Hymel David, Grant Robert A, Tsuji Kohei, Yaffe Michael B, Burke Terrence R
Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702, USA.
Department of Biology and Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Bioorg Med Chem Lett. 2018 Oct 15;28(19):3202-3205. doi: 10.1016/j.bmcl.2018.08.018. Epub 2018 Aug 19.
Transition toward peptide mimetics of reduced size is an important objective of peptide macrocyclization. We have previously shown that PLHSpT (2a) (where H indicates the presence of a -(CH)Ph 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.
向更小尺寸的肽模拟物转变是肽大环化的一个重要目标。我们之前已经表明，PLHSpT（2a）（其中H表示在N(π)位置存在一个-(CH)Ph基团，pT表示磷酸苏氨酸）是polo样激酶1（Plk1）polo盒结构域（PBD）的一种极高亲和力配体。在此我们报告，使用N(π),N(τ)-双烷基化的His残基作为环连接点对2a进行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具有高效力，并且相对于Plk2和Plk3的PBD，对Plk1 PBD保持良好的靶标选择性。重要的是，以5d为例，我们目前的方法允许删除N端的“Pro-Leu”基序，以产生分子量降低的三肽配体，这些配体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一般肽大环化合物的未来发展，尤其是影响与Plk
