Sialidases discovery

An overview of the role of the virus-associated glycoprotein sialidase (neuraminidase) and some of the most recent developments towards the discovery of anti-influenza drugs based on the inhibition of influenza virus sialidase is provided in this chapter. 

In the following sections, an overview of some of the key developments in the discovery of potent influenza vims sialidase inhibitors is provided. In the first instance, the discovery of the influenza vims sialidase inhibitors that have become the current first-hne-of-defence anti-influenza dmgs will be described, followed by a description of some of the other important sialidase inhibitor developments to date. 

The discovery of the potent in vitro sialidase inhibitory activity and in vivo efficacy of zanamivir 12, and the increasing availability of 3D structural data for influenza virus sialidases in the 1990s, particularly with Neu5Ac and various inhibitors bound into the active site, provided a platform for further drug discovery efforts targeting... 

Smith PW, Sollis SL, Howes PD, Cherry PC, Starkey ID, Cobley KN, Weston H, Scicinski J, Merritt A, Whittington A, Wyatt P, Taylor N, Green D, BetheU R, Madar S, Fenton RJ, Motley PJ, Pateman T, Beresford A (1998) Dihydropyrancarboxamides related to zanamivir a new series of inhibitors of influenza virus sialidases. 1. Discovery, synthesis, biological activity, and structure-activity relationships of 4-guanidino- and 4-amino H-pyran-6-carboxamides. J Med Chem 41 787-797... 

Dyason JC, Wilson JC, Von Itzstein M. Sialidases Targets for rational drug design. In Bultinck P, De Winter H, Langenaeker W, Tollenaere JP, editors. Computational medicinal chemistry for drug discovery. New York Dekker, 2004. 

Influenza Virus Sialidase as a Drug-Discovery Target 300... 

Because of the essential role of sialidase in influenza virus replication and the highly conserved enzyme active-site in influenza viruses A and B, most interest has been focused on the development of selective inhibitors of this enzyme.10 This chapter discusses the tremendous progress that has been made in the discovery of this new class of anti-influenza agents, in addition to some background information to understand the fundamental role of influenza. 

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. Exploration of these SAR studies were undertaken to optimize inhibitory activity and to improve the physicochemical properties of the sialic acid-based influenza virus sialidase inhibitor. A few in vitro assays are commonly employed to measure the effectiveness of influenza virus sialidase inhibitors. The first involves a fluorometric assay that measures release of a synthetic fluorophore following its cleavage from Neu5Ac by sialidase. Dye-uptake assay, such as the Neutral Red uptake assay, measures the uptake of a vital stain, Neutral Red in cell culture. The process requires intact membranes and active metabolism in the cell, and is expressed as percent protective rate against virus infection. The plaque-reduction assay is used to measure sialidase inhibition indirectly in cell culture, and provides some measure of the inhibitor s effect on the viability of the influenza virus. In vitro and in vivo systems for analysis of inhibitors of influenza virus enzymes have been reviewed.71... 

INFLUENZA VIRUS SIALIDASE AS A DRUG DISCOVERY TARGET... 

Thomson, R. von Itzstein, M. In Influenza Virus Sialidase—A Drug Discovery Target, von Itzstein, M., Ed. Springer Basel, 2012, pp 77-104. 

INFLUENZA VIRUS SIALIDASE A TARGET FOR DRUG DISCOVERY... 

The discovery, in the early 1990s, that zanamivir was a potent and selective inhibitor of influenza virus sialidase prompted several researchers to investigate the synthesis of Neu5Ac2en based analogues of zanamivir. Much of this effort was a consequence of the fact that zanamivir (12) must be administered as a nasal spray, due to its poor oral bioavailability and rapid excretion [101,102], and the desire to identify new sialidase inhibitors with modified physicochemical properties. Several researchers have described structure-activity relationship studies based on zanamivir (vide infra), with most modifications reported at C-4, C-5, and the glycerol side-chain. 

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