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

基本信息

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
项目类别：
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

项目摘要

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资金来开发一种新技术，该技术将极大地加速细胞因子受体的肽激动剂，并将使这些新发现的激动剂的重新工程以展示新颖的和医学上可取代的生物活性概况。这项技术将使庞大的随机生产肽的巨大文库分类，以直接识别患有适当受体的人激活特性。这是依赖于筛选与目标受体结合的肽激动剂发现方法的当前最新进展，其次是命中确认，肽重新合成以及一次测试激动剂活性在一次化合物中的测试。相比之下，Medikine提出了一种筛选大量肽的高吞吐量方法，不仅仅是用于结合的功能性能。这将通过创建肽库产生肽的库来完成，该肽以适合直接测试超高通量格式的细胞因子受体激活的形式表达肽。所得的功能测定旨在鉴定具有新型细胞因子样特性的肽，可用于许多在糖尿病，肥胖，纤维化，癌症和免疫疗法中的治疗应用。在第一阶段的研究中，将构建合适的产生肽的细菌，并评估细胞因子受体激活测定法中肽的性能。 I期目标的实现将为II期SBIR计划提供基础，以开发高通量，“无良好”技术，以筛选大型肽库的活动；并利用这种方法来发现忠实地模仿天然细胞因子活性的肽。第二阶段的具体目标将包括制定方案t筛查新的细胞因子受体激动剂的大型肽收集，以及选择诱导新颖的信号转导激活模式的肽的方法，导致新的和有用的细胞因子样生物活性。