Su Aoze, Wang Siyuan, Sada Akane, Otani Yuko, Zhai Luhan, Liu Xin, Sayama Misa, Ohki Rieko, Ohwada Tomohiko
Graduate School of Pharmaceutical Sciences, University of Tokyo.
Laboratory of Fundamental Oncology, National Cancer Center Research Institute.
Chem Pharm Bull (Tokyo). 2019;67(10):1139-1143. doi: 10.1248/cpb.c19-00501.
We have discovered that β-amino acid homooligomers with cis- or trans-amide conformation can fold themselves into highly ordered helices. Moreover, unlike α-amino acid peptides, which are significantly stabilized by intramolecular hydrogen bonding, these helical structures are autogenous conformations that are stable without the aid of hydrogen bonding and irrespective of solvent (protic/aprotic/halogenated) or temperature. A structural overlap comparison of helical cis/trans bicyclic β-proline homooligomers with typical α-helix structure of α-amino acid peptides reveals clear differences of pitch and diameter per turn. Bridgehead substituents of the present homooligomers point outwards from the helical surface. We were interested to know whether such non-naturally occurring divergent helical molecules could mimic α-helix structures. In this study, we show that bicyclic β-proline oligomer derivatives inhibit p53-MDM2 and p53-MDMX protein-protein interactions, exhibiting MDM2-antagonistic and MDMX-antagonistic activities.
我们发现，具有顺式或反式酰胺构象的β-氨基酸同聚体能够自行折叠成高度有序的螺旋结构。此外，与通过分子内氢键显著稳定的α-氨基酸肽不同，这些螺旋结构是自发构象，无需氢键辅助且不受溶剂（质子性/非质子性/卤代）或温度影响即可保持稳定。将螺旋状顺式/反式双环β-脯氨酸同聚体与α-氨基酸肽的典型α-螺旋结构进行结构重叠比较，结果显示每圈螺距和直径存在明显差异。本同聚体的桥头取代基从螺旋表面向外突出。我们很想知道这种非天然存在的不同螺旋分子是否能够模拟α-螺旋结构。在本研究中，我们表明双环β-脯氨酸寡聚体衍生物可抑制p53-MDM2和p53-MDMX蛋白-蛋白相互作用，表现出MDM2拮抗活性和MDMX拮抗活性。
