School of Chemistry, The University of Sydney, Camperdown, NSW 2006, Australia.
ARC Centre of Excellence for Innovations in Peptide and Protein Science, The University of Sydney, Camperdown, NSW 2006, Australia.
Org Biomol Chem. 2024 Jul 31;22(30):6095-6102. doi: 10.1039/d4ob00901k.
Bicyclic peptides are a powerful modality for engaging challenging drug targets such as protein-protein interactions. Here, we use 1,2,3-tris(bromomethyl)benzene (1,2,3-TBMB) to access bicyclic peptides with diverse conformations that differ from conventional bicyclisation products formed with 1,3,5-TBMB. Bicyclisation at cysteine residues under aqueous buffer conditions proceeds efficiently, with broad substrate scope, compatibility with high-throughput screening, and clean conversion (>90%) for 96 of the 115 peptides tested. We envisage that the 1,2,3-TBMB linker will be applicable to a variety of peptide screening techniques in drug discovery.
双环肽是一种强大的模式，可用于结合具有挑战性的药物靶点，如蛋白质-蛋白质相互作用。在这里，我们使用 1,2,3-三（溴甲基）苯（1,2,3-TBMB）来获得具有不同构象的双环肽，这些构象与用 1,3,5-TBMB 形成的常规双环化产物不同。在水缓冲条件下，半胱氨酸残基的双环化反应高效进行，具有广泛的底物范围，与高通量筛选兼容，并且 115 个测试肽中的 96 个转化率高（>90%）。我们设想 1,2,3-TBMB 连接子将适用于药物发现中各种肽筛选技术。
