Glycosidase inhibition: assessing mimicry of the transition state.
Glycosidase inhibition: assessing mimicry of the transition state.
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DOI：
10.1039/b915870g
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发表时间：
2010-01-21
影响因子：
3.2
通讯作者：
Davies GJ
中科院分区：
文献类型：
--
作者：
Gloster TM;Davies GJ
糖苷酶抑制在许多疾病中具有广泛的应用，特别是通过检查那些可能模拟过渡态的抑制剂，在解决糖苷酶抑制方面取得的进展的审查。糖苷水解酶，负责水解二糖、寡糖和多糖以及糖缀合物中的糖苷键的酶，在自然界中普遍存在并且是存在的基础。糖苷键的极端稳定性意味着这些酶已经发展成为高度有效的催化剂，估计比未催化的反应速率提高了1017倍。这样的速率增强意味着酶以非凡的亲和力在过渡态结合底物;过渡态的解离常数预计为10-22 M。糖苷水解酶的抑制在治疗病毒感染如流感和HIV、溶酶体贮积症、癌症和糖尿病中具有广泛的应用。如果抑制剂被设计成模拟过渡态，那么应该可以利用一些过渡态亲和力，从而产生高效和特异性的药物。在这里，我们检查了一些糖苷酶抑制剂，已开发了在过去的半个世纪，无论是自然或人工合成。已提出了一些标准，以确定这些抑制剂是真正的过渡态模拟物，但这些功能只有在极少数情况下进行了严格的研究。
A review of the progress made in tackling glycosidase inhibition, which has widespread application in a number of diseases, in particular by examining those inhibitors that may mimic the transition state. Glycoside hydrolases, the enzymes responsible for hydrolysis of the glycosidic bond in di-, oligo- and polysaccharides, and glycoconjugates, are ubiquitous in Nature and fundamental to existence. The extreme stability of the glycosidic bond has meant these enzymes have evolved into highly proficient catalysts, with an estimated 1017 fold rate enhancement over the uncatalysed reaction. Such rate enhancements mean that enzymes bind the substrate at the transition state with extraordinary affinity; the dissociation constant for the transition state is predicted to be 10–22 M. Inhibition of glycoside hydrolases has widespread application in the treatment of viral infections, such as influenza and HIV, lysosomal storage disorders, cancer and diabetes. If inhibitors are designed to mimic the transition state, it should be possible to harness some of the transition state affinity, resulting in highly potent and specific drugs. Here we examine a number of glycosidase inhibitors which have been developed over the past half century, either by Nature or synthetically by man. A number of criteria have been proposed to ascertain which of these inhibitors are true transition state mimics, but these features have only be critically investigated in a very few cases.
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影响因子：
3.2
作者：
Aguilar-Moncayo, Matilde;Gloster, Tracey M.;Garcia Fernandez, Jose M.
通讯作者：
Garcia Fernandez, Jose M.
影响因子：
3.2
作者：
Aguilar, Matilde;Gloster, Tracey M.;Fernandez, Jose M. Garcia
通讯作者：
Fernandez, Jose M. Garcia
影响因子：
4.1
作者：
AXAMAWATY, MTH;FLEET, GWJ;SINNOTT, ML
通讯作者：
SINNOTT, ML
影响因子：
4.3
作者：
Bols, M;Hazell, RG;Thomsen, IB
通讯作者：
Thomsen, IB
影响因子：
1.1
作者：
COLEGATE, SM;DORLING, PR;HUXTABLE, CR
通讯作者：
HUXTABLE, CR