Peptide-based nanoparticle inhibition of CCR3-mediated inflammatory cell recruitm

基于肽的纳米颗粒抑制 CCR3 介导的炎症细胞募集

基本信息

批准号：
8663608
负责人：
VADIM V GAPONENKO
金额：
$ 19.54万
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：
2013
资助国家：
美国
起止时间：
2013-05-20 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8663608
关键词：
Address Allergens Allergic Reaction Amino Acids Antibodies Antigens Asthma Basophils Binding Biochemical Blood Bone Marrow C-terminal CC chemokine receptor 3 CXCR4 Receptors CXCR4 gene Cells Cellular biology Charge Chemotaxis Development Diagnosis Disease Drug Compounding Drug Delivery Systems Eotaxin Exhibits Extrinsic asthma Goals HIV Health Health Benefit Immigration In Vitro Incidence Inflammation Inflammatory Inflammatory Response Interleukin-5 Knowledge Leukocytes Lung Lymphocyte Mediating Modeling Molecular Biology Mucous body substance Mus Nanotechnology Neoplasm Metastasis Neutrophil Infiltration Pathogenesis Patients Peptides Pharmaceutical Preparations Pharmacologic Substance Play Problem Solving Property Proteins Quality of life Receptor Inhibition Research Respiratory physiology Role Severities Signal Transduction Solutions Stream Surface Symptoms T-Lymphocyte Testing Therapeutic Therapeutic Agents Time Tissues Toxic effect Uncertainty United States Work airway inflammation airway remodeling aqueous base cell motility chemokine chemokine receptor design eosinophil extracellular improved in vivo inhibitor/antagonist innovation malignant breast neoplasm mast cell migration nanoassembly nanoparticle nanoscale neutrophil novel peptide analog prevent protein aminoacid sequence public health relevance receptor receptor binding receptor function response small molecule

项目摘要

DESCRIPTION (provided by applicant): Chemokine signaling plays a critical role in the pathogenesis of asthma through the activation of eosinophil, Th2 lymphocyte, basophil, and neutrophil migration and recruitment into the lung. Recent studies indicate that targeting eosinophils in patients with properly diagnosed eosinophilic asthma can provide a significant health benefits. However, patients with the non-eosinophilic endotype of asthma exhibit more prevalent neutrophilic inflammation, but there are currently no successful treatments for this endotype. There is a growing realization that to efficiently interfere with the chemotaxis of inflammatory cells in asthma, more than one chemokine receptor needs to be inhibited. Currently, there are no drugs capable of multi-faceted interference with chemoattraction of eosinophils and neutrophils. The CCR3 chemokine receptor binds its preferred chemokines, the eotaxins, and facilitates recruitment of eosinophils to the lungs. In addition to eotaxins, CCR3 also binds chemokines responsible for the chemotaxis of Th2 lymphocytes, basophils, mast cells and neutrophils. This binding is mediated by the receptor's extracellular loops. We propose to design novel peptide- based nanoparticles with CCR3 extracellular loop presentation to act as decoy CCR3 receptors or to directly inhibit receptor function. These nanoparticles would sequester chemokines that target both eosinophils and potentially other inflammatory cells such as neutrophils. Unlike commonly available nanoscale passive carriers used for drug delivery, our novel CCR3 nanoparticles will act as drugs themselves. We used this approach to develop peptide-based nanoparticles that antagonize CXCR4, a chemokine receptor similar to CCR3. X4-2-6, a transmembrane helical peptide analog that includes the extracellular loop 1, targets CXCR4 receptors for inhibition of HIV entry and breast cancer metastasis. Based on the ability of x4-2-6 to assemble into nanoparticles, and to sequester SDF-1, we similarly propose to develop peptides containing transmembrane and extracellular loop portions of CCR3. These peptide sequences consist of hydrophobic amino acids with a high helical propensity and include N- and C-terminal charges. These peptide properties are responsible for the peptide's assembly into spherical nanoparticles in aqueous solution. We hypothesize that peptide analogs of CCR3 can be designed that will display properties similar to the CXCR4 peptide x4-2-6, namely, they will be able to form nanoparticles and sequester chemokines (i.e. eotaxins) that are involved in eosinophil and possibly neutrophil migration/recruitment into tissues or directly inhibit CCR3 function. To address this hypothesis, two specific aims are proposed: (1) Determine the ability of CCR3 transmembrane peptides to assemble into nanoparticles and to sequester chemokines involved in eosinophil and neutrophil recruitment; and (2) Demonstrate the ability of CCR3 peptide nanoparticles to inhibit chemokine-dependent inflammatory responses in vitro and in vivo in the mouse triple antigen allergic asthma model. The proposed project is highly likely to significantly impact the general approach to the development of novel asthma therapeutics.

