Anomeric 1,2,3-triazole-linked sialic acid derivatives show selective inhibition towards a bacterial neuraminidase over a trypanosome trans-sialidase.
Anomeric 1,2,3-triazole-linked sialic acid derivatives show selective inhibition towards a bacterial neuraminidase over a trypanosome trans-sialidase.
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DOI：
10.3762/bjoc.18.24
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发表时间：
2022
影响因子：
2.7
通讯作者：
Field RA
中科院分区：
文献类型：
--
作者：
de Andrade P;Ahmadipour S;Field RA
唾液酸是唾液酸酶的天然底物，其化学修饰是产生有效和选择性抑制剂的有用方法。为了推进选择性克氏锥虫转唾液酸酶 (TcTS) 抑制剂的发现，我们通过铜催化的叠氮-炔环加成（CuAAC，点击化学）合成了一系列异头 1,2,3-三唑连接的唾液酸衍生物，产量高、纯度高，并评估了它们对 TcTS 和神经氨酸酶的活性。令人惊讶的是，这些化合物几乎没有表现出 TcTS 抑制作用，而约。与带有疏水取代基的类似物相比，观察到神经氨酸酶有 70% 的抑制作用。极性较大的取代基为 5%。这些结果表明，由于疏水性对抑制的影响存在巨大差异，神经氨酸酶对极性变化的耐受性较差，因此表明了区分这两种酶的简单方法。此外，这种选择性可能是基于位于 TcTS 活性位点上方的庞大疏水环引起的可能空间位阻，并可能阻止疏水抑制剂结合。本研究在利用唾液酸酶的细微结构差异方面向前迈出了一步，需要解决这些差异以实现选择性抑制。
Sialic acid is the natural substrate for sialidases and its chemical modification has been a useful approach to generate potent and selective inhibitors. Aiming at advancing the discovery of selective Trypanosoma cruzi trans-sialidase (TcTS) inhibitors, we have synthesised a small series of anomeric 1,2,3-triazole-linked sialic acid derivatives in good yields and high purity via copper-catalysed azide–alkyne cycloaddition (CuAAC, click chemistry) and evaluated their activity towards TcTS and neuraminidase. Surprisingly, the compounds showed practically no TcTS inhibition, whereas ca. 70% inhibition was observed for neuraminidase in relation to the analogues bearing hydrophobic substituents and ca. 5% for more polar substituents. These results suggest that polarity changes are less tolerated by neuraminidase due to the big difference in impact of hydrophobicity upon inhibition, thus indicating a simple approach to differentiate both enzymes. Moreover, such selectivity might be reasoned based on a possible steric hindrance caused by a bulky hydrophobic loop that sits over the TcTS active site and may prevent the hydrophobic inhibitors from binding. The present study is a step forward in exploiting subtle structural differences in sialidases that need to be addressed in order to achieve selective inhibition.
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影响因子：
5
作者：
Bowles WHD;Gloster TM
通讯作者：
Gloster TM
DOI：
10.2147/dddt.s176220
发表时间：
2018
期刊：
Drug design, development and therapy
影响因子：
--
作者：
Glanz VY;Myasoedova VA;Grechko AV;Orekhov AN
通讯作者：
Orekhov AN
影响因子：
16.6
作者：
Buchini, Sabrina;Buschiazzo, Alejandro;Withers, Stephen G.
通讯作者：
Withers, Stephen G.
影响因子：
8.4
作者：
Campo, Vanessa L.;Carvalho, Ivone;Field, Robert A.
通讯作者：
Field, Robert A.
影响因子：
7.3
作者：
Guo, Tianlin;Heon-Roberts, Rachel;Cairo, Christopher W.
通讯作者：
Cairo, Christopher W.