D-peptide activators of p53 as anticancer therapeutics

p53 的 D 肽激活剂作为抗癌疗法

• 批准号: 8774207
• 负责人: WUYUAN LU
• 金额: $ 16.69万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8774207
• 关键词: Affinity; Animals; Antineoplastic Agents; Apoptotic; Binding; Biochemical; Biological; Biological Availability; Breast; Cancer Biology; Cancer Patient; Cancerous; Cell Culture Techniques; Cell Cycle Arrest; Cell Membrane Permeability; Cell membrane; Cells; Cellular Stress; Chemicals; Clinical; Colon Carcinoma; Complex; DNA Binding Domain; Development; Experimental Designs; Funding; Genes; Goals; Growth; Hand; Health; Homologous Gene; Human; Hydrocarbons; Image; Impairment; In Vitro; Induction of Apoptosis; Laboratories; Lead; Left; Ligands; Liposomes; Lung; MDM2 gene; Malignant Neoplasms; Malignant neoplasm of liver; Membrane; Modification; Molecular; Molecular Conformation; Molecular Target; Mus; Mutate; N-terminal; Normal Cell; Oncogenic; Parents; Pathway interactions; Peptide Hydrolases; Peptides; Phage Display; Play; Predisposition; Property; Protein Chemistry; Protein p53; Proteins; Proteolysis; Reporting; Research; Resistance; Role; Series; Side; Signal Pathway; Structure; TP53 gene; Techniques; Testing; Therapeutic; Transactivation; Tumor Cell Line; Tumor Suppressor Proteins; Uterine Cancer; Xenograft Model; analog; anti-cancer therapeutic; base; biophysical techniques; cancer therapy; cell injury; chemotherapy; crosslink; design; drug discovery; human disease; in vivo; inhibitor/antagonist; innovation; killings; malignant stomach neoplasm; neoplastic cell; novel; novel therapeutics; nutlin 3; peptidomimetics; prevent; response; structural biology; synthetic peptide; therapeutic target; transcription factor; tumor; tumor growth; tumorigenesis; ubiquitin-protein ligase; uptake; weapons

DESCRIPTION (provided by applicant): The proposed multi-disciplinary research combines contemporary synthetic peptide/protein chemistry, structural biology, cancer biology, and various biochemical and biophysical techniques, showcasing a powerful, innovative, and integrated approach to filling an important gap in peptide-based anticancer drug discovery. If funded, this project will lead to the addition of new weapons to the existing anticancer arsenal, and broadly impact the development of peptide therapeutics for targeted molecular therapy of many other human diseases as well. Background: p53 is activated as a transcription factor to induce powerful growth inhibitory and apoptotic responses to cellular stress, but is otherwise tightly controlled in normal cells by its negative regulators MDM2 and MDMX. Impairment of the p53 pathway is a hallmark of almost all human tumors where either the TP53 gene is mutated or the p53 protein is functionally inactivated by MDM2 and MDMX. Over-expression or amplification of MDM2 and MDMX in many tumors correlates with a normal (wild type) status of p53, contributing to robust p53 inhibition and degradation. Recent studies have validated inhibition of the p53-MDM2/MDMX interaction as a new therapeutic paradigm for cancer treatment. Our laboratory has developed a series of high-affinity D- peptide antagonists of MDM2 and MDMX (DPMI-α,β,γ,δ) that, when delivered via a liposomal carrier vehicle, are capable of killing tumor cells in vitro and in vivo by activating the p53 pathway. Objective: Using DPMI-δ as a parent molecule (KD = 220 pM for MDM2 and 200 nM for MDMX), we seek to develop high-affinity, protease-resistant, and cell-penetrating D-peptide antagonists of MDM2 and MDMX for potential anticancer therapy. Specific Aims: (1) Design side-chain cross- linked forms of DPMI-δ capable of traversing the cell membrane to stabilize intracellular p53. We will use the hydrocarbon stapling technique to design a series of side-chain cross-linked analogs of DPMI- δ, and evaluate their functional and structural properties with respect to α-helicity, MDM2/MDMX binding, and membrane permeabilization. (2) Test the hypothesis that high-affinity, protease- resistant, and cell-penetrating D-peptide antagonists of MDM2 and MDMX reactivate the p53 pathway and kill tumor cells through cell cycle arrest and/or apoptosis induction. We will evaluate tumor-killing activity of side-chain cross-linked forms of DPMI-δ using a variety of tumor cell lines with or without wild type p53. Our long-term objective is to develop D-peptide-based p53 activators as a novel class of anticancer therapeutics for clinical use.

项目描述（由申请人提供）：本项目拟开展的多学科研究结合了当代合成肽/蛋白质化学、结构生物学、癌症生物学以及各种生物化学和生物物理技术，展示了一种强大的、创新的、综合的方法，以填补基于肽的抗癌药物发现的重要空白。如果获得资助，该项目将为现有的抗癌武器库增加新的武器，并广泛影响用于许多其他人类疾病靶向分子治疗的肽疗法的发展。背景：p53作为一种转录因子被激活，在细胞应激时诱导强大的生长抑制和凋亡反应，但在正常细胞中，p53受到其负调节因子MDM2和MDMX的严格控制。p53通路的损伤是几乎所有人类肿瘤的一个标志，在这些肿瘤中，要么TP53基因突变，要么p53蛋白被MDM2和MDMX功能性失活。在许多肿瘤中，MDM2和MDMX的过度表达或扩增与p53的正常（野生型）状态相关，有助于p53的强抑制和降解。最近的研究证实，抑制p53-MDM2/MDMX相互作用是一种新的癌症治疗模式。我们的实验室已经开发了一系列MDM2和MDMX （DPMI-α,β,γ,δ）的高亲和力D肽拮抗剂，当通过脂质体载体传递时，能够通过激活p53途径在体外和体内杀死肿瘤细胞。

项目成果

A stapled peptide antagonist of MDM2 carried by polymeric micelles sensitizes glioblastoma to temozolomide treatment through p53 activation.

• DOI: 10.1016/j.jconrel.2015.09.061
• 发表时间: 2015-11-28
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: Chen X;Tai L;Gao J;Qian J;Zhang M;Li B;Xie C;Lu L;Lu W;Lu W
• 通讯作者: Lu W

Lanthanide-doped nanoparticles conjugated with an anti-CD33 antibody and a p53-activating peptide for acute myeloid leukemia therapy.

• DOI: 10.1016/j.biomaterials.2018.03.025
• 发表时间: 2018-06
• 期刊: Biomaterials
• 影响因子: 14
• 作者: Niu F;Yan J;Ma B;Li S;Shao Y;He P;Zhang W;He W;Ma PX;Lu W
• 通讯作者: Lu W

Peptide-Induced Self-Assembly of Therapeutics into a Well-Defined Nanoshell with Tumor-Triggered Shape and Charge Switch.

• DOI: 10.1021/acs.chemmater.8b02572
• 发表时间: 2018
• 期刊: Chemistry of materials : a publication of the American Chemical Society
• 作者: He W;Yan J;Jiang W;Li S;Qu Y;Niu F;Yan Y;Sui F;Wang S;Zhou Y;Jin L;Li Y;Ji M;Ma PX;Liu M;Lu W;Hou P
• 通讯作者: Hou P