Design of Therapeutic Peptide-Based Nanoparticles

治疗性肽纳米颗粒的设计

基本信息

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
项目类别：
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

项目摘要

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）：随着对制药行业投资的增加，市场上新药的数量却出现了矛盾的下降。造成这种现象的原因之一是制药公司将重点放在小分子上以开发治疗药物。尽管它们是靶蛋白的有效抑制剂，但小分子以其低特异性而闻名。更大、更复杂的分子（例如肽）可提供更具体的目标识别。然而，肽不稳定，需要设计细胞递送机制。利用生物溶剂中肽分子的结构可塑性是解决肽药剂问题的一种新方法。在水溶液中，某些肽表现出独特的β-发夹构象，使它们能够组装成球形纳米结构。纳米结构遇到质膜的疏水环境，分解，插入膜中，改变其构象，并抑制靶蛋白。我假设，通过研究肽组装成纳米颗粒的机制，可以为能够形成纳米颗粒的肽的设计制定一系列要求。长期目标是确定肽之间分子间相互作用的要求，从而允许组装成纳米颗粒。了解肽结构转变的机制将有助于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、纳米粒子组装的机制以及脂质环境中的结构变化来解决此类肽的设计要求。我提出以下具体目标：（1）确定单体肽的结构要求，以便使用核磁共振（NMR）技术组装成纳米颗粒； (2) 使用核磁共振、电子显微镜和动态光散射鉴定负责肽组装成纳米颗粒的分子间相互作用； (3)通过NMR分析肽分子在脂质环境中发生的结构变化。公共健康相关性：本申请致力于阐明肽组装成球形纳米粒子的机制以及趋化因子受体 CXCR4 抑制剂肽 f22 的抗癌活性的基于结构的优化。聚乙二醇化的 f22 肽组装成球形纳米颗粒，抑制乳腺癌生长，并延长小鼠乳腺癌消散模型的生存期。 F22 自组装成纳米颗粒可以防止肽在血流中降解，并由于增强的渗透性和保留效应而将 f22 靶向递送至表达 CXCR4 的肿瘤。通过拟议的研究获得的知识可以应用于新型肽药剂的开发。