Institute for Glycomics, Gold Coast Campus, Griffith University, Queensland 4222, Australia.
Org Biomol Chem. 2012 Nov 21;10(43):8628-39. doi: 10.1039/c2ob25627d.
Novel 3-C-alkylated-Neu5Ac2en derivatives have been designed to target the expanded active site cavity of influenza virus sialidases with an open 150-loop, currently seen in X-ray crystal structures of influenza A virus group-1 (N1, N4, N5, N8), but not group-2 (N2, N9), sialidases. The compounds show selectivity for inhibition of H5N1 and pdm09 H1N1 sialidases over an N2 sialidase, providing evidence of the relative 150-loop flexibility of these sialidases. In a complex with N8 sialidase, the C3 substituent of 3-phenylally-Neu5Ac2en occupies the 150-cavity while the central ring and the remaining substituents bind the active site as seen for the unsubstituted template. This new class of inhibitors, which can 'trap' the open 150-loop form of the sialidase, should prove useful as probes of 150-loop flexibility.
已设计新型 3-C-烷基化-Neu5Ac2en 衍生物以针对流感病毒神经氨酸酶的扩展活性位点腔，该活性位点腔具有开放的 150 环，目前在 X 射线晶体结构中可见于流感病毒 A 组-1（N1、N4、N5、N8），但不在组-2（N2、N9）神经氨酸酶中。这些化合物显示出对 H5N1 和 pdm09 H1N1 神经氨酸酶的选择性抑制作用，而对 N2 神经氨酸酶没有抑制作用，这为这些神经氨酸酶的相对 150 环灵活性提供了证据。在与 N8 神经氨酸酶的复合物中，3-苯丙基-Neu5Ac2en 的 C3 取代基占据 150 腔，而中环和其余取代基结合活性位点，就像未取代的模板一样。这种新型抑制剂可以“捕获”神经氨酸酶的开放 150 环形式，应该可用作 150 环灵活性的探针。
