Enzymatic glycosylation of triazole-linked GlcNAc/Glc-peptides: synthesis, stability and anti-HIV activity of triazole-linked HIV-1 gp41 glycopeptide C34 analogues.
Enzymatic glycosylation of triazole-linked GlcNAc/Glc-peptides: synthesis, stability and anti-HIV activity of triazole-linked HIV-1 gp41 glycopeptide C34 analogues.
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DOI：
10.1002/cbic.200800741
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发表时间：
2009-05-04
期刊：
影响因子：
3.2
通讯作者：
Wang, Lai-Xi
中科院分区：
文献类型：
--
作者：
Huang, Wei;Groothuys, Stan;Heredia, Alonso;Kuijpers, Brian H. M.;Rutjes, Floris P. J. T.;van Delft, Floris L.;Wang, Lai-Xi
以合成糖恶唑啉为底物，实现了三唑连接葡萄糖(GLC)和N-乙酰氨基葡萄糖(GlcNAc)二肽和多肽的内切糖苷酶催化转糖基化反应。研究发现，N-和C-连接的Glc/Glc-NAc-三唑类化合物都是来自节杆菌的Endo-β-N-乙酰氨基葡萄糖苷酶(Endo-A)的有效底物，对Endo-A具有广泛的受体底物专一性。该化学酶方法成功地合成了HIV-1囊膜糖蛋白gp41三唑连接的C34糖肽。结果表明，合成的C34糖肽具有较强的抗HIV活性，其IC50为21 nM。三唑连接的C34糖肽对蛋白水解酶和糖胺酶催化的消化表现出较高的稳定性，显示了糖基化的保护作用和三唑连接的稳定性。这些良好的性质表明，三氮唑连接的C34糖肽作为抗HIV候选药物可能具有进一步开发的价值。
Endoglycosidase-catalyzed transglycosylation of triazole-linked glucose (Glc) and N-acetylglucosamine (GlcNAc)-containing dipeptides and polypeptides was achieved, using synthetic sugar oxazoline as the donor substrate. It was found that both N- and C-linked Glc/GlcNAc-containing triazole derivatives were effective substrates for endo-β-N-acetylglucosaminidase from Arthrobacter (Endo-A) for transglycosylation, demonstrating a broad acceptor substrate specificity for Endo-A. This chemoenzymatic method was successfully used for the synthesis of a novel triazole-linked C34 glycopeptide derived from HIV-1 envelope glycoprotein gp41. It was shown that the synthetic C34 glycopeptide possessed potent anti-HIV activity with an IC50 of 21 nM. The triazole-linked C34 glycopeptide demonstrated much enhanced stability toward protease- and glycoamidase-catalyzed digestion, showing the protective effects of glycosylation and the stability of the triazole linkage. These favorable properties suggest that the triazole-linked C34 glycopeptide may be valuable for further development as an anti-HIV drug candidate.
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