Novel oseltamivir-resistant mutations distant from the active site of influenza B neuraminidase.

Abstract

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.

• Authors: Yusuke Kato, Kazuhiro Takahashi, Fuyu Ito, Shoichi Suzuki, Kiyoshi Fukui, Masakazu Mimaki, Kazuo Suzuki
• Journal: Journal of biomolecular structure & dynamics (J Biomol Struct Dyn) Vol. 39 Issue 10 Pg. 3491-3500 (Jul 2021) ISSN: 1538-0254 [Electronic] England
• PMID: 32406800 (Publication Type: Journal Article)

Chemical References

• Antiviral Agents
• Enzyme Inhibitors
• Viral Proteins
• Oseltamivir
• NA protein, influenza B virus
• Neuraminidase

Topics

• Amino Acid Substitution
• Antiviral Agents (pharmacology, therapeutic use)
• Catalytic Domain
• Child
• Drug Resistance, Viral (genetics)
• Enzyme Inhibitors (pharmacology)
• Humans
• Influenza, Human (drug therapy)
• Mutation, Missense
• Neuraminidase (genetics)
• Oseltamivir (pharmacology)
• Viral Proteins (genetics)