Drug design against a shifting target: a structural basis for resistance to inhibitors in a variant of influenza virus neuraminidase
Drug design against a shifting target: a structural basis for resistance to inhibitors in a variant of influenza virus neuraminidase
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DOI：
10.1016/s0969-2126(98)00075-6
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发表时间：
1998-06-15
期刊：
影响因子：
--
通讯作者：
Colman, PM
中科院分区：
文献类型：
--
作者：
Varghese, JN;Smith, PW;Colman, PM
背景资料：流感病毒神经氨酸酶的抑制剂已被证明是人类中有效的抗病毒剂。几项研究已经报道了当病毒与神经氨酸酶抑制剂一起体外培养时，新流感毒株的选择。这些抗性病毒在神经氨酸酶或病毒血凝素中具有突变，其中2-脱氧-2，3-二氧杂环戊烯的6位甘油侧链，3-脱氢-N-乙酰神经氨酸（Neu 5Ac 2 en）已被羧酰胺连接的疏水取代基取代，最近已报道并显示选择神经氨酸酶变体。本研究旨在阐明用其他化学成分取代抑制剂的甘油侧链的结构和功能后果。神经氨酸酶变体Arg 292-->Lys在包围底物的羧酸酯基团的三个精氨酸残基之一中被修饰，该变体的结构与用于其选择的羧酰胺抑制剂以及与其他Neu 5Ac 2 en类似物复合，与野生型神经氨酸酶相比，突变的结构后果与化合物的改变的抑制活性相关。结论：流感神经氨酸酶的Arg 292->Lys变体通过修饰与底物羧酸的相互作用来影响底物的结合。这可能是变体的降低的酶活性的结构相关性之一。在Arg 292->Lys变体中，在位置6处具有甘油替代物的抑制剂进一步受到影响，因为结合位点的结构变化明显提高了适应这种抑制剂所需的酶中构象变化的能垒。这些结果提供了证据，即当靶标具有高突变频率时，药物设计的一般策略是将抑制剂设计为尽可能与靶标的天然配体密切相关。
Background: Inhibitors of the influenza virus neuraminidase have been shown to be effective antiviral agents in humans, Several studies have reported the selection of novel influenza strains when the virus is cultured with neuraminidase inhibitors in vitro, These resistant viruses have mutations either in the neuraminidase or in the viral haemagglutinin, Inhibitors in which the glycerol sidechain at position 6 of 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (Neu5Ac2en) has been replaced by carboxamide-linked hydrophobic substituents have recently been reported and shown to select neuraminidase variants. This study seeks to clarify the structural and functional consequences of replacing the glycerol sidechain of the inhibitor with other chemical constituents.Results: The neuraminidase variant Arg292-->Lys is modified in one of three arginine residues that encircle the carboxylate group of the substrate, The structure of this variant in complex with the carboxamide inhibitor used for its selection, and with other Neu5Ac2en analogues, is reported here at high resolution, The structural consequences of the mutation correlate with altered inhibitory activity of the compounds compared with wild-type neuraminidase,Conclusions: The Arg292-->Lys variant of influenza neuraminidase affects the binding of substrate by modification of the interaction with the substrate carboxylate. This may be one of the structural correlates of the reduced enzyme activity of the variant, Inhibitors that have replacements for the glycerol at position 6 are further affected in the Arg292-->Lys variant because of structural changes in the binding site that apparently raise the energy barrier for the conformational change in the enzyme required to accommodate such inhibitors. These results provide evidence that a general strategy for drug design when the target has a high mutation frequency is to design the inhibitor to be as closely related as possible to the natural ligands of the target.