Development of surfactant protein A-derived peptidomimetics for the treatment of asthma

开发表面活性蛋白 A 衍生的肽模拟物用于治疗哮喘

基本信息

批准号：
10019073
负责人：
Scott Boitano
金额：
$ 21.49万
依托单位：
RAESEDO, LLC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-15 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10019073
关键词：
Active Sites Adaptive Immune System Adult Affect Animal Model Antiinflammatory Effect Apoptosis Arizona Asthma Automobile Driving Cell Line Cell physiology Cells Cessation of life Characteristics Child Clinic Collaborations Complex Custom Development Dose Drug Kinetics Drug Screening Engineering Environment Enzyme-Linked Immunosorbent Assay Epithelial Cells Extrinsic asthma Flow Cytometry Generations Goals Health Care Costs Health Expenditures Immune response Immunomodulators Infection Inflammation Interleukin-13 Lead Length Link Lung Lung diseases Measurement Modeling Modification Morbidity - disease rate Mucins Outcome Peptide Hydrolases Peptides Pharmaceutical Preparations Pharmacology Phase Phenotype Phosphorylation Population Predisposition Production Productivity Property Proteins Pulmonary Surfactant-Associated Protein A Resolution Respiratory Signs and Symptoms Respiratory System Respiratory physiology Ribavirin Syndrome System Testing Therapeutic Time Toxic effect United States Universities airway epithelium airway hyperresponsiveness airway inflammation analog asthma exacerbation asthma model asthmatic base cell analyzer cell type cellular targeting clinical candidate cytokine design eosinophil experience improved in vivo inflammatory lung disease injured airway innate immune function lead candidate mimetics mortality mouse model novel therapeutics patient subsets peptide analog peptide structure peptidomimetics phase 2 study pre-clinical protein aminoacid sequence response screening

项目摘要

Current treatments for asthma, while reducing exacerbations in a subset of patients by focusing on airway inflammation, do not eliminate them. There is no current innate immune modulator for the treatment of asthma. Asthma exacerbations are a significant cause of morbidity and mortality in asthma as they can lead to airway injury, lung function decline and death. The cause of an exacerbation is often an infection in the setting of abnormal airway inflammation. The response to infection is complex, involving both the innate and adaptive immune systems. Exacerbations in more severe asthmatics are of particular concern, as health care costs and lost productivity account for $21 billion/year in US annual health care expenditures. Thus, there is a critical need to develop new therapies to be used in the treatment of inflammatory lung diseases including asthma. The objective of this Phase I proposal is to develop new short peptide derivatives and mimetics of the active region of surfactant protein-A (SP-A), a protein that regulates key innate immune functions in the lung, and perform a drug screen that identifies those most active and stable with similar efficacy as the full-length protein. SP-A-derived peptides do not occur naturally and by synthetically produced analogs, we can create custom modifications with improved pharmacokinetic properties and stability. We will use asthma as our test model where SP-A peptide analogs modulate eosinophil and epithelial cell functions, key targets where cellular mechanisms drive the allergic asthma phenotype. The rationale for this study is based on our findings that the SP-A peptide reduces airway hyperresponsiveness (AHR), a fundamental characteristic of asthma, in two different pre-clinical mouse models of asthma. We have strong evidence to support that the mechanisms of protective action are due to 1) direct interaction with eosinophils to induce apoptosis and promote their resolution from the airway and 2) direct interaction with epithelial cells to inhibit mucin production. Therefore, our central hypothesis is that through direct effects upon airway eosinophil and epithelial cells, SP-A-derived peptides reduce airway inflammation and hyperresponsiveness associated with asthma. We propose to test this hypothesis through two specific aims. In Aim 1 we will synthesize, engineer and optimize peptides and structural mimetics derived from SP-A to identify a lead mimetic. In aim 2 we will characterize the bioactivity of SP-A-derived peptides and mimetics at specific cellular targets to identify a lead compound using a high throughput. Our company, RaeSedo LLC, was founded on the principle that we can create custom modifications with improved pharmacokinetic properties and stability for the development of this new class of asthma therapeutics.

目前对哮喘的治疗方法，同时通过聚焦减少患者部分的加重在气道炎症上，不要消除它们。目前没有先天性免疫调节剂哮喘的治疗。哮喘恶化是发病率和死亡率的重要原因在哮喘中，它们可能导致气道受伤，肺功能下降和死亡。原因在异常气道炎症的情况下，加重通常是一种感染。反应感染很复杂，涉及先天和适应性免疫系统。加重由于医疗保健成本和生产力降低，更严重的哮喘患者特别关注美国年度医疗保健支出为210亿美元。因此，有急需开发用于用于治疗炎症性肺部疾病的新疗法哮喘。该阶段I建议的目的是开发新的短肽衍生物，并表面活性剂蛋白A（SP-A）活性区域的模拟物，一种调节关键先天物的蛋白质肺部的免疫功能，并执行一个识别最活跃的药物筛查的药物筛查稳定具有与全长蛋白相似的功效。 SP-A衍生的肽不会自然发生通过合成产生的类似物，我们可以通过改进来创建自定义修改药代动力学特性和稳定性。我们将使用哮喘作为SP-A的测试模型肽类似物调节嗜酸性粒细胞和上皮细胞功能，关键靶标的细胞机制驱动过敏性哮喘表型。这项研究的理由是基于我们的 SP-A肽可降低气道高反应性（AHR）的发现，这是一种基本哮喘的特征，在两种不同的链式小鼠哮喘模型中。我们有强大证据支持保护行动的机制是由于1）直接相互作用嗜酸性粒细胞诱导凋亡并促进其从气道促进其分辨率，2）直接与上皮细胞相互作用以抑制粘蛋白的产生。因此，我们的中心假设是通过对气道嗜酸性粒细胞和上皮细胞的直接影响，SP-A衍生的肽减少与哮喘相关的气道炎症和反应性过高。我们建议通过两个具体目标检验该假设。在AIM 1中，我们将合成，设计和优化从SP-A得出的肽和结构模拟物来鉴定铅模拟物。在目标2中，我们将表征特定细胞靶标的SP-A衍生肽和模拟物的生物活性使用高吞吐量识别铅化合物。我们的公司Raesedo LLC成立于我们可以通过改进的药代特性创建自定义修改的原则以及开发这种新的哮喘治疗剂的稳定性。