Influenza sialidase inhibitor drug

Anti-Influenza Drugs The Development of Sialidase Inhibitors... 

It may be possible to increase the utility of our resources to treat influenza virus infection through combinations of antiviral agents with different modes of action (discussed in Cinatl et al. 2007a De Clercq and Neyts 2007). The sialidase inhibitors, for example, may be able to be used in conjunction with the adamantane-based M2 ion channel inhibitors (Govorkova et al. 2004 Ilyushina et al. 2006), with Ribavirin (Smee et al. 2002) or with non-influenza virus specific therapeutics such as anti-inflammatory drugs (Carter 2007). Combination therapy may also reduce the potential of resistance development (Ilyushina et al. 2006). 

The development of sialidase-based inhibitors as anti-influenza drugs has provided a first line-of-defence to safeguard humanity against a potential pandemic and most importantly to buy time for vaccine and further anti-influenza drug development. Most exciting is that new opportunities exist for next generation sialidase inhibitor development. 

A number of researchers have reported and demonstrated that maintaining the appropriate position of the substituents on a cyclic scaffold to interact with the established conserved amino acid residues involved in substrate binding can lead to development of new classes of influenza virus sialidase inhibitors [117]. Two drugs based on five-membered ring scaffolds have been developed as potent sialidase inhibitors. Cyclopentane derivative 24 (BCX-1812, peramivir) [117, 118] and pyrrolidine derivative 25 (ABT-675) [119] show nanomolar levels of inhibition of both influenza A and B viral sialidases (Fig. 17.13). 

An interesting example of how this approach can be used to assess the validity of a drug design hypothesis is provided by the receptor-based design of sialidase inhibitors as potential anti-influenza drugs. 

M. von Itzstein, The war against influenza Discovery and development of sialidase inhibitors, Nat. Rev. Drug Discov., 6 (2007) 967-974. 

M. Itzstein and R. Thomson, Anti-influenza drugs The development of sialidase inhibitors, Handb. Exp. Pharmacol., 189 (2009) 111-154. 

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