Ribosomal Synthesis of Peptides with Unnatural Building Blocks

具有非天然结构单元的肽的核糖体合成

• 批准号: 8268133
• 负责人: PETER G SCHULTZ
• 金额: $ 35.59万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8268133
• 关键词: Affinity; Amino Acids; Bacteria; Biological; Chemicals; Complement; Cyclic Peptides; Development; Disease; Electronics; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Generations; Genetic; Libraries; Metalloproteases; Methodology; Methods; Molecular Structure; Mutagenesis; Mutation; Peptide Library; Peptide Synthesis; Peptides; Phage Display; Preparation; Property; Proteins; Serine Protease; System; Technology; Therapeutic; Therapeutic Uses; Time; base; functional group; in vivo; inhibitor/antagonist; intein; novel; novel strategies; protein function; research study

DESCRIPTION (provided by applicant): We will attempt to use our unnatural amino acid mutagenesis methodology to genetically encode libraries of cyclic and linear peptides containing a diverse array of unnatural amino acids. These peptide libraries will be generated both intracellularly in bacteria and in a phage-displayed format to allow in vivo selections and display-based affinity panning, respectively. This strategy will enable direct genetic encoding of molecular structure, random or directed mutagenesis, selection, and biological amplification, while at the same time allowing chemical diversity beyond what the canonical 20 amino acid repertoire can offer. The integration of unnatural amino acids into genetically encoded peptide libraries should facilitate both evolutionary experiments and the generation of peptides with novel biological activities that may ultimately find therapeutic use. This will be achieved through the following specific aims: 1. The preparation and incorporation of novel unnatural amino acids with unique reactivities and with functional groups capable of targeting specific proteins involved in disease states (e.g., serine proteases, metalloproteases, etc.) 2. The use of intein-based intracellular cyclic peptide synthesis methodologies together with unnatural amino acid technology to generate novel cyclic peptide libraries and select specific enzyme inhibitors 3. The use of phage display systems to generate and screen libraries of peptides containing unnatural amino acids for inhibitors of specific protein targets.

描述（由申请人提供）：我们将尝试使用我们的非天然氨基酸诱变方法来对含有多种非天然氨基酸阵列的环状和线性肽的遗传库进行遗传编码。这些肽文库将在细菌和噬菌体播种格式中分别细胞内生成，以分别允许体内选择和基于显示的亲和力平移。该策略将实现分子结构，随机或定向诱变，选择和生物学扩增的直接遗传编码，同时允许化学多样性超出规范20氨基酸库所提供的。将非天然氨基酸的整合到遗传编码的肽库中，应促进进化实验和具有新型生物学活性的肽的产生，这些活性最终可能会发现治疗性。这将通过以下特定目的来实现：1。具有独特反应率的新型非天然氨基酸的制备和融合，并与能够靶向涉及疾病状态的特定蛋白质的功能组（例如，丝氨酸蛋白酶，金属蛋白酶，金属蛋白酶等）2。文库并选择特定的酶抑制剂3。使用噬菌体显示系统来生成和筛选含有特定蛋白质靶标的抑制剂的肽的肽库和筛选。