Rational Design of Right-Handed Heterogeneous Peptidomimetics as Inhibitors of Protein-Protein Interactions.
Rational Design of Right-Handed Heterogeneous Peptidomimetics as Inhibitors of Protein-Protein Interactions.
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DOI：
10.1021/acs.jmedchem.0c01638
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发表时间：
2020-11-12
影响因子：
7.3
通讯作者：
Cai J
中科院分区：
文献类型：
--
作者：
Shi Y;Sang P;Lu J;Higbee P;Chen L;Yang L;Odom T;Daughdrill G;Chen J;Cai J
Peptidomimetics have gained great attention for their function as protein–protein interaction (PPI) inhibitors. Herein, we report the design and investigation of a series of right-handed helical heterogeneous 1:1 α/Sulfono-γ-AA peptides as unprecedented inhibitors for p53-MDM2 and p53-MDMX. The most potent helical heterogeneous 1:1 α/Sulfono-γ-AA peptides were shown to bind tightly to MDM2 and MDMX, with Kd of 19.3 and 66.8 nM, respectively. Circular dichroism spectra, 2D-NMR spectroscopy, and the computational simulations suggested that these helical sulfono-γ-AA peptides could mimic the critical side chains of p53 and disrupt p53/MDM2 PPI effectively. It was noted that these 1:1 α/Sulfono-γ-AA peptides were completely resistant to proteolytic degradation, boosting their potential for biomedical applications. Furthermore, effective cellular activity is achieved by the stapled 1:1 α/Sulfono-γ-AA peptides, evidenced by significantly enhanced p53 transcriptional activity and much more induced level of MDM2 and p21. The 1:1 α/Sulfono-γ-AA peptides could be an alternative strategy to antagonize a myriad of PPIs.
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影响因子：
4
作者：
Rezaei Araghi R;Ryan JA;Letai A;Keating AE
通讯作者：
Keating AE
影响因子：
2.9
作者：
Murray, Justin K.;Gellman, Samuel H.
通讯作者：
Gellman, Samuel H.
影响因子：
15
作者：
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通讯作者：
Arora, Paramjit S.
DOI：
10.1073/pnas.1303002110
发表时间：
2013-09-03
影响因子：
11.1
作者：
Chang, Yong S.;Graves, Bradford;Sawyer, Tomi K.
通讯作者：
Sawyer, Tomi K.
影响因子：
4.9
作者：
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通讯作者：
Cai, Jianfeng