Stereoselective recognition of the Ac-Glu-Tyr-OH dipeptide by pseudopeptidic cages
Stereoselective recognition of the Ac-Glu-Tyr-OH dipeptide by pseudopeptidic cages
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DOI：
10.1039/c5ob01889g
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发表时间：
2015-01-01
影响因子：
3.2
通讯作者：
Alfonso, Ignacio
中科院分区：
文献类型：
--
作者：
Faggi, Enrico;Vicent, Cristian;Alfonso, Ignacio
假肽分子笼是吸引人的受体，因为它们可以显示不同的极性和非极性相互作用位点的模块化框架和控制的处置。受先前的主客体知识的启发，设计并合成了基于丝氨酸和苏氨酸（分别为CySer和CyThr）的两个假肽分子笼，作为结合酪氨酸激酶的靶序列Ac-Glu-Tyr-OH二肽的四种可能的立体异构体的宿主。在乙腈水溶液中的仔细的NMR滴定实验允许的结合常数的测定，并反映了相应的非对映体的主-客体复合物的稳定性的差异。CySer笼证明比CyThr对应物稍微更有效，尽管两者显示出相似的立体选择性趋势：LL > DD = LD > DL。该立体选择性结合保留在气相中，如使用对映体标记方法（EL）的ESI-MS竞争实验以及CID实验所示。因此，MS确定的歧视遵循相同的趋势观察到的NMR，这表明，这些系统中观察到的立体选择性必须主要由极性主-客体相互作用。尽管短肽序列在竞争性介质中的立体选择性结合是超分子化学中的一个具有挑战性的问题，我们的研究结果表明，假肽笼在分子识别中的力量，在化学生物学中具有可预见的影响。
Pseudopeptidic molecular cages are appealing receptors since they can display different polar and nonpolar interaction sites in a modular framework and a controlled disposition. Inspired by previous hostguest knowledge, two pseudopeptidic molecular cages based on serine and threonine (CySer and CyThr, respectively) were designed and synthesized as hosts for the binding of the four possible stereoisomers of the Ac-Glu-Tyr-OH dipeptide, a target sequence of tyrosine kinases. The careful NMR titration experiments in aqueous acetonitrile allowed the determination of the binding constants and reflected a difference in the stability of the corresponding diastereomeric host-guest complexes. The CySer cage proved to be slightly more efficient than the CyThr counterpart, although both showed similar stereoselectivity trends: LL > DD = LD > DL. This stereoselective binding was retained in the gas phase, as shown by ESI-MS competition experiments using the enantiomer-labelled method (EL), as well as CID experiments. Thus, the MS-determined discriminations follow the same trends observed by NMR, suggesting that the stereoselectivity observed for these systems must be mainly dictated by the polar host-guest interactions. Despite the stereoselective binding of short peptide sequences in competitive media being a challenging issue in supramolecular chemistry, our results demonstrate the power of pseudopeptidic cages in molecular recognition with foreseen implications in chemical biology.