着给予Ethanol(200m M)和VE(100μM)等相应刺激处理AML-12细胞24h,用ELISA来检测氧化应激指标;透射电镜来检测过表达mdmx对AML-12细胞线粒体的影响;同时Fe实验用来探究过表达mdmx对VE抑制铁死亡的影响。结果显示在AML-12细胞中过表达mdmx后,VE抑制AML-12铁死亡的能力减弱。4.mdmx通过影响PPARα活性对脂质过氧化和铁死亡的影响为了确定mdmx的分子作用机制,在AML-12细胞中进行免疫共沉淀(Co-IP)实验。结果表明,mdmx会影响PPARα。接着使用PPARα活性试剂盒测定mdmx对其活性的影响。有文献表明PPAR是参与调节脂质稳态的转录因子。我们假设mdmx可能通过介导PPARα来影响铁死亡。为了验证这一点,我们用PPARα特异性激动剂pirinixic acid(10μM)和Ethanol(200m M)刺激的AML-12细胞处理24小时。通过ELISA来检

关键词：马鞭草苷酒精性脂肪性肝炎 mdmx PPARα 铁死亡