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Title: Complementary approaches to target human respiratory syncytial virus using small molecule ligands
Author: Lardeau, Charles-Hugues Claude Jean
ISNI:       0000 0004 2744 2124
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2012
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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.
Supervisor: Nelson, A. ; Barr, J. ; Hiscox, J. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available