Institute for Enzyme Research, Tokushima University, Tokushima, Japan.
Asia International Institute of Infectious Disease Control, Teikyo University, Tokyo, Japan.
J Biomol Struct Dyn. 2021 Jul;39(10):3491-3500. doi: 10.1080/07391102.2020.1765872. Epub 2020 May 25.
We performed a neuraminidase sequence analysis of thirty-two pediatric patients with influenza B who visited Teikyo University Hospital from January 2016 to March 2017, and found oseltamivir-resistant samples belonging to the Yamagata and Victoria lineages. Comparison with the neuraminidase sequence of oseltamivir-susceptible B/Brisbane/60/2008 revealed 5 common amino acid substitutions in many of these samples. According to the binding free energy calculation, the N340D and E358K substitutions reduced the affinity of oseltamivir to neuraminidase. Unexpectedly, these substitutions were located distant from the oseltamivir-binding site in neuraminidase. According to the molecular dynamics simulations, the N340D substitution rearranged complicated hydrogen bond networks in an extensive surface region of neuraminidase. The E358K substitution extensively altered the electrostatic potential map of the overall neuraminidase structure. Through these novel mechanisms, the N340D and E358K substitutions indirectly influenced the affinity reduction. These results may be useful for designing drugs for the treatment of oseltamivir-resistant virus infections.Communicated by Ramaswamy H. Sarma.
我们对 2016 年 1 月至 2017 年 3 月期间在帝京大学医院就诊的 32 名流感 B 患儿进行了神经氨酸酶序列分析，发现了属于 Yamagata 和 Victoria 谱系的奥司他韦耐药样本。与奥司他韦敏感的 B/Brisbane/60/2008 的神经氨酸酶序列比较，这些样本中的许多都有 5 个常见的氨基酸取代。根据结合自由能计算，N340D 和 E358K 取代降低了奥司他韦对神经氨酸酶的亲和力。出乎意料的是，这些取代位于神经氨酸酶中奥司他韦结合位点的远处。根据分子动力学模拟，N340D 取代重新排列了神经氨酸酶广泛表面区域中复杂的氢键网络。E358K 取代广泛改变了整个神经氨酸酶结构的静电势图。通过这些新的机制，N340D 和 E358K 取代间接影响了亲和力的降低。这些结果可能有助于设计治疗奥司他韦耐药病毒感染的药物。通讯作者为 Ramaswamy H. Sarma。
