Strategies for N to C solid-phase peptide synthesis

项目摘要 基于肽的药物在晚期临床应用中变得越来越普遍。 试验和FDA批准。肽合成传统上在C至N方向上进行， 固体载体。以N到C方向的肽合成将使新的机会， 提高肽纯度和产率，因为它将避免困扰C至N SPPS副反应 并在肽的组装过程中潜在地改变肽的聚集状态。然而，在这方面， 例如恶唑酮形成和哌嗪二酮形成的挑战长期以来阻止了 这种方法的实施。这项研究计划的长期目标是 以促进复杂的生物活性多肽的合成。的目的 应用程序是建立一个平台，N到C SPPS，避免问题的障碍， 由恶唑酮形成引起的差向异构化和由二酮哌嗪引起的肽截短 阵我们将通过采用温和的羰基活化策略来实现这一目标， 使N到C的SPPS不会引起这些不希望的副反应。我们将开发 专门的方法来解决反应缓慢，具有挑战性的序列，和独特的功能， 这些基团对于制备生物活性肽是重要的。我们将建立 这些方法与最先进的SPPS技术（如微波和 流动方法与NIH国家普通医学研究所的使命一致 科学，这项基础研究将最终促进生物学研究的发展。 流程.此外，这项研究符合重点技术的目标 研究和开发计划，因为具体目标侧重于技术 与实施我们的肽创新战略相关的挑战和里程碑 合成.如果成功的话，拟议中的化学将通过积极的方式推进生物医学研究。 影响了所有需要合成肽的领域。

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.