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Histidine N(τ)-cyclized macrocycles as a new genre of polo-like kinase 1 polo-box domain-binding inhibitors.
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2018-08-19 , DOI: 10.1016/j.bmcl.2018.08.018
David Hymel 1 , Robert A Grant 2 , Kohei Tsuji 1 , Michael B Yaffe 2 , Terrence R Burke 1
Affiliation  

Transition toward peptide mimetics of reduced size is an important objective of peptide macrocyclization. We have previously shown that PLH∗SpT (2a) (where H∗ indicates the presence of a -(CH2)8Ph group at the N(π) position and pT indicates phosphothreonine) is an extremely high affinity ligand of the polo-like kinase 1 (Plk1) polo-box domain (PBD). Herein we report that C-terminal macrocyclization of 2a employing N(π),N(τ)-bis-alkylated His residues as ring junctions can be achieved in a very direct fashion. The resulting macrocycles are highly potent in biochemical assays and maintain good target selectivity for the Plk1 PBD versus the PBDs of Plk2 and Plk3. Importantly, as exemplified by 5d, our current approach permits deletion of the N-terminal "Pro-Leu" motif to yield tripeptide ligands with decreased molecular weight, which retain high affinity and show improved target selectivity. These findings could fundamentally impact the future development of peptide macrocycles in general and Plk1 PBD-binding peptide mimetics in particular.

中文翻译:


组氨酸 N(τ)-环化大环化合物作为一种新型的 polo 样激酶 1 polo-box 结构域结合抑制剂。



向尺寸减小的肽模拟物的转变是肽大环化的一个重要目标。我们之前已经证明 PLH*SpT (2a)(其中 H* 表示 N(π) 位上存在 -(CH2)8Ph 基团,pT 表示磷酸苏氨酸)是 polo 样激酶的极高亲和力配体1 (Plk1) polo 框域 (PBD)。在此,我们报道了使用 N(π),N(τ)-双烷基化 His 残基作为环连接点的 2a 的 C 端大环化可以以非常直接的方式实现。所得大环化合物在生化测定中非常有效,并且对 Plk1 PBD 相对于 Plk2 和 Plk3 的 PBD 保持良好的靶标选择性。重要的是,如 5d 所示,我们目前的方法允许删除 N 末端“Pro-Leu”基序,以产生分子量降低的三肽配体,其保留高亲和力并显示出改善的靶标选择性。这些发现可能从根本上影响肽大环化合物的未来发展,特别是 Plk1 PBD 结合肽模拟物。
更新日期:2018-08-19
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