Development of Specific Inhibitors for Oncogenic Phosphatase PPM1D by Using Ion-Responsive DNA Aptamer Library
Development of Specific Inhibitors for Oncogenic Phosphatase PPM1D by Using Ion-Responsive DNA Aptamer Library
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DOI：
10.3390/catal10101153
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发表时间：
2020-10
期刊：
影响因子：
3.9
通讯作者：
A. Kaneko;Miyuu Watari;Masataka Mizunuma;H. Saito;K. Furukawa;Y. Chuman
中科院分区：
文献类型：
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作者：
A. Kaneko;Miyuu Watari;Masataka Mizunuma;H. Saito;K. Furukawa;Y. Chuman
(1)背景：丝氨酸/苏氨酸蛋白磷酸酶PPM 1D是一种致癌蛋白。然而，在正常细胞中，PPM 1D在精子发生和免疫反应中起着重要作用。因此，有必要开发对正常细胞没有副作用的新型PPM 1D抑制剂。刺激响应分子适用于抑制活性的时空调节。(2)研究方法：在这项研究中，我们设计了一个基于G-四链体DNA的离子响应DNA适体库，可以改变其构象和功能，以响应单价阳离子。(3)结果：利用该文库，我们鉴定了PPM 1D特异性抑制剂M1 D-Q5 F适体。M1 D-Q5 F适体显示出对乳腺癌MCF 7细胞的抗癌活性。有趣的是，在单价阳离子刺激下，诱导结构变化导致G-四链体的形成，从而增强M1 D-Q5 F的抑制活性和结合亲和力。(4)结论：这些数据表明，M1 D-Q5 F适体可能作为一种新的刺激响应性抗癌剂。
(1) Background: Ser/Thr protein phosphatase PPM1D is an oncogenic protein. In normal cells, however, PPM1D plays essential roles in spermatogenesis and immune response. Hence, it is necessary to develop novel PPM1D inhibitors without side effects on normal cells. Stimuli-responsive molecules are suitable for the spatiotemporal regulation of inhibitory activity. (2) Methods: In this study, we designed an ion-responsive DNA aptamer library based on G-quadruplex DNA that can change its conformation and function in response to monovalent cations. (3) Results: Using this library, we identified the PPM1D specific inhibitor M1D-Q5F aptamer. The M1D-Q5F aptamer showed anti-cancer activity against breast cancer MCF7 cells. Interestingly, the induction of the structural change resulting in the formation of G-quadruplex upon stimulation by monovalent cations led to the enhancement of the inhibitory activity and binding affinity of M1D-Q5F. (4) Conclusions: These data suggest that the M1D-Q5F aptamer may act as a novel stimuli-responsive anti-cancer agent.