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Identification of Protein Drug Leads That Address Challenges to Small Molecule Ce

鉴定解决小分子 Ce 挑战的蛋白质药物先导物

基本信息

批准号：
9067398
负责人：
Brian R McNaughton
金额：
$ 28万
依托单位：
COLORADO STATE UNIVERSITY
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：
2014-05-15 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9067398
关键词：
Address Affinity Ankyrin Repeat Antibodies Basic Science Binding Binding Proteins Biochemical Biochemical Process Biological Assay California Calorimetry Cell physiology Cells Communities Complex Data Development Diagnostic Disease Drug Targeting Engineering Evolution Exhibits Exons Face Fluorescence Polarization Generations HIV HIV-1 Health Human Immunoglobulin Fragments In Vitro Lead Libraries Measures Membrane Proteins Methods Mutagenesis Nucleotides Phage Display Pharmaceutical Preparations Phase Phenotype Physiological Play Production Property Proteins RNA RNA Recognition Motif RNA Splicing RNA-Binding Proteins Randomized Reagent Research Response Elements Role Shapes Signal Transduction Specificity Structure Surface Surface Plasmon Resonance Techniques Technology Therapeutic Therapeutic Human Experimentation Titrations Transactivation Universities Variant Work base cellular targeting design drug discovery functional group high throughput screening improved in vivo interest macromolecule member nanomolar novel therapeutic intervention overexpression professor protein protein interaction scaffold small molecule therapeutic development tool

项目摘要

DESCRIPTION (provided by applicant): Macromolecules have demonstrated great value as research tools, human therapeutics, and diagnostics. The size and complexity of folded macromolecules can result in potencies and specificities of action that are not easily achievable using small molecules. Features unique to folded macromolecules make them well suited for therapeutic and basic research applications. The theoretical functional diversity of human health-related antibodies, or their fragments, is large because antibodies and antibody fragments can be raised against a theoretically infinite number of disease-related targets in vivo, including targets that are typically viewed as "undruggable" using small molecules. However, the generation, production, and purification of antibodies and their fragments is often difficult and expensive. Methods to identify unnatural proteins that bind therapeutically relevant cellular targets in vivo are of considerable interest to the biomedical community because they may significantly increase the number of proteins with therapeutic activity, and represent an alternative strategy to antibody-based macromolecular therapeutic development. Here, we propose to exploit our recent development of split-superpositive GFP reassembly to identify unnatural proteins with affinity for ankyrin repeat domain proteins overexpressed in disease, and which frustrate small molecule-based drug discovery. In addition, we will use protein evolution and engineering to identify RNA binding proteins with high affinity and specificity for RNA hairpins critical to HIV replication. The therapeutic potential of these new protein reagents will be measured using a number of in vitro and cell-based assays. Taken together, the findings revealed in this research will potentially lead to the generation of proteins that overcome limitations to small molecule-centered drug discovery, and may point the way to new therapeutic strategies.

描述(申请人提供)：大分子已显示出作为研究工具、人类治疗学和诊断学的巨大价值。折叠的大分子的大小和复杂性可以导致使用小分子不容易实现的作用的效力和特异性。折叠大分子的独特特性使其非常适合于治疗和基础研究应用。人类健康相关抗体或其片段的理论功能多样性很大，因为抗体和抗体片段可以在体内针对理论上无限数量的疾病相关靶点进行提升，包括通常被认为是使用小分子“无法下药”的靶点。然而，抗体及其片段的产生、生产和纯化往往是困难和昂贵的。在体内识别与治疗相关的细胞靶点的非天然蛋白质的方法引起了生物医学界的极大兴趣，因为它们可以显著增加具有治疗活性的蛋白质的数量，并代表了一种替代基于抗体的大分子治疗开发的策略。在这里，我们建议利用我们最新的分裂超阳性GFP重组技术来识别与疾病中过度表达的Ankyrin重复结构域蛋白具有亲和力的非自然蛋白，这些蛋白阻碍了基于小分子的药物开发。此外，我们将利用蛋白质进化和工程学来鉴定对HIV复制至关重要的RNA发夹具有高亲和力和特异性的RNA结合蛋白。这些新的蛋白质试剂的治疗潜力将使用一些体外和基于细胞的分析来衡量。综上所述，这项研究中揭示的发现可能会导致蛋白质的产生，从而克服以小分子为中心的药物发现的限制，并可能为新的治疗策略指明方向。