Department of Chemistry, School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo, 113-0033, Japan.
Department of Chemistry, College of Chemistry and Chemical Engineering, The MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surface, Xiamen University, Xiamen, 361005, P. R. China.
Angew Chem Int Ed Engl. 2019 Apr 1;58(15):4880-4885. doi: 10.1002/anie.201813827. Epub 2019 Mar 12.
Bicyclic and tricyclic peptides have emerged as promising candidates for the development of protein binders and new therapeutics. However, convenient and efficient strategies that can generate topologically controlled bicyclic and tricyclic peptide scaffolds from fully-unprotected peptides are still much in demand, particularly for those amenable to the design of biosynthetic libraries. In this work, we report a reliable chemical and ribosomal synthesis of topologically controlled bicyclic and tricyclic peptide scaffolds. Our strategy involves the combination of selenoether cyclization followed by disulfide or thioether cyclization, yielding desirable bicyclic and tricyclic peptides. This work thus lays the foundation for developing peptide libraries with controlled topology of multicyclic scaffolds for in vitro display techniques.
双环和三环肽已成为开发蛋白质结合物和新型治疗药物的有前途的候选物。然而，人们仍然非常需要能够从完全非保护的肽中生成拓扑控制的双环和三环肽支架的方便且有效的策略，特别是对于那些适合生物合成文库设计的策略。在这项工作中，我们报告了拓扑控制的双环和三环肽支架的可靠的化学和核糖体合成。我们的策略涉及硒醚环化随后进行二硫键或硫醚环化的组合，得到所需的双环和三环肽。因此，这项工作为开发具有受控拓扑结构的多环支架的肽文库奠定了基础，可用于体外展示技术。
