Strategies for N to C solid-phase peptide synthesis

N 到 C 固相肽合成策略

• 批准号: 10183269
• 负责人: Jennifer Lynn Stockdill
• 金额: $ 30.05万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10183269
• 关键词: Address; Amino Acid Sequence; Amino Acids; Basic Science; Biological; Biological Process; Biomedical Research; C-terminal; Carboxylic Acids; Chemicals; Chemistry; Clinical Trials; Complex; Conversion disorder; Coupling; Data; Development; Diamines; Elements; Gene Expression; Goals; Hydrophobicity; Improve Access; Lasso; Link; Mediating; Medical; Methodology; Methods; Mission; Modeling; National Institute of General Medical Sciences; Peptide Library; Peptide Synthesis; Peptides; Pharmacologic Substance; Phase; Plague; Prevalence; Program Development; Property; Protocols documentation; Reaction; Recombinants; Reporting; Research; Scheme; Side; Solid; Study models; Sulfhydryl Compounds; Sulfur; Technology; Temperature; United States National Institutes of Health; Urea; Vertebral column; Work; base; biological preparation; chemical synthesis; design; diketopiperazine; epimerization; functional group; improved; innovation; microwave electromagnetic radiation; non-Native; novel; novel strategies; polypeptide; prevent; programs; protein protein interaction; reactivation from latency; synthetic peptide; technology research and development; tool

PROJECT SUMMARY Peptide based pharmaceuticals are becoming increasingly prevalent in late-stage clinical trials and FDA approvals. Peptide synthesis is traditionally performed in the C to N direction on solid supports. Peptide synthesis in the N to C direction would enable new opportunities to improve peptide purity and yield because it will avoid side reactions that plague C to N SPPS and potentially alter the aggregation state of the peptide during its assembly. However, challenges such as oxazalone formation and diketopiperazine formation have long prevented the implementation of such an approach. The long-term objective of this program of research is to facilitate the synthesis of complex biologically active polypeptides. The objective of this application is to establish a platform for N to C SPPS that avoids the problematic hurdles of epimerization caused by oxazalone formation and peptide truncation due to diketopiperazine formation. We will achieve this objective by employing a mild carbonyl activation strategy that enable N to C SPPS without causing these undesirable side reactions. We will develop specialized methods to address slow reactions, challenging sequences, and unique functional groups that are important to the preparation of biologically active peptides. We will establish the compatibility of these methods with state-of-the-art SPPS technologies such as microwave and flow methods. Consistent with the mission of the NIH’s National Institute of General Medical Sciences, this basic research will ultimately facilitate developments in the study of biological processes. Furthermore, this research meets the objectives of the Focused Technology Research and Development Program because the specific aims focus on the technical challenges and milestones associated with implementing our innovative strategy for peptide synthesis. If successful, the proposed chemistry will advance biomedical research by positively impacting all fields where synthetic peptides are needed.

项目摘要 在晚期临床中，基于肽的药物越来越普遍 试验和FDA批准。传统上，肽合成是在C到N方向上进行的 固体支持。 N到C方向的肽合成将使新的机会 提高肽的纯度和产量 并可能改变肽组装过程中的聚集状态。然而， 长期以来，诸如奥卡酮形成和二酮替代的形成等挑战已经阻止了 这种方法的实施。该研究计划的长期目标是 促进复杂的生物活性多肽的合成。这个目的 应用是为n到c spps建立平台，以避免 由奥沙舍酮的形成和肽截断引起的呈现 形成。我们将采用轻度的羰基激活策略来实现这一目标 启用n至c spp，而不会引起这些不良的侧反应。我们将发展 解决缓慢反应，挑战序列和独特功能的专业方法 对于制备生物活性辣椒很重要的群体。我们将建立 这些方法与最先进的SPPS技术（例如微波）和 流量方法。与NIH国家通用医学研究所的任务一致 科学，这项基础研究最终将促进生物学研究的发展 过程。此外，这项研究符合集中技术的目标 研发计划，因为具体的目的是专注于技术 与实施我们的肽创新战略相关的挑战和里程碑 合成。如果成功，提出的化学将通过积极地推进生物医学研究 影响需要合成胡椒的所有领域。