描述（由申请人提供）：趋化因子信号传导通过激活嗜酸性粒细胞，Th2淋巴细胞，嗜碱性粒细胞和中性粒细胞迁移和募集到肺中，在哮喘发病中起关键作用。最近的研究表明，适当诊断的嗜酸性哮喘患者靶向嗜酸性粒细胞可以带来重大健康益处。但是，患有哮喘的非嗜酸性粒细胞内型患者表现出更为普遍的嗜中性炎症，但目前尚无该内型的成功治疗方法。越来越多的意识到，要有效地干扰哮喘炎性细胞的趋化性，需要抑制多个趋化因子受体。当前，没有能够多方体干扰嗜酸性粒细胞和中性粒细胞的药物。 CCR3趋化因子受体结合其首选的趋化因子，eotaxins，并促进嗜酸性粒细胞募集到肺部。除eotaxins外，CCR3还结合了负责Th2淋巴细胞，嗜碱性粒细胞，肥大细胞和中性粒细胞的趋化因子的趋化因子。该结合是由受体的细胞外回路介导的。我们建议用CCR3细胞外环呈现设计新型基于肽的纳米颗粒，以充当诱饵CCR3受体或直接抑制受体功能。这些纳米颗粒将隔离趋化因子，该趋化因子均靶向嗜酸性粒细胞和潜在的其他炎性细胞，例如中性粒细胞。与用于药物输送的常见纳米级被动载体不同，我们的新型CCR3纳米颗粒本身将充当药物。我们使用这种方法来开发基于肽的纳米颗粒，使CXCR4拮抗了类似于CCR3的趋化因子受体。 X4-2-6是一种跨膜螺旋肽类似物，包括细胞外环1，靶向CXCR4受体，用于抑制HIV进入和乳腺癌转移。基于X4-2-6组装成纳米颗粒的能力，以及隔离SDF-1的能力，我们类似地建议开发含有CCR3的跨膜和细胞外环的肽。这些肽序列由具有高螺旋倾向的疏水性氨基酸组成，包括N-和C末端电荷。这些肽特性负责水溶液中肽的组装到球形纳米颗粒中。我们假设可以设计CCR3的肽类似物，它将显示类似于CXCR4肽X4-2-6的特性，即，它们将能够形成纳米颗粒并序列化趋化因子（即eotaxins）（即eotaxins），这些因子（即eotaxins）与嗜酸性粒细胞有关，并可能与中性粒细胞/募集到组织中或直接在组织CCR中cr insccr insccr insccr insccr。为了解决这一假设，提出了两个具体的目的：（1）确定CCR3跨膜肽组装成纳米颗粒并隔离参与嗜酸性粒细胞和中性粒细胞募集的趋化因子的能力；（2）证明了CCR3肽纳米颗粒在小鼠三抗原过敏性哮喘模型中抑制趋化因子依赖性炎症反应的能力。拟议的项目极有可能显着影响新型哮喘治疗剂发展的一般方法。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Novel peptide nanoparticle-biased antagonist of CCR3 blocks eosinophil recruitment and airway hyperresponsiveness.

DOI：
10.1016/j.jaci.2018.05.003
发表时间：
2019-03
期刊：
The Journal of allergy and clinical immunology
影响因子：
0
作者：
Grozdanovic M;Laffey KG;Abdelkarim H;Hitchinson B;Harijith A;Moon HG;Park GY;Rousslang LK;Masterson JC;Furuta GT;Tarasova NI;Gaponenko V;Ackerman SJ
通讯作者：
Ackerman SJ