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Complementary approaches to target human respiratory syncytial virus using small molecule ligands

Lardeau, Charles-Hugues Claude Jean (2012) Complementary approaches to target human respiratory syncytial virus using small molecule ligands. PhD thesis, University of Leeds.

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Abstract

In the current project, situated at the interface of chemistry and virology, complementary drug discovery approaches (high-throughput screening and structurebased drug design) have been exploited in order to discover novel small molecule inhibitors of hRSV. Thus, a novel fluorescence-based high-throughput screening assay was developed using known anti-virals for validation: EC50 of Ribavirin ca. 30 μM, and EC50 of JNJ- 4749914 ca. 0.4 nM. This assay was then used to screen a natural product-like library. The crystal structure of a small molecule in complex with the fusion protein of hRSV was used in a virtual high-throughput screening campaign. A range of virtual libraries (libraries of likely synthetically accessible and commercially available molecule) were screened virtually using eHiTS against this binding cavity. This led to the identification of a potential novel series of hRSV fusion inhibitors, whose syntheses and biological evaluation have been described. Novel confocal imaging experiments were also carried out on a known hRSV fusion inhibitor (JNJ-4749914) in order to gain more insight in the compound's mode of action by visualising virus entry inhibition in epithelial cells.

Item Type: Thesis (PhD)
ISBN: 978-0-85731-323-2
Academic Units: The University of Leeds > Faculty of Biological Sciences (Leeds)
Identification Number/EthosID: uk.bl.ethos.577357
Depositing User: Repository Administrator
Date Deposited: 10 Jul 2013 11:45
Last Modified: 07 Mar 2014 11:27
URI: http://etheses.whiterose.ac.uk/id/eprint/4145

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