Recent progress and challenges in the discovery of new neuraminidase inhibitors

At present, the key public health concern is to define the way in which the next influenza pandemic should be controlled. While influenza vaccines are available, their effectiveness could be significantly reduced if new strains differ significantly from those of the vaccines. Therefore, antiviral drugs play an important role in the prevention and management of influenza. The influenza neuraminidase (NA), a surface-glycoprotein enzyme involved in releasing the virus from the host cell, has been considered as an essential therapeutic target for treatment and prophylaxis of influenza infection. It is a highly conserved feature of the active site across all influenza A and B viruses and is of particular interest because compounds NA inhibitors (NAIs) can be cross-reactive against multiple types and subtypes of influenza. Currently, there are two NAI drugs which are licensed worldwide: oseltamivir and zanamivir, and two more drugs which have received recent approval in Japan: peramivir and laninamivir. Sudden changes in NAI susceptibility have stressed the urgent need in searching for novel inhibitors.

In this review, a potential pitfall in NA-based assays and the progress in the chemical synthesis of all patented NAIs from February 2006 to July 2012 are discussed.

Both NA enzyme inhibition and X-ray crystallography data have suggested that the strategy of designing NAIs binding to the highly conserved region of NA can lead to inhibitors that are effective against all influenza NA subtypes. A number of new synthetic entries having unique structural frameworks that were designed based on computational study of X-ray structures of NA. They strongly exhibited the activity of NA in the low nanomolar range such as phosphonate congeners of zanamivir and oseltarmivir. Screening strategies based on the chemical diversity of natural products have revealed that flavonoids are the most prominent scaffolds possessing NA inhibitory activity. However, these substituted phenyl-benzopyrane compounds have been reported to exert a considerable quenching effect, causing false-positive results in the commonly used method of enzyme-based NA inhibition assays, and thus, reliability of the flavonoid-based NAIs reported in the literature.