Molecular Basis for Differential Patterns of Drug Resistance in Influenza N1 and N2 Neuraminidase
Molecular Basis for Differential Patterns of Drug Resistance in Influenza N1 and N2 Neuraminidase
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DOI：
10.1021/acs.jctc.6b00703
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发表时间：
2016-12-01
影响因子：
5.5
通讯作者：
Schiffer, Celia A.
中科院分区：
文献类型：
--
作者：
Prachanronarong, Kristina L.;Ozen, Aysegul;Schiffer, Celia A.
神经氨酸酶（NA）抑制剂用于预防和治疗甲型流感病毒感染。NA的两种亚型，N1和N2，在感染人类的病毒中占主导地位，但尽管活性位点高度同源，但每种亚型都出现了不同的耐药性模式。为了了解这些耐药突变选择的分子基础，研究人员对N1和N2 NA与底物和抑制剂的配合物进行了结构和动力学分析。动态底物和抑制剂包膜的比较以及活性位点的相互作用揭示了特异性耐药突变的不同模式，即N1中的I222、S246和H274残基和N2中的E119残基。我们的研究结果表明，抑制剂与底物在NA活性位点的分子间相互作用，特别是范德华接触的差异，有效地解释了两种亚型中抗性突变的选择。通过更好地模拟底物的动力学和分子间相互作用，避免这种使抑制剂容易产生耐药性的接触，可以开发出避免两种亚型耐药的新型抑制剂。
Neuraminidase (NA) inhibitors are used for the prevention and treatment of influenza A virus infections. Two subtypes of NA, N1 and N2, predominate in viruses that infect humans, but differential patterns of drug resistance have emerged in each subtype despite highly homologous active sites. To understand the molecular basis for the selection of these drug resistance mutations, structural and dynamic analyses on complexes of N1 and N2 NA with substrates and inhibitors were performed. Comparison of dynamic substrate and inhibitor envelopes and interactions at the active site revealed how differential patterns of drug resistance have emerged for specific drug resistance mutations, at residues I222, S246, and H274 in N1 and E119 in N2. Our results show that the differences in intermolecular interactions, especially van der Waals contacts, of the inhibitors versus substrates at the NA active site effectively explain the selection of resistance mutations in the two subtypes. Avoiding such contacts that render inhibitors vulnerable to resistance by better mimicking the dynamics and intermolecular interactions of substrates can lead to the development of novel inhibitors that avoid drug resistance in both subtypes.