A highly selective and potent PTP-MEG2 inhibitor with therapeutic potential for type 2 diabetes.
A highly selective and potent PTP-MEG2 inhibitor with therapeutic potential for type 2 diabetes.
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DOI：
10.1021/ja308212y
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发表时间：
2012-10-31
影响因子：
15
通讯作者：
Zhang, Zhong-Yin
中科院分区：
文献类型：
--
作者：
Zhang, Sheng;Liu, Sijiu;Tao, Rongya;Wei, Dan;Chen, Lan;Shen, Weihua;Yu, Zhi-Hong;Wang, Lina;Jones, David R.;Dong, Xiaocheng C.;Zhang, Zhong-Yin
蛋白酪氨酸磷酸酶 (PTP) 构成了控制细胞内蛋白酪氨酸磷酸化水平的信号酶大家族。由于缺乏 PTP 特异性、细胞渗透性小分子药物，对正常生理学和致病条件下 PTP 功能的详细了解受到阻碍。我们提出了一种逐步聚焦的库方法，将弱且一般的不可水解 pTyr 模拟物（F2Pmp，膦酰二氟甲基苯丙氨酸）转化为 PTP-MEG2 的高效选择性抑制剂，PTP-MEG2 是肝胰岛素信号传导的拮抗剂。 PTP-MEG2-抑制剂复合物的晶体结构提供了直接证据，表明通过在 F2Pmp 支架中引入分子多样性以接合活性位点和独特的附近外周结合袋，可以获得有效且选择性的 PTP 抑制剂。重要的是，PTP-MEG2 抑制剂具有高效的细胞活性，能够增强胰岛素信号传导，改善饮食诱导的肥胖小鼠的胰岛素敏感性和葡萄糖稳态。结果表明，F2Pmp可以转化为高效、选择性的PTP抑制剂，具有优异的体内功效。鉴于该方法的一般性质，该策略应该适用于 PTP 超家族的其他成员。
Protein tyrosine phosphatases (PTPs) constitute a large family of signaling enzymes that control the cellular levels of protein tyrosine phosphorylation. A detailed understanding of PTP functions in normal physiology and in pathogenic conditions has been hampered by the absence of PTP-specific, cell-permeable small molecule agents. We present a stepwise focused library approach that transforms a weak and general nonhydrolyzable pTyr mimetic (F2Pmp, phosphonodifluoromethyl phenylalanine) into a highly potent and selective inhibitor of PTP-MEG2, an antagonist of hepatic insulin signaling. The crystal structures of the PTP-MEG2-inhibitor complexes provide direct evidence that potent and selective PTP inhibitors can be obtained by introducing molecular diversity into the F2Pmp scaffold to engage both the active site and unique nearby peripheral binding pockets. Importantly, the PTP-MEG2 inhibitor possesses highly efficacious cellular activity and is capable of augmenting insulin signaling and improving insulin sensitivity and glucose homeostasis in diet-induced obese mice. The results indicate that F2Pmp can be converted into highly potent and selective PTP inhibitory agents with excellent in vivo efficacy. Given the general nature of the approach, this strategy should be applicable to other members of the PTP superfamily.
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影响因子：
29
作者：
Dong XC;Copps KD;Guo S;Li Y;Kollipara R;DePinho RA;White MF
通讯作者：
White MF
影响因子：
4.8
作者：
Liu, Hui-Yu;Collins, Qu Fan;Cao, Wenhong
通讯作者：
Cao, Wenhong
影响因子：
29
作者：
Cho, Charles Y.;Koo, Seung-Hoi;Chanda, Surnit K.
通讯作者：
Chanda, Surnit K.
影响因子：
4.8
作者：
Sun, JP;Fedorov, AA;Zhang, ZY
通讯作者：
Zhang, ZY
DOI：
10.1107/s0907444998003254
发表时间：
1998-09-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
Brunger, AT;Adams, PD;Warren, GL
通讯作者：
Warren, GL