Knudson Isaac J, Dover Taylor L, Dilworth Diondra A, Paloutzian Cameron, Paz Orel, Lin Jieye, Cho Hannah, Gonen Tamir, Schepartz Alanna, Miller Scott J
Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA.
Department of Chemistry, Yale University, New Haven, CT, USA.
Nat Chem. 2025 Sep 17. doi: 10.1038/s41557-025-01935-4.
Potent peptide ligands for therapeutically relevant targets are regularly returned from screening trillion-member libraries of ribosomally synthesized peptides containing non-canonical amino acids and macrocyclic architectures. Yet the chemical space explored by these peptides is a fraction of that embodied by natural products and pharmaceuticals, and most peptide leads require exhaustive medicinal chemistry optimization to improve potency and physicochemistry. To address the need for strategies to introduce chemical complexity and conformational control into peptide macrocycles, we report here that linear peptides with a reactive N-terminal β-keto or γ-keto amide can be synthesized ribosomally. Subsequent Friedländer reactions generate quinoline-peptide hybrids, some of which contain stable biaryl atropisomeric axes. We also demonstrate intramolecular Friedländer macrocyclization reactions-sufficiently mild to be employed on unprotected and in vitro-translated peptides-that embed a quinoline pharmacophore directly within the peptide backbone. The introduction of N-terminal ketone motifs into genetically encoded materials and their post-translational derivatization provides a paradigm for the programmed synthesis of peptide-derived materials that more closely resemble complex natural products.
用于治疗相关靶点的强效肽配体通常是从筛选含有非天然氨基酸和大环结构的核糖体合成肽的万亿成员文库中获得的。然而，这些肽所探索的化学空间只是天然产物和药物所体现的化学空间的一小部分，并且大多数肽先导物需要进行详尽的药物化学优化以提高效力和物理化学性质。为了满足将化学复杂性和构象控制引入肽大环的策略需求，我们在此报告，具有反应性N端β-酮或γ-酮酰胺的线性肽可以通过核糖体合成。随后的Friedländer反应生成喹啉-肽杂化物，其中一些含有稳定的联芳基阻转异构轴。我们还展示了分子内Friedländer大环化反应——足够温和，可以用于未保护的和体外翻译的肽——该反应将喹啉药效团直接嵌入肽主链中。将N端酮基序引入基因编码材料及其翻译后衍生化提供了一种用于程序化合成更类似于复杂天然产物的肽衍生材料的范例。
