H274Y突变型H5N1流感病毒神经氨酸酶对奥司他韦的耐药机制研究  

Study on the mechanism of resistance to oseltamivir in neuraminidase with H274Y mutation from H5N1 influenza virus

作　　者：李凯[1] 李爱秀[1,2] 罗力[1] 靳玉瑞[1] 刘兴太[2,3] 

机构地区：[1]武警后勤学院基础部药物设计实验室,天津300309 [2]武警后勤学院天津市职业与环境危害防制重点实验室,天津300309 [3]武警后勤学院训练部,天津300309

出　　处：《武警后勤学院学报（医学版）》2014年第10期805-809,F0002,共6页Journal of Logistics University of PAP（Medical Sciences）

基　　金：国家自然科学基金项目(81241114;30472166);天津市科技攻关计划重点科技攻关专项基金资助项目(06YFGZSH07000)

摘　　要：【目的】揭示H274Y突变型H5N1流感病毒神经氨酸酶(Neuraminidase,NA)对奥司他韦(Oseltamivir,OTV)产生耐药的机制。【方法】利用BLAST序列比对工具和MOE软件的蛋白质结构比对模块,对野生型和突变型NA(PDB ID:3TI6和3CL0)的一级结构、二级结构、三级结构以及活性位点进行比对,在分子水平探讨H274Y突变型H5N1流感病毒NA对OTV产生耐药的机制。【结果】3CL0中S1区与OTV羧基形成氢键作用的残基由保守残基Arg292变为了非保守残基Asn347;在S2区增加了OTV与Ile222的疏水作用;由于受到突变后酪氨酸残基较大侧链对羟基苄基的空间位阻作用,3CL0中Glu276的空间形态发生较大变化,影响了活性位点S5疏水口袋的形成。【结论】3CL0活性位点S1区保守残基与OTV的氢键作用被非保守残基取代,S2区突变型NA与OTV之间的疏水作用增加,且突变残基的空间位阻影响了活性位点S5区疏水口袋的形成,均可能是造成H274Y突变型H5N1流感病毒NA对OTV耐药的重要原因。【Objective】To find the reason for the oseltamivir（OTV） resistance in the neuraminidase of H5N1 avian influenza virus with the H274 Y mutation.【Methods】Through BLAST and MOE procedure,two NA crystal structures（PDB ID：3CL0 and 3TI6） were selected to study the mechanism of resistance at molecular level by carrying out the comparison of the primary,secondary and tertiary structure,and the subtle structure at the active site was also analyzed.【Results】The hydrogen bond between a conservative residue（Arg292） in the active site of S1 and OTV was replaced by a non-conservative residue（Asn347） in 3CL0.There was a new hydrogen bond between OTV and Ile222 in the active site of S2.Moreover,the stereospecific blockade from p-hydroxy benzyl of side chain in tyrosine had a effect on the formation of the hydrophobic pocket in the active site of S5,and it influenced the spatial form of Glu276.【Conclusions】It is concluded that the hydrogen bond,the hydrophobic interaction and the stereospecific blockade of mutational residue all might cause the resistance to OTV.

关 键 词：H5N1 流感病毒 神经氨酸酶 H274Y突变 结构比对 奥司他韦 耐药 

分 类 号：R914[医药卫生—药物化学]