Technology for bioactivity based discovery of novel cytokine receptor agonists

基于生物活性的新型细胞因子受体激动剂发现技术

• 批准号: 8454138
• 负责人: WILLIAM J DOWER
• 金额: $ 23.99万
• 依托单位: MEDIKINE, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-02 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8454138
• 关键词: Achievement; Address; Adverse effects; Agonist; Bacteria; Binding; Biological; Biological Assay; Biological Products; CSF3 gene; Cell surface; Cells; Collection; Complex Mixtures; Coupling; Cytokine Receptors; Detection; Diabetes Mellitus; Engineering; Escherichia coli; Evaluation; Exhibits; Family; Fibrosis; Foundations; Funding; Goals; Growth; Half-Life; Insulin; Interferons; Libraries; Mammalian Cell; Marketing; Medical; Medicine; Membrane; Methods; Nutrient; Obesity; Pattern; Peptide Library; Peptides; Performance; Phase; Property; Receptor Activation; Recovery; Relative (related person); Reporter; Reporting; Signal Transduction; Small Business Innovation Research Grant; Solutions; Somatropin; Sorting - Cell Movement; Surface; System; Technology; Testing; Therapeutic; Time; Work; base; cancer immunotherapy; chemical stability; cost; cytokine; design; design and construction; extracellular; immunogenicity; improved; member; new technology; novel; phase 1 study; programs; promoter; protein aminoacid sequence; protocol development; public health relevance; rapid technique; receptor; recombinant peptide; screening; success

DESCRIPTION (provided by applicant): Medikine will use SBIR funding to develop a new technology that will greatly accelerate the discovery of peptide agonists of cytokine receptors, and will make possible the re-engineering of these newly discovered agonists to exhibit novel and medically-valuable bioactivity profiles. This technology will enable the sorting of enormous libraries of stochastically-produced peptides to directly identify those with appropriate receptor- activating properties. This is an important advance beyond the current state-of-the-art in peptide agonist discovery methods that rely on screening for binding to a target receptor, followed by hit confirmation, peptide re-synthesis, and testing for agonist activity one compound at a time. In contrast, Medikine proposes to develop a high throughput method of screening large collections of peptides for functional properties, not simply for binding. This will be accomplished by creating libraries of peptide producing bacteria engineered to express the peptides in a form suitable for direct testing for cytokine receptor activation in ultra-high-throughput formats. The resulting functional assays are designed to identify peptides with new cytokine-like properties useful for many therapeutic applications in diabetes, obesity, fibrosis, cancer, and immunotherapy. In Phase I studies, a suitable strain of peptide-producing bacteria will be constructed, and performance of the peptide in a cytokine receptor activation assay will be assessed. Achievement of Phase I objectives will provide the groundwork for a Phase II SBIR program to develop a high-throughput, "well-free" technology to screen the activity of large peptide libraries; and to utilize this method for the discovery of peptides that faithfully mimic te activities of natural cytokines. Specific goals of Phase II will include development of protocols t screen large peptide collections for novel cytokine receptor agonists, and methods of selecting peptides that induce novel patterns of signal transduction activation leading to new and useful cytokine-like bioactivities.

描述（由申请人提供）：Medikine将使用SBIR资金开发一种新技术，该技术将大大加速细胞因子受体肽激动剂的发现，并将使这些新发现的激动剂的重新设计成为可能，以展示新的和有医学价值的生物活性特征。这项技术将能够对随机产生的大量肽库进行分类，以直接鉴定具有适当受体的肽。 激活属性。这是肽激动剂发现方法的一个重要进步，超越了目前最先进的方法，这些方法依赖于筛选与靶受体的结合，然后进行命中确认，肽再合成，并一次测试一种化合物的激动剂活性。相比之下，Medikine提出开发一种高通量方法，用于筛选大量肽的功能特性，而不仅仅是结合。这将通过创建产肽细菌文库来实现，所述产肽细菌被工程化以表达适合于以超高通量形式直接测试细胞因子受体活化的形式的肽。所得到的功能测定被设计用于鉴定具有新的类精氨酸性质的肽，其可用于糖尿病、肥胖症、纤维化、癌症和免疫疗法中的许多治疗应用。在I期研究中，将构建合适的产肽细菌菌株，并评估肽在细胞因子受体活化试验中的性能。第一阶段目标的实现将为第二阶段SBIR计划提供基础，以开发高通量、“无孔”技术来筛选大肽文库的活性;并利用该方法发现忠实地模拟天然细胞因子活性的肽。II期的具体目标将包括开发用于筛选新的细胞因子受体激动剂的大肽集合的方案，以及选择诱导新的信号转导激活模式的肽的方法，所述信号转导激活模式导致新的和有用的精氨酸样生物活性。