Strategies for N to C solid-phase peptide synthesis

项目总结 基于多肽的药物在晚期临床中变得越来越普遍 试验和FDA批准。传统上，肽的合成是在C到N方向上进行的 坚实的支撑物。从N到C方向的多肽合成将带来新的机会 提高多肽纯度和产率，因为它将避免困扰C到N SPPS的副反应 并可能在其组装过程中改变多肽的聚集状态。然而， 像恶唑酮形成和二酮哌嗪形成这样的挑战长期以来一直阻碍着 这种方法的实施。这项研究计划的长期目标是 目的：促进复杂生物活性多肽的合成。这样做的目的是 应用是为N到C SPP建立一个平台，避免存在问题的障碍 恶唑酮形成引起的异构化和二酮基哌嗪引起的肽截断 队形。我们将通过采用温和的羰基活化策略来实现这一目标 在不引起这些不良副作用的情况下启用N到C SPPS。我们将发展 处理缓慢反应、具有挑战性的序列和独特功能的专门方法 对制备生物活性多肽很重要的基团。我们将建立 这些方法与最先进的SPPS技术的兼容性，如微波和 流动法。与美国国立卫生研究院国家普通医学研究所的使命一致 科学，这项基础研究最终将促进生物学研究的发展 流程。此外，本研究符合聚焦技术的目标 研发计划，因为具体目标侧重于技术 与实施多肽创新战略相关的挑战和里程碑 综合。如果成功，建议的化学将积极地推动生物医学研究 影响到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.