Novel Approaches to the Total Chemical Synthesis of Lasso Peptides as a Scaffold

套索肽作为支架的全化学合成新方法

• 批准号: 8868928
• 负责人: STEPHEN B.H. KENT
• 金额: $ 19.75万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-13 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8868928
• 关键词: Amides; Amino Acid Sequence; Amino Acids; Anabolism; Anti-Bacterial Agents; Antiviral Agents; Architecture; Aspartic Acid; Biological; Biological Assay; Biological Factors; C-terminal; Chemicals; Chemistry; Chicago; Crystallography; Development; Dissection; Distal; Engineering; Enzymes; Glutamic Acid; Gram-Negative Bacteria; Grant; Health; Laboratories; Lactams; Lasso; Ligation; Link; MccJ25; Mediating; Methods; Molecular Conformation; N-terminal; Nature; Peptide Hydrolases; Peptide Synthesis; Peptides; Physiological; Proteins; Reporting; Resistance; Roentgen Rays; Route; Side; Solutions; Structure; Structure-Activity Relationship; Universities; Untranslated RNA; Work; analog; analytical method; antimicrobial drug; aqueous; base; chemical synthesis; covalent bond; desulfurization; novel; novel strategies; pathogenic bacteria; peptide structure; polypeptide; protein aminoacid sequence; receptor; scaffold; success; synthetic peptide; thioester

DESCRIPTION (provided by applicant): In this exploratory grant we will systematically develop the first total chemical synthesis of lasso peptides of native structure. Lasso peptides are ribosomally synthesized bacterial natural products that have a broad spectrum of biological activities as antimicrobial or antiviral agents, and as potent receptor antagonists. Lasso peptides isolated from nature have ~20 amino acids and have a unique folded structure that is essential for their stability and for full biological activity. This folded structure has a macrolactam ring between the N-terminal amino acid and the side chain carboxyl of a glutamic acid or aspartic acid residue; the C-terminal linear peptide segment is threaded through this ring. The challenge in total chemical synthesis of lasso peptides is forming this threaded structure. Although the biosynthesis of lasso peptides is quite well understood and can be used to engineer novel sequences, to date there has been no successful total chemical synthesis of a lasso peptide of native folded structure. Here we describe novel approaches to the synthesis of lasso peptides. The synthetic strategies draw on the broad range of cutting edge synthetic and analytical methods in this laboratory, and are prioritized in order of increasing synthetic complexity to provide for versatile implementation of alternatives if/when synthetic obstacles are encountered. The proposed routes are novel extensions of the thioester-mediated, amide-forming native chemical ligation methods developed in this laboratory, used in combination with our extensive expertise in peptide synthetic methods. The folded structures of our synthetic products will be unambiguously determined by established NMR and mass spectrometric methods, and by the racemic protein crystallography method recently pioneered in this laboratory for the determination of unknown Xray structures. All synthetic products will be screened against a panel of pathogenic bacteria. Successful total chemical synthesis of lasso peptides will enable the systematic dissection of the structure-function relationships in this important class of natura products and will enable the use of a much wider range of building blocks for the exploitation of the lasso peptide scaffold in the development of novel antibacterials.

描述（由申请人提供）：在此探索性赠款中，我们将系统地发展天然结构的套索肽的第一个总化学合成。拉索肽是核糖体合成的细菌天然产物，具有广泛的生物学活性，例如抗菌或抗病毒药，并且是有效的受体拮抗剂。拉索肽 与大自然分离的具有约20个氨基酸，具有独特的折叠结构，这对于它们的稳定性和完全的生物学活性至关重要。这种折叠的结构在N末端氨基酸和谷氨酸或天冬氨酸残基的侧链羧基之间具有大花生酰胺环。 C末端线性肽段通过该环螺纹。拉索肽的总化学合成的挑战是形成了这种螺纹结构。尽管套管肽的生物合成已广为人知，并且可以用于设计新型序列，但迄今为止，还没有成功的总化学合成天然折叠结构的套索肽。在这里，我们描述了套索肽合成的新方法。合成策略借鉴了该实验室中的各种尖端合成和分析方法的广泛范围，并以增加合成复杂性的顺序排序，以便在遇到合成障碍时提供多功能实施替代方案。所提出的途径是该实验室中开发的硫酯介导的，形成酰胺的天然化学连接方法的新型扩展，并与我们在肽合成方法方面的广泛专业知识结合使用。我们的合成产品的折叠结构将通过已建立的NMR和质谱法明确确定，以及最近在该实验室中率先确定未知X射线结构的外星蛋白晶体学方法。所有合成产品将针对一组致病细菌进行筛选。成功的套管肽的成功总化学合成将使在这一重要类别的Natura产品中的结构功能关系的系统解剖，并将能够在新型抗体的开发中使用较宽的构建块来利用套索肽支架的开发。