Influenza virus sialidase inhibitors development

Further Developments of Influenza Virus Sialidase Inhibitors. 123... 

X-ray crystal structures of a-Neu5Ac and 11 in complex with influenza virus sialidases in the 1980s and early 1990s led to the opportunity for structure-based design and development of influenza virus sialidase inhibitors [66, 85],... 

In the challenge to develop potent influenza virus sialidase inhibitors, a large amount of research has been dedicated to the manipulation of every position on 11 except C3. Structure-activity relationship (SAR) studies carried out on compounds derived from 11 before and during the development of zanamivir (reviewed in [101-103]) revealed structural requirements to conserve the main interactions between the substrate inhibitor and the active site of NA, particularly with regards to the carboxylate, C4-guanidino, and C5-acetamido moieties. 

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). 

Another remarkable influenza virus sialidase inhibitor, derivative 25 [119], was developed based on a pyrrolidine core by Abbott Laboratories [119, 123], X-ray crystal studies surprisingly observed hydrophobic interactions of the d.s-propenyl group within S2, which is normally involved in charge-charge interaction as with the guanidino moiety in zanamivir [69], The side-chain methyl and methoxy groups of... 

Several excellent articles describing various aspects of influenza virus, both with respect to the virus itself as well as approaches towards the development of anti-influenza agents, have been published in recent years [4-16]. In view of the comprehensive nature of these reports it is the aim of this account, apart from providing the background information necessary to a fundamental understanding of influenza, to focus on advances in the development of influenza virus sialidase inhibitors over the last decade. ... 

Streicher, H. and Stanley, M. (2012) The development of non-carbohydrate-based influenza virus sialidase inhibitors, in Influenza Virus Sialidase A Drug Discovery Target (ed. M. von Itzstein), Springer, Basel, pp. 105-130. 

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