Anti-Influenza Drug Discovery: Are We Ready for the Next Pandemic?

Abstract

Publisher Summary This chapter examines the different aspects of the progress in anti-influenza drug discovery. Influenza viruses are enveloped single-stranded RNA viruses with a pleomorphic appearance and an average diameter of 120 nm. They are members of the orthomyxovirus family and can be classified into three serologically distinct types—A, B, and C. Both hemagglutinin and sialidase are carbohydrate-recognizing proteins and in humans recognize the well-known sialic acid, N-acetylneura minic acid, associated as the terminal carbohydrate unit of upper respiratory tract and lung-associated glycoconjugates. Influenza virus sialidase poses a highly attractive target for antiviral drug design due to its prominent position at the surface of the virion and its profound role in viral pathogenesis. The discovery of Zanamivir as a potent and selective inhibitor of influenza virus sialidase prompted several researchers to investigate the synthesis and structure–activity relationship studies of Neu5Ac2en-based compounds as potential sialidase inhibitors. Modifications of the guanidino function of Zanamivir at the primary nitrogen resulted in a dramatic reduction in the inhibition of neuraminidase (NA) and of viral replication in vivo. It is found that the success of such C-6 amides in the series against influenza A NA was in part due to a match between the spatial arrangement of the two binding pockets and the favored orientation of the amide rotamer that featured a trans-relationship between the larger substituent and the pyran ring.