Cell-Based Screening for Multi-Functional Chemokine Receptor Modulators

描述(申请人提供)：十种CC趋化因子受体中有八种与过敏、哮喘和其他免疫性疾病的病理有关。在多种动物模型中，对五种不同受体的药理抑制已被证明可以改善疾病，使CC趋化因子受体家族成为哮喘和过敏性疾病的靶向丰富的受体。尽管经过了几十年的开发和几次临床试验，但还没有针对炎症性疾病的趋化因子受体的药物进入公众。目前的假设是，由于大多数趋化因子受体被多个配体激活，三分之一的趋化因子配体激活多个受体，这种复杂性和冗余性可能不能通过一个靶点、一个药物筛选模型有效地解决。大多数内源性趋化因子以多个受体为靶标，通过“选择性非选择性”实现特定的生物学效应，即一小部分受体被特定的配体不同程度地激活。同样，许多非常有效的药物之所以有效，是因为它们调节了复杂的多组分疾病的多个靶点，如炎症和过敏性疾病。在疾病进展中涉及几个趋化因子受体的情况下，治疗干预的途径将受益于能够同时筛选化合物对整个靶点家族的影响，以分离具有适当激活或抑制曲线的药物。这一第一阶段SBIR建议的主题是开发一种基于细胞的检测系统，以实现同时筛选9种与疾病相关的趋化因子受体，以寻找具有所需选择性特征的新型激动剂和拮抗剂。这些研究的成功完成将创建一个系统来表征一种化合物对一系列受体的抑制情况，并使发现具有新的选择性特性的治疗候选药物成为可能。 公共卫生相关性：哮喘和过敏性疾病涉及一个高度冗余功能的复杂受体网络，使用传统的一药一受体模式很难达到治疗效果。这里描述的系统是一种在广泛的靶点上识别新疗法的效果的方法，以发现已知药物的意想不到的活性，并使专门针对多种受体的药物发现工作成为可能。

DESCRIPTION (provided by applicant): Eight of the ten CC chemokine receptors have been implicated in the pathology of allergy, asthma, and other immunological diseases. Pharmacological inhibition of five separate receptors has been shown to ameliorate disease in a variety of animal models making the CC chemokine receptor family a target-rich class of receptors for asthma and allergic disease. In spite of decades of development and several clinical trials, no drugs targeting chemokine receptors for inflammatory disease have progressed to the public. The current hypothesis is that since the majority of chemokine receptors are activated by multiple ligands and one-third of chemokine ligands activate multiple receptors, this complexity and redundancy may not be efficiently addressed by the one target, one drug screening model. Most endogenous chemokines target multiple receptors and thus achieve specific biological effects through a "selective non-selectivity" whereby a small subset of receptors is activated to varying degrees by a specific ligand. Similarly, many very efficacious drugs are only effective because they modulate multiple targets For complex multi-component diseases such as inflammation and allergic disease where several chemokine receptors have been implicated in disease progression, the path to therapeutic intervention would benefit from being able to screen compounds for their effects across the entire family of targets simultaneously, to isolate drugs with the proper activation or inhibition profiles. The subject of this Phase I SBIR proposal is the development of a cell-based assay system to enable the simultaneous screening of nine disease-relevant chemokine receptors to find novel agonists and antagonists with the desired selectivity profiles. The successful completion of these studies will create a system to characterize the inhibitory profile of a compound over a range of receptors and enable the discovery of therapeutic candidates with novel selectivity properties. PUBLIC HEALTH RELEVANCE: Asthma and allergic diseases involve a complex web of receptors with highly redundant functions making it difficult to achieve therapeutic efficacy using the traditional, one drug one receptor model. The system described here is a method of identifying the effects of novel therapies across a broad range of targets to find unexpected activities of known drugs and enable drug discovery efforts that specifically target multiple receptors.