Abstract
The 2009 H1N1 influenza pandemic (pH1N1) led to record sales of neuraminidase (NA) inhibitors, which has contributed significantly to the recent increase in oseltamivir-resistant viruses. Therefore, development and careful evaluation of novel NA inhibitors is of great interest. Recently, a highly potent NA inhibitor, laninamivir, has been approved for use in Japan. Laninamivir is effective using a single inhaled dose via its octanoate prodrug (CS-8958) and has been demonstrated to be effective against oseltamivir-resistant NA in vitro. However, effectiveness of laninamivir octanoate prodrug against oseltamivir-resistant influenza infection in adults has not been demonstrated. NA is classified into 2 groups based upon phylogenetic analysis and it is becoming clear that each group has some distinct structural features. Recently, we found that pH1N1 N1 NA (p09N1) is an atypical group 1 NA with some group 2-like features in its active site (lack of a 150-cavity). Furthermore, it has been reported that certain oseltamivir-resistant substitutions in the NA active site are group 1 specific. In order to comprehensively evaluate the effectiveness of laninamivir, we utilized recombinant N5 (typical group 1), p09N1 (atypical group 1) and N2 from the 1957 pandemic H2N2 (p57N2) (typical group 2) to carry out in vitro inhibition assays. We found that laninamivir and its octanoate prodrug display group specific preferences to different influenza NAs and provide the structural basis of their specific action based upon their novel complex crystal structures. Our results indicate that laninamivir and zanamivir are more effective against group 1 NA with a 150-cavity than group 2 NA with no 150-cavity. Furthermore, we have found that the laninamivir octanoate prodrug has a unique binding mode in p09N1 that is different from that of group 2 p57N2, but with some similarities to NA-oseltamivir binding, which provides additional insight into group specific differences of oseltamivir binding and resistance.
Highlights
The 2009 pandemic swine origin influenza A H1N1 virus has reminded the world of the threat of pandemic influenza [1,2,3]
A new drug, laninamivir (Inavir), has been approved for use in Japan can be administered effectively using a single dose via its octanoate prodrug (CS-8958), its effectiveness against oseltamivirresistant influenza infection has not been demonstrated in clinical studies
In this study we comprehensively evaluate the effectiveness of laninamivir and its prodrug using NA from different groups with different active site features
Summary
The 2009 pandemic swine origin influenza A H1N1 virus (pH1N1) has reminded the world of the threat of pandemic influenza [1,2,3]. In 2009, the total sales of Tamiflu (oseltamivir phosphate) increased to over 3 billion US dollars (Annual General Meeting of Roche Holding Ltd, 2 March 2010). Throughout the world, vaccinations have still been strongly advocated and stockpiles of oseltamivir and zanamivir are on reserve in case of another severe influenza outbreak in the near future. Both oseltamivir and zanamivir are excellent examples of modern structure-based drug-design and function as competitive inhibitors of the influenza neuraminidase (NA), and are by far the most commonly used influenza drugs [5,6,7,8]
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