Bicyclic peptides are a powerful modality for the engagement of challenging drug targets such as protein-protein interactions. The most common crosslinkers used to generate bicyclic peptides are C3-symmetrical, with evenly positioned peptide loops facing radially outwards from a linker core to favour globular conformations. In contrast, linkers with alternative symmetries can potentially provide access to a more diverse conformational landscape of bicyclic peptides. Here, we use 1,2,3-tris(bromomethyl) benzene (1,2,3-TBMB) to access bicyclic peptides with multiple isomeric configurations, leading to conformations that differ substantially from both the parent linear peptides and the conventional bicyclization products formed with 1,3,5-TBMB, as observed in 2D NMR and CD experiments. Bicyclization at cysteine residues proceeds efficiently under standard aqueous buffer conditions, with broad substrate scope, compatibility with high-throughput screening, and clean conversion (>90%) of linear precursors to bicyclic products for 88 of the 106 diverse peptide sequences tested. We envisage that the 1,2,3-TBMB linker will be applicable to a variety of peptide screening techniques, thereby enabling the discovery of unconventional bicyclic peptides that can engage a broad range of novel drug targets.

中文翻译：

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使用 1,2,3-TBMB 作为连接体获取不同的双环肽构象

双环肽是参与具有挑战性的药物靶点（例如蛋白质-蛋白质相互作用）的强大方式。用于生成双环肽的最常见交联剂是 C3 对称的，其均匀定位的肽环从接头核心径向向外，有利于球状构象。相比之下，具有替代对称性的连接体有可能提供更多样化的双环肽构象景观。在这里，我们使用 1,2,3-三（溴甲基）苯 (1,2,3-TBMB) 来获得具有多种异构体构型的双环肽，从而产生与母体线性肽和传统双环化产物显着不同的构象如 2D NMR 和 CD 实验中观察到的那样，与 1,3,5-TBMB 形成。半胱氨酸残基的双环化在标准水性缓冲液条件下高效进行，底物范围广泛，与高通量筛选兼容，并且在测试的 106 种不同肽序列中的 88 种中，线性前体完全转化为双环产物（>90%）。我们预计 1,2,3-TBMB 连接体将适用于各种肽筛选技术，从而能够发现能够与广泛的新型药物靶点结合的非常规双环肽。