Neuraminidase (NA) inhibitors are one of the effective drugs for the treatment of seasonal and pandemic flu infection at present. The 2009 H1N1 influenza pandemic led to record sales and use of the classical NA inhibitors, zanamivir and oseltamivir, which has contributed to the increase in drug-resistant viruses, especially oseltamivir-resistant viruses. Furthermore, the 2009 pandemic H1N1 NA protein did not possess a 150-cavity like all previous group 1 NA structures as determined by Prof. George F Gao’s research group. Therefore, the development and careful evaluation of novel NA inhibitors to cover all variations of NA has become even more critical.
A novel NA inhibitor, laninamivir, has received approval for human use in Japan and has advantages over the commonly used influenza drugs, oseltamivir and zanamivir. Laninamivir is effective against oseltamivir-resistant viruses and only requires a single inhaled dose via its octanoate prodrug. There have been many clinical studies to demonstrate the effectiveness of laninamivir against flu infection; however the structural basis of its action has been unreported.
In a study from Professor George F Gao’s lab at the Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, laninamivir binding and inhibition was comprehensively investigated. A typical group 1 NA (avian H12N5 N5), a typical Group 2 NA (1957 pandemic H2N2 N2), and an atypical Group 1 NA (2009 pandemic H1N1 N1), were all utilized in order to cover all of the major types of influenza A NA. Their results indicate that laninamivir is highly effective against all NA types, however zanamivir and laninamivir exhibit a preference toward Group 1 NA, which contain a 150-cavity, over Group 2 NA, with no 150-cavity. They, therefore have proposed a model that NA inhibitors with bulky side chains at the 4-position (sialic acid numbering) more easily bind Group 1 NA via accessibility of the bulky C4 group to its binding site beneath the 150-loop. They have also determined that the binding mode of the prodrug, laninamivir octanoate, to 2009 N1 and 1957 N2, which are completely different. This provides the structural basis of the higher inhibition of N2 by laninamivir octanoate and provides insight into the group specific dynamics of the Glu276 residue, a key residue for binding of the hydrophobic oseltamivir side chain and the most flexible residue in the NA active site. Further understanding about differences in rotation of Glu276 also provides important insight into the group specificity of oseltamivir-resistance.
This work has been accepted to be published by PLoS Pathogens and is currently in production (DOI: 10.1371/journal.ppat.1002249). Research in Professor George Fu Gao’s lab is supported by Ministry of Science and Technology of China (MOST) and National Institutes of Health (NIH). Chris Vavricka, a first author of the manuscript, is a Young International Scientists Research Fellow of the Chinese Academy of Sciences, and is also supported by International Young Scientist Research Fellowship of National Natural Science Foundation of China.