Sialic acid derivatives and mimetics: tools for the investigation of sialic acid processing enzymes

Stanley, Mathew (2011) Sialic acid derivatives and mimetics: tools for the investigation of sialic acid processing enzymes. Doctoral thesis (DPhil), University of Sussex.

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Abstract

I. Synthesis and inhibitory activity of sialic acid derivatives targeting viral
sialate-O-acetylesterases and sialate-O-acetyltransferases

Sialate-O-acetylation is a common structural modification of sialic acid, which has been
associated with many human disease states (including cancer and autoimmune
disease). This highly regulated and tissue-specific modification is carried out by sialate-
O-acetylesterase (SOAE) and sialate-O-acetyltransferase (SOAT) enzymes.
The availability of these enzymes make inhibition studies a viable endeavour,
considering that SOAT/SOAE inhibitors may provide interesting tools/drug leads for the
development of antiviral compounds or treatments for various disease states. A
synthesis of suitable 4-O- and 9-O-functionalised sialic acid derivatives has been
established which enabled the investigation of 4- and 9-sialate-O-acetylesterase
enzymes. Sialic acid derivatives were screened for the inhibition of a set of viral SOAEs
and while no inhibition of 4-SOAE could be detected, a 9-O-methyl derivative showed
inhibition of the recombinant influenza C virus SOAE. The functionalised sialic acid motif
thus serves as an initial template for the design and synthesis of future sialic acid
derivatives towards SOAT/SOAT inhibition.

II. New tools for the characterization and investigation of influenza virus
neuraminidases: towards novel influenza virus sensors

Tamiflu™ (Oseltamivir), has been employed as a mimetic of the sialic acid
“oxocarbenium” intermediate formed during enzymatic hydrolysis, leading to inhibition of
virus-bound neuraminidase (NA) enzyme. Phospha-isosteres of oseltamivir provide
access to monoesters which retain the efficacy of the pharmacophore and allow the
synthesis of novel influenza neuraminidase-specific materials.
Phospha-oseltamivir-stabilised gold nanoparticles (“TamiGold”) have been synthesised
and NA inhibition studies with “small TamiGold” show activity against influenza virus
strains investigated compared to control gold nanoparticles. The binding interactions
displayed by “large TamiGold” may provide the basis for a colorimetric method of
influenza detection and as such a novel prototype influenza sensor. To the best of our
knowledge this is the first example of a multivalent approach to influenza virus binding
utilising sialylmimetic scaffolds immobilised on a nanoparticle platform which specifically
target the NA (instead of the hemagglutinin, HA). The synthesis of phospha-oseltamivir
conjugates and their ligation to biological reporter groups afford small molecule tools with
high affinity and selectivity towards influenza NA. These derivatives can be applied
towards novel multivalent phospha-oseltamivir materials and used as novel diagnostics,
independent of existing methods.

Item Type: Thesis (Doctoral)
Schools and Departments: School of Life Sciences > Chemistry
Subjects: Q Science > QD Chemistry > QD0241 Organic chemistry
Depositing User: Library Cataloguing
Date Deposited: 05 Oct 2011 12:57
Last Modified: 12 Oct 2015 11:11
URI: http://sro.sussex.ac.uk/id/eprint/7415

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