Broadly Applicable and Comprehensive Synthetic Method for <i>N</i>‑Alkyl-Rich Drug-like Cyclic Peptides

We report a versatile and durable method for synthesizing highly N-alkylated drug-like cyclic peptides. This is the first reported method for synthesizing such peptides in parallel with a high success rate and acceptable purity that does not require optimizations for a particular sequence. We set up each reaction condition by overcoming the following issues: (1) diketopiperazine (DKP) formation, (2) insufficient peptide bond formation due to the steric hindrance of the N-alkylated amino acid, and (3) instability of highly N-alkylated peptides under acidic conditions. Using this newly established method, we successfully synthesized thousands of cyclic peptides to explore the scope of this modality in drug discovery. We here demonstrate the syntheses of a hundred representative examples, including our first clinical N-alkyl-rich cyclic peptide (LUNA18) that inhibits an intracellular tough target (RAS), in 31% total yield and 97% purity on average after 23 or 24 reaction steps.本研究报道了一种通用且稳健的高N-烷基化类药环肽合成方法。这是首款无需针对特定序列进行优化、可并行合成且兼具高成功率与合格纯度的此类肽类合成方法。我们通过攻克以下三大难题确立了各反应条件：(1) 二酮哌嗪（diketopiperazine, DKP）的副反应生成；(2) 因N-烷基化氨基酸位阻效应导致的肽键形成不足；(3) 高N-烷基化肽在酸性条件下的不稳定性。依托该新建立的方法，我们成功合成了数千个环肽，以探索该合成策略在药物发现领域的应用范围。本研究展示了100个代表性合成案例，其中包括首款进入临床阶段的富N-烷基化环肽（LUNA18）——该肽可抑制细胞内难治靶点RAS，其经23或24步反应后总收率达31%，平均纯度为97%。