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

• 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
• 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

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部，在哮喘的发病机制中发挥关键作用。最近的研究表明，针对正确诊断的嗜酸性粒细胞性哮喘患者的嗜酸性粒细胞可以带来显着的健康益处。然而，非嗜酸性粒细胞内型哮喘患者表现出更普遍的中性粒细胞炎症，但目前还没有针对这种内型的成功治疗方法。人们越来越认识到，为了有效干扰哮喘中炎症细胞的趋化性，需要抑制不止一种趋化因子受体。目前尚无药物能够多方面干扰嗜酸性粒细胞和中性粒细胞的趋化作用。 CCR3趋化因子受体结合其首选趋化因子嗜酸细胞趋化因子，并促进嗜酸性粒细胞募集至肺部。除了嗜酸细胞趋化因子外，CCR3 还结合负责 Th2 淋巴细胞、嗜碱性粒细胞、肥大细胞和中性粒细胞趋化作用的趋化因子。这种结合是由受体的细胞外环介导的。我们建议设计具有 CCR3 细胞外环呈现的新型肽基纳米粒子，以充当诱饵 CCR3 受体或直接抑制受体功能。这些纳米粒子会隔离针对嗜酸性粒细胞和潜在的其他炎症细胞（例如中性粒细胞）的趋化因子。与用于药物输送的常用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。我们使用这种方法开发了基于肽的纳米颗粒，可以拮抗 CXCR4（一种类似于 CCR3 的趋化因子受体）。 X4-2-6 是一种跨膜螺旋肽类似物，包含细胞外环 1，靶向 CXCR4 受体，抑制 HIV 进入和乳腺癌转移。基于 x4-2-6 组装成纳米颗粒和隔离 SDF-1 的能力，我们同样建议开发含有 CCR3 跨膜和细胞外环部分的肽。这些肽序列由具有高螺旋倾向的疏水性氨基酸组成，并包含 N 端和 C 端电荷。这些肽特性决定了肽在水溶液中组装成球形纳米粒子。我们假设可以设计 CCR3 的肽类似物，使其表现出与 CXCR4 肽 x4-2-6 类似的特性，即它们将能够形成参与嗜酸性粒细胞和可能的中性粒细胞迁移的纳米颗粒和螯合趋化因子（即嗜酸细胞趋化因子） /招募到组织中或直接抑制CCR3功能。为了解决这一假设，提出了两个具体目标：（1）确定CCR3跨膜肽组装成纳米颗粒以及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)在小鼠三抗原过敏性哮喘模型中证明CCR3肽纳米颗粒在体外和体内抑制趋化因子依赖性炎症反应的能力。拟议的项目很可能会对开发新型哮喘疗法的一般方法产生重大影响。

项目成果

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

新型肽纳米粒子偏向的 CCR3 拮抗剂可阻止嗜酸性粒细胞募集和气道高反应性。

• 发表时间: 2019-02
• 作者: Grozdanovic, Milica;Laffey, Kimberly G;Abdelkarim, Hazem;Hitchinson, Ben;Harijith, Anantha;Moon, Hyung;Park, Gye Young;Rousslang, Lee K;Masterson, Joanne C;Furuta, Glenn T;Tarasova, Nadya I;Gaponenko, Vadim;Ackerman, Steven J
• 通讯作者: Ackerman, Steven J