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

目前治疗哮喘的方法，同时通过集中精力减少部分患者的病情恶化 对呼吸道炎症，不要消除它们。目前还没有先天免疫调节剂来治疗 哮喘的治疗。哮喘加重是发病率和死亡率的重要原因。 在哮喘中，因为它们会导致呼吸道损伤，肺功能下降和死亡。一家公司的事业 恶化通常是在异常呼吸道炎症的背景下发生的感染。他们的回应 感染是复杂的，既涉及先天免疫系统，也涉及获得性免疫系统。中国的情况恶化 更严重的哮喘患者尤其令人担忧，因为医疗费用和生产力损失 占美国每年医疗保健支出的210亿美元。因此，迫切需要 开发用于治疗炎症性肺部疾病的新疗法，包括 哮喘。这项第一阶段建议的目标是开发新的短肽衍生物和 表面活性蛋白-A(SP-A)活性区域的模拟 肺部的免疫功能，并进行药物筛选，以识别那些最活跃和 稳定，与全长蛋白质的功效相似。SP-A衍生的多肽不是自然产生的 通过合成类似物，我们可以创建自定义修改，并改进 药代动力学特性和稳定性。我们将使用哮喘作为我们的测试模型，其中SP-A 多肽类似物调节嗜酸性粒细胞和上皮细胞的功能，这是细胞 机制驱动过敏性哮喘的表型。这项研究的理由是基于我们的 研究发现，SP-A肽可降低呼吸道高反应性(AHR)，这是一种基本的 哮喘的特征，在两种不同的临床前哮喘小鼠模型中。我们有很强的 支持保护作用机制的证据是由于1)直接与 嗜酸性粒细胞诱导细胞凋亡并促进其从呼吸道分解和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 通过直接作用于气道嗜酸性粒细胞和上皮细胞，SP-A衍生的多肽 减少与哮喘相关的呼吸道炎症和高反应性。我们建议 通过两个具体目标来检验这一假设。在目标1中，我们将综合、设计和优化 从SP-A衍生的多肽和结构模拟物来鉴定一个铅模拟物。在《目标2》中我们将 SP-A衍生肽的生物活性及其在特定细胞靶点的模拟 使用高吞吐量来鉴定先导化合物。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饰的原则 为这类新的哮喘治疗药物的开发提供了稳定的条件。

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.