Design of Therapeutic Peptide-Based Nanoparticles

治疗性肽纳米颗粒的设计

• 批准号: 8020925
• 负责人: VADIM V GAPONENKO
• 金额: $ 31.6万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-04 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8020925
• 关键词: Address; Amino Acid Substitution; Antineoplastic Agents; Binding; Biodistribution; Biological; Biological Assay; Blood; CCR5 gene; CXCR4 gene; Cell membrane; Circular Dichroism; Clinical; Complex; Development; Dimethyl Sulfoxide; Disease; Drug Industry; Electron Microscopy; Environment; Exhibits; Goals; Growth; Guidelines; HIV; HIV Entry Inhibitors; Hydrophobic Interactions; Investments; Joints; Knowledge; Learning; Life; Lipids; Liposomes; Lysosomes; Malignant Neoplasms; Marketing; Medicine; Membrane; Membrane Proteins; Micelles; Modeling; Molecular Conformation; Multi-Drug Resistance; Mus; Mutation; Nanostructures; Nuclear Magnetic Resonance; P-Glycoprotein; Peptide Conformation; Peptides; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Problem Solving; Property; Proteins; Receptor Inhibition; Reporting; Research; Resistance development; Retinal Cone; Secretin; Serum; Solutions; Solvents; Specificity; Stream; Structure; Techniques; Testing; Therapeutic; Therapeutic Agents; Treatment Efficacy; amphiphilicity; aqueous; base; cancer cell; chemokine receptor; common rule; design; inhibitor/antagonist; intermolecular interaction; light scattering; malignant breast neoplasm; mutant; nanoparticle; novel; novel strategies; novel therapeutics; particle; peptide analog; peptide hormone; peptide structure; prevent; public health relevance; self assembly; small molecule; targeted delivery; tumor

DESCRIPTION (provided by applicant): With increasing investment into pharmaceutical industry there is a paradoxical decline in the number of new medicines on the market. One of the reasons for this phenomenon is the focus of pharmaceutical companies on small molecules for development of therapeutic agents. Although they are potent inhibitors of target proteins, small molecules are known for their low specificity. Larger and more complex molecules, such as peptides, provide more specific target recognition. However, peptides are unstable and require design of cellular delivery mechanisms. Utilization of structural plasticity of peptide molecules in biological solvents is a novel approach to solve the problems with peptide pharmaceutical agents. In aqueous solutions certain peptides exhibit a distinct beta-hairpin conformation that allows them to assemble into spherical nanostructures. Nanostructures encounter a hydrophobic environment of the plasma membrane, disassemble, insert into the membrane, change their conformation, and inhibit target proteins. I hypothesize that by studying the peptide assembly mechanism into nanoparticles it is possible to formulate a set of requirements for the design of peptides capable to form nanoparticles. The long term goal is to define the requirements for intermolecular interactions between peptides allowing assembly into nanoparticles. Understanding the mechanism of peptide structure transitions will enable development of novel therapeutic nanoparticles capable of performing an encoded sequence of tasks. I shall address the requirements for the design of such peptides by studying the structure of the monomeric peptides, the mechanism of nanoparticle assembly, and the structural changes in the lipid environment. I propose the following specific aims: (1) Determine the structural requirements for the monomeric peptide that allow assembly into nanoparticles using nuclear magnetic resonance (NMR) techniques; (2) Identify the intermolecular interactions responsible for peptide assembly into nanoparticles using NMR, electron microscopy, and dynamic light-scattering; (3) Analyze structural changes that the peptide molecules undergo in the lipid environment by NMR. PUBLIC HEALTH RELEVANCE: This application addresses elucidation of mechanisms of peptide assembly into spherical nanoparticles and structure-based optimization of anti-cancer activity of chemokine receptor CXCR4 inhibitor peptide f22. PEGylated f22 peptide assembles into spherical nanoparticles, inhibits breast cancer growth, and prolongs survival in mouse breast cancer dissipation model. F22 self-assembly into nanoparticles may prevent peptide degradation in the blood stream and provide targeted delivery of f22 to CXCR4 expressing tumors due to the enhanced permeability and retention effect. The knowledge acquired as a result of the proposed research may be applied to the development of novel peptide pharmaceutical agents.

描述（由申请人提供）：随着对制药行业的投资越来越多，市场上新药物的数量有矛盾的下降。这种现象的原因之一是制药公司的重点是用于开发治疗剂的小分子。尽管它们是靶蛋白的有效抑制剂，但小分子以低特异性而闻名。更大，更复杂的分子（例如肽）提供了更具体的靶标识别。但是，肽是不稳定的，需要设计细胞递送机制。生物溶剂中肽分子的结构可塑性的利用是一种解决肽药物问题的新方法。在水溶液中，某些肽表现出独特的β发构构象，使它们可以组装成球形纳米结构。纳米结构遇到质膜的疏水环境，拆卸，插入膜，改变其构象并抑制靶蛋白。我假设通过研究肽组装机制到纳米颗粒中，可以制定一组能够形成纳米颗粒的肽设计的要求。长期目标是定义肽之间的分子间相互作用的要求，从而使组装成纳米颗粒。了解肽结构过渡的机制将使能够开发能够执行编码任务序列的新型治疗纳米颗粒。我将通过研究单体肽的结构，纳米颗粒组件的机理以及脂质环境中的结构变化来解决这种肽设计的要求。我提出以下特定目的：（1）确定单体肽的结构要求，该肽允许使用核磁共振（NMR）技术将组装到纳米颗粒中； （2）使用NMR，电子显微镜和动态光散射确定负责肽组装到纳米颗粒中的分子间相互作用； （3）分析NMR在脂质环境中肽分子经历的结构变化。 公共卫生相关性：该应用程序阐明了将肽组装机制阐明到球形纳米颗粒中的机制，并基于结构的趋化因子受体CXCR4抑制剂肽F22的抗癌活性优化。聚乙二醇化的F22肽聚集到球形纳米颗粒中，抑制乳腺癌的生长，并延长小鼠乳腺癌耗散模型的生存。 F22自组装到纳米颗粒中可能会防止血流中的肽降解，并由于渗透性增强和保留效应而靶向f22向CXCR4表达肿瘤的靶向递送。提出的研究获得的知识可能应用于新型肽药物的发展。