Design and evaluation of novel analogs of 2-amino-4-boronobutanoic acid (ABBA) as inhibitors of human gamma-glutamyl transpeptidase.
Design and evaluation of novel analogs of 2-amino-4-boronobutanoic acid (ABBA) as inhibitors of human gamma-glutamyl transpeptidase.
复制标题
2-氨基-4-硼丁酸（ABBA）的新型类似物的设计和评估，作为人γ-谷氨酰基肽酶的抑制剂。
DOI：
10.1016/j.bmc.2022.116986
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发表时间：
2022-11-01
影响因子：
3.5
通讯作者：
Hanigan, Marie H.
中科院分区：
文献类型：
--
作者：
Nguyen, Luong;Schultz, Daniel C.;Terzyan, Simon S.;Rezaei, Mohammad;Songb, Jinhua;Li, Chenglong;You, Youngjae;Hanigan, Marie H.
关键词：
γ-谷氨酰转移酶(GGT1，又名γ-谷氨酰转移酶)的抑制剂是治疗癌症、心血管疾病和其他疾病所必需的。抑制GGT1的化合物已经在临床上进行了评估，但没有一种抑制剂成功地显示出特异性和系统性的GGT1抑制作用。所有这些都有严重的副作用。L-2-氨基-4-硼丁酸(L-ABBA)是一种谷氨酸类似物，是体外最有效的GGT1抑制剂。在本研究中，我们解决了活性中心结合了ABBA的人GGT1(HGGT1)的晶体结构。询问结构以确定酶和抑制剂之间的相互作用。基于这些数据，设计并合成了一系列新的ABBA类似物。测定了它们对hGGT1水解酶和转肽酶活性的抑制活性。用hGGT1对先导化合物进行了晶化，并进行了结构解析。这些复合体的动力学数据和结构为蛋白质结构动力学在开发抑制hGGT1的化合物中的关键作用提供了新的见解。
Inhibitors of gamma-glutamyl transpeptidase (GGT1, aka gamma-glutamyl transferase) are needed for the treatment of cancer, cardiovascular illness and other diseases. Compounds that inhibit GGT1 have been evaluated in the clinic, but no inhibitor has successfully demonstrated specific and systemic GGT1 inhibition. All have severe side effects. L-2-amino-4-boronobutanoic acid (l-ABBA), a glutamate analog, is the most potent GGT1 inhibitor in vitro. In this study, we have solved the crystal structure of human GGT1 (hGGT1) with ABBA bound in the active site. The structure was interrogated to identify interactions between the enzyme and the inhibitor. Based on these data, a series of novel ABBA analogs were designed and synthesized. Their inhibitory activity against the hydrolysis and transpeptidation activities of hGGT1 were determined. The lead compounds were crystalized with hGGT1 and the structures solved. The kinetic data and structures of the complexes provide new insights into the critical role of protein structure dynamics in developing compounds for inhibition of hGGT1.
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DOI：
10.1107/s1399004713031222
发表时间：
2014-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Ida T;Suzuki H;Fukuyama K;Hiratake J;Wada K
通讯作者：
Wada K
DOI：
10.1016/j.jbc.2022.101703
发表时间：
2022-03
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Hayashima K;Katoh H
通讯作者：
Katoh H
影响因子：
3.2
作者：
Hanigan, MH;Frierson, HF
通讯作者：
Frierson, HF
影响因子：
82.9
作者：
通讯作者：
--
DOI：
10.1073/pnas.74.8.3330
发表时间：
1977-01-01
影响因子：
11.1
作者：
GRIFFITH, OW;MEISTER, A
通讯作者：
MEISTER, A