Peptides may revolutionize the treatment of disease by combining the pharmacological benefits found in both large and small molecules into once-daily oral formulations. For decades, batch-mode solid-phase peptide synthesis (SPPS) has been employed throughout peptide drug discovery and development; however, numerous drawbacks have persisted despite advancements in the technology. Herein, we describe a continuous-flow (CF) SPPS workflow to optimize and deliver multigram quantities of peptide fragments, which are easily transformed to macrocyclic or linear peptide APIs. To develop this workflow, we leveraged a 10-amino acid peptide based on a recently disclosed macrocyclic peptide inhibitor of PCSK9. Compared with batch-mode SPPS, CF-SPPS enables rapid, data-rich optimization of peptide sequences with drastic reductions in development efforts, process execution timelines, and waste generation. To meet project demands and deliver multigram quantities, a hydraulically controlled CF-SPPS prototype was developed, which leverages small-scale optimization data to facilitate a seamless transition to larger deliveries of peptides.

中文翻译：

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连续流固相肽合成可实现快速、多克的肽交付


通过将大分子和小分子的药理益处结合到每日一次的口服制剂中，肽可能会彻底改变疾病的治疗。几十年来，批量模式固相肽合成 (SPPS) 已应用于肽药物的发现和开发过程中。然而，尽管技术取得了进步，但仍然存在许多缺点。在此，我们描述了连续流 (CF) SPPS 工作流程，用于优化和交付数克数量的肽片段，这些片段很容易转化为大环或线性肽 API。为了开发此工作流程，我们利用了基于最近公开的 PCSK9 大环肽抑制剂的 10 个氨基酸肽。与批量模式 SPPS 相比，CF-SPPS 能够快速、数据丰富地优化肽序列，并大幅减少开发工作、流程执行时间和废物产生。为了满足项目需求并交付数克数量，开发了液压控制的 CF-SPPS 原型，该原型利用小规模优化数据来促进无缝过渡到更大规模的肽交付。