Screening of Combinatorial Libraries for Complement C5 Inhibitors

补体 C5 抑制剂组合文库的筛选

基本信息

批准号：
8773082
负责人：
Richard DiScipio
金额：
$ 22.75万
依托单位：
TORREY PINES INST FOR MOLECULAR STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8773082
关键词：
Age related macular degeneration Anemia Arthritis Attention Autoimmune Diseases Binding Biochemistry Biological Assay Blood Chemicals Complement Complement 3 Convertase Complement 3b Complement 5a Complement Activation Complement Membrane Attack Complex Complement component C5 Coupled Demyelinations Detection Development Disease Dose Energy Transfer Ensure Enzymes FDA approved Fluorescence Fluorescence Resonance Energy Transfer Future Gel Chromatography Generations Goals Hemolytic Anemia Horseradish Peroxidase Immune Immune system Immunity Inflammation Inflammatory Institutes Intervention Lead Libraries Measures Mediating Medical Medicine Membrane Methods Molecular Molecular Target Multiple Sclerosis Neuropathy New Agents Outcome Pathology Pathway interactions Penetration Peptide Library Peptides Pharmaceutical Preparations Positioning Attribute Procedures Process Proteins Reaction Research Resources Safety Signal Transduction Solvents Specificity Syndrome System Testing Therapeutic Time Tissues combinatorial complement C5b cost design experience fast protein liquid chromatography fluorophore follow-up high throughput screening improved inhibitor/antagonist interest microorganism novel therapeutics prevent protein protein interaction public health relevance research study response screening small molecule small molecule libraries therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Complement is an immune effector system present in blood that functions to protect the body against microorganisms, but in situations of dysregulation, complement participates in a variety of pathologies inclusive of age-related macular degeneration, multiple sclerosis, Guillain-Barr syndrome, arthritis, and hemolytic anemias. However, to date only one complement therapeutic, Eculizumab, a mAb directed against C5, has attained FDA approval to treat hemolytic anemias. Accordingly, there is a pressing need for effective therapeutics that can tame aberrant complement inflammation and membranolysis in a variety of disorders. Given the diversity of complement mediated pathologies, an arsenal of therapeutic strategies requires development. Molecular targets to control unwanted complement activation currently under development include those to C3 and C5, which act pivotally in the pathways. C5 is of particular interest to us because activation results in the release of the inflammatory peptide C5a, and a larger fragment C5b that initiates the formation of the Membrane Attack Complex, which damages target membranes. Furthermore, we have experience investigating many functional and structural aspects of C5; therefore, we are well positioned to focus at C5 for discovery of specific inhibitors. For this purpose, assays are being developed that are suitable for screening chemical libraries in order to identify probes that antagonize C5 interactions. These include three sets of binding assays to measure C5 interactions, namely the reversible interaction with C3b, the reversible interaction with C6 and C7, and the irreversible binding to C6. These assays are suitable for medium (Aim 1) and high throughput screening (Aim 2). The plan is to screen initially combinatorial peptide libraries from the Torrey Pines Institute for Molecular Studies (Aim 3). These are a unique resource that were developed at this Institute, and are constituted by millions of entries. If the screening succeeds and yields inhibitory peptides that are specific, this would constitute the initial step of a long range project to discover new agents that can therapeutically intervene in pathological situations in which uncontrolled complement activation occurs.

描述（申请人提供）：补体是血液中存在的一种免疫效应系统，可保护身体免受微生物的作用，但是在失调的情况下，补体参与了多种病理学，包括与年龄相关的黄斑变性，多发性硬化症，多发性硬化症，吉兰 - 巴兰 - 巴龙综合症，关节炎和树脂性疾病。但是，迄今为止，只有一种补体治疗性的eculizumab是针对C5的mAb，已获得FDA批准以治疗溶血性贫血。因此，在各种疾病中迫切需要有效的治疗剂，这些治疗剂可能会驯服异常补体炎症和膜溶解。鉴于补体介导的病理多样性，治疗策略的库需要发展。控制当前正在开发的不良补体激活的分子靶标包括对C3和C5的靶标，这些靶标在途径中偶然起作用。 C5对我们特别感兴趣，因为激活会导致炎症肽C5A的释放，以及较大的片段C5B，它启动了膜攻击复合物的形成，该膜攻击复合物会损害靶膜。此外，我们还研究了C5的许多功能和结构方面的经验。因此，我们非常有能力将重点放在C5上，以发现特定的抑制剂。为此，正在开发适合筛选化学文库的测定方法，以识别与C5相互作用的探针。其中包括三组结合测定，以测量C5相互作用，即与C3B的可逆相互作用，与C6和C7的可逆相互作用以及与C6的不可逆结合。这些测定适用于培养基（AIM 1）和高吞吐量筛选（AIM 2）。该计划是从Torrey Pines分子研究研究所筛选出最初的组合肽库（AIM 3）。这些是该研究所开发的独特资源，由数百万条目组成。如果筛选成功并产生特定的抑制性肽，这将构成一个远程项目的第一步，以发现可以在病理情况下进行治疗的新药物，在这种情况下发生不受控制的补体激活。