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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.

目前的哮喘治疗方法，同时通过关注对气道炎症，不消除它们。目前还没有先天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，它们可导致气道损伤、肺功能下降和死亡。的根源急性发作通常是在异常气道炎症情况下的感染。响应感染是复杂的，涉及先天和适应性免疫系统。有病情加重更严重的哮喘患者尤其令人担忧，因为医疗保健费用和生产力损失占美国每年医疗保健支出的210亿美元。因此，开发用于治疗炎性肺病的新疗法，包括哮喘该I期提案的目标是开发新的短肽衍生物，表面活性蛋白A（SP-A）活性区的模拟物，SP-A是一种调节关键先天性肺中的免疫功能，并进行药物筛选，以确定那些最活跃，稳定，具有与全长蛋白质相似的功效。SP-A衍生肽不天然存在通过合成产生的类似物，我们可以创建具有改进的药代动力学性质和稳定性。我们将使用哮喘作为我们的测试模型，肽类似物调节嗜酸性粒细胞和上皮细胞功能，过敏性哮喘表型的驱动机制。这项研究的基本原理是基于我们的 SP-A肽降低气道高反应性（AHR），这是一个基本的在两种不同的哮喘临床前小鼠模型中，我们有强大有证据表明，保护作用机制是由于1）与嗜酸性粒细胞诱导凋亡，并促进其从气道中的解决和2）直接与上皮细胞相互作用以抑制粘蛋白产生。因此，我们的中心假设是通过直接作用于气道嗜酸性粒细胞和上皮细胞，SP-A衍生肽减少与哮喘相关的气道炎症和高反应性。我们建议通过两个具体目标来检验这个假设。在目标1中，我们将综合、设计和优化衍生自SP-A的肽和结构模拟物以鉴定先导模拟物。在目标2中，表征SP-A衍生肽和模拟物在特定细胞靶点的生物活性，使用高通量鉴定先导化合物。我们的公司，RaeSedo LLC，成立于我们可以创建具有改进的药代动力学特性的定制修改的原则和稳定性，用于开发这类新的哮喘治疗药物。