The yeast surface as a platform for inhibitor discovery
酵母表面作为抑制剂发现的平台
基本信息
- 批准号:9797047
- 负责人:
- 金额:$ 33.4万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-07-01 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:Active SitesAmino AcidsAntibodiesBindingBiologicalBiological AssayBiological ProcessBiologyCellsChemicalsChemistryDiseaseDisease ProgressionEnzyme InhibitionEnzyme Inhibitor DrugsEnzymesExhibitsExtracellular MatrixFamilyGoalsHealthHumanLeadLigand BindingLigandsMedicalMetalloproteasesModalityPathologic ProcessesPhysiologyPlayProcessPropertyProteinsQuantitative EvaluationsReporterRoleSignal TransductionSpecificitySurfaceTechnologyTestingYeastsantibody librarieschemical functionchemical grouphigh throughput screeninghuman diseaseinhibitor/antagonistinsightpreventprogramsscreeningsmall moleculetool
项目摘要
Advances in screening technologies have made ligand discovery against biological targets routine, but
converting binding ligands into specific enzyme inhibitors is extremely challenging, even for metalloproteinases
and other enzymes with well-defined active sites. The lack of specific inhibitors prevents full elucidation of
biological processes as basic as extracellular matrix remodeling. Proteins and small molecules each lack key
features of inhibitors. Antibodies and other proteins rarely disrupt enzyme function, but usually exhibit high
binding specificity. Small molecules frequently lack single-enzyme specificity, but interfere with enzymatic
activity. Neither of these modalities is well-suited for generating potent, specific enzyme inhibitors.
My long-term goals are to 1) establish general principles for discovering potent, specific inhibitors against
medically relevant enzymes;; and 2) utilize the resulting inhibitors to understand the roles of enzymes such as
metalloproteinases in normal physiology and pathological processes. I hypothesize that simultaneously
leveraging the complementary strengths of proteins and small molecules will give rise to entirely new classes
of potent, specific inhibitors. The goal during this proposal period is to convert yeast display, a powerful
ligand discovery platform, into a comprehensive inhibitor discovery platform. My lab has already established
strategies for expanding the chemical functionality that can be utilized in combination with yeast display. Here,
we will enhance our platform further and use it to identify inhibitors against a test set of metalloproteinase
targets. In the process, we will gain fundamental insights into how to generate inhibitors that are not accessible
using any current inhibitor discovery approaches, setting the stage for 1) a greatly expanded toolkit for studying
basic biology;; and 2) much broader inhibitor discovery efforts. The initial directions we will pursue are:
Direction 1. Expand the range of chemistries that can be encoded in yeast-displayed proteins.
Proteins containing canonical amino acids lack key groups found in enzyme inhibitors. We will utilize our
quantitative reporter of ncAA incorporation to encode these functionalities in yeast-displayed proteins.
Direction 2. Establish assays for quantitatively evaluating enzyme inhibition on the yeast surface.
No existing display technologies support quantitative evaluations of enzyme inhibition during high
throughput screening. We will utilize dual yeast display technology to establish these capabilities.
Direction 3. Use chemically augmented antibody libraries to evolve potent, specific inhibitors.
Antibodies rarely inhibit enzymes. We will generate and screen libraries of antibodies containing added
chemical groups to establish general principles for inhibitor isolation in this unexplored discovery space.
To focus our discovery efforts, we and our collaborators have identified metalloproteinases from multiple
families that play important roles in human health and disease. The general discovery principles we establish
here will lead directly to new classes of inhibitors for understanding and treating human disease.
筛选技术的进步使得针对生物靶点的配体发现成为常规,但是
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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James Allen Van Deventer其他文献
James Allen Van Deventer的其他文献
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{{ truncateString('James Allen Van Deventer', 18)}}的其他基金
The yeast surface as a platform for inhibitor discovery
酵母表面作为抑制剂发现的平台
- 批准号:
10597525 - 财政年份:2019
- 资助金额:
$ 33.4万 - 项目类别:
The yeast surface as a platform for inhibitor discovery
酵母表面作为抑制剂发现的平台
- 批准号:
10386824 - 财政年份:2019
- 资助金额:
$ 33.4万 - 项目类别:
Discovering hybrid inhibitors for tumor microenvironment disruption
发现破坏肿瘤微环境的混合抑制剂
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9924473 - 财政年份:2018
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New Approaches to the Selective Targeting of Cancer-associated Fibroblasts
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8461821 - 财政年份:2012
- 资助金额:
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New Approaches to the Selective Targeting of Cancer-associated Fibroblasts
选择性靶向癌症相关成纤维细胞的新方法
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8312910 - 财政年份:2012
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New Approaches to the Selective Targeting of Cancer-associated Fibroblasts
选择性靶向癌症相关成纤维细胞的新方法
- 批准号:
8685911 - 财政年份:2012
- 资助金额:
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