Genetically Encoded Fragment-based Drug Discovery

基于基因编码片段的药物发现

• 批准号: 8843018
• 负责人: Christopher Murray
• 金额: $ 6.43万
• 依托单位: GALEN BIOTECHNOLOGIES, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8843018
• 关键词: Address; Affect; Affinity; Amino Acids; Amino Acyl Transfer RNA; Aminoacylation; Antineoplastic Agents; BCL2 gene; Binding; Biochemical; Biological; Cells; Chemical Structure; Chemicals; Copper; DNA; Data; Development; Disease; Drug Design; Effectiveness; Genetic; Genetic Transcription; Goals; Health; In Vitro; Individual; Lead; Libraries; Ligands; Ligation; Malignant Neoplasms; Messenger RNA; Methods; Molecular; Molecular Biology; Organic Chemistry; Organized by Structure Protein; Outcome; Oximes; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Protein Biosynthesis; Protein Engineering; Proteins; RNA, Transfer, Amino Acid-Specific; Research; Resolution; Ribosomes; Risk; Scaffolding Protein; Side; Site; Solutions; Speed; Structure; Technology; Terminator Codon; Therapeutic Intervention; Thinking; Transfer RNA; Translations; Validation; Work; alpha helix; base; chemical reaction; combinatorial; cycloaddition; design; drug development; drug discovery; human disease; in vitro testing; inhibitor/antagonist; innovative technologies; molecular recognition; next generation sequencing; novel; novel strategies; novel therapeutics; peptidomimetics; pharmacophore; protein folding; protein protein interaction; protein structure; small molecule; synthetic biology; theories

DESCRIPTION (provided by applicant): The ultimate goal of this project is to develop a new approach for discovering small molecules against intractable protein-protein interaction (PPI) interfaces that are difficult to address using current fragment-based library approaches. Our strategy involves reengineering ribosomal translation to encode libraries of diverse pharmacophore side chains embedded in known protein structures. This approach will allow rapid searches of large chemical space with exquisitely controlled resolution in order to find drug leads more rapidly and with less expense. The experimental approach is based on well validated cell-free synthesis of proteins. The principle aims are to (i) develop chemical and biochemical methods of fragment library assembly (ii) design, build, and test an in vitro ribosomal 'chassis' for genetic encoding of fragment-based libraries, and (iii) identify novel pharmacophore structures presented on alpha-helical proteins that will be able to affect a PPI. The first demonstration protein studied, Bcl-2, is a validated target for anti-cancer agents, and will therefore lead to development of new drugs. Successful completion of this project would demonstrate a platform technology that could produce unprecedented improvements in our ability to modulate PPIs across multiple target classes and diseases with small molecule ligands.

描述（由申请人提供）：该项目的最终目标是开发一种新方法，以发现针对棘手的蛋白质 - 蛋白质相互作用（PPI）接口，这些方法很难使用当前基于碎片的库方法来解决。我们的策略涉及重新设计核糖体翻译，以编码已知蛋白质结构中嵌入的不同药效侧链的库。这种方法将允许以精美控制的分辨率快速搜索大型化学空间，以便找到药物 领导更快，费用较低。实验方法基于经过良好验证的蛋白质无细胞合成。该原则的目的是（i）开发碎片库组装的化学和生化方法（II）设计，构建和测试用于基于碎片库的遗传编码的体外核糖体“底盘”，（iii）鉴定出在α-螺旋蛋白上呈现的新型药物团结构，这些蛋白会影响PPI。研究的第一个示范蛋白Bcl-2是抗癌药物的验证靶标，因此将导致新药的发展。该项目的成功完成将展示一种平台技术，该技术可以在我们跨多个目标类别和小分子配体疾病调节PPI的能力方面取得前所未有的改进。