English
español
Please use this identifier to cite or link to this item:
http://hdl.handle.net/10261/124193
Share/Impact:
Statistics |
![]() ![]() ![]() |
|
|
Visualizar otros formatos: MARC | Dublin Core | RDF | ORE | MODS | METS | DIDL | DATACITE | |||
|
Title: | A novel benzonitrile analogue inhibits rhinovirus replication |
Authors: | Lacroix, Céline; Querol-Audí, Jordi ![]() ![]() |
Keywords: | rhinovirus 14 VP1 capsid binder pleconaril |
Issue Date: | 1-Oct-2014 |
Publisher: | American Society for Microbiology |
Citation: | Antimicrobial Agents and Chemotherapy 69: 2723-2732 (2014) |
Abstract: | OBJECTIVES: To study the characteristics and the mode of action of the anti-rhinovirus compound 4-[1-hydroxy-2-(4,5-dimethoxy-2-nitrophenyl)ethyl]benzonitrile (LPCRW_0005). METHODS: The antiviral activity of LPCRW_0005 was evaluated in a cytopathic effect reduction assay against a panel of human rhinovirus (HRV) strains. To unravel its precise molecular mechanism of action, a time-of-drug-addition study, resistance selection and thermostability assays were performed. The crystal structure of the HRV14/LPCRW_0005 complex was elucidated as well. RESULTS: LPCRW_0005 proved to be a selective inhibitor of the replication of HRV14 (EC(50) of 2 ± 1 μM). Time-of-drug-addition studies revealed that LPCRW_0005 interferes with the earliest stages of virus replication. Phenotypic drug-resistant virus variants were obtained (≥30-fold decrease in susceptibility to the inhibitory effect of LPCRW_0005), which carried either an A150T or A150V amino acid substitution in the VP1 capsid protein. The link between the mutant genotype and drug-resistant phenotype was confirmed by reverse genetics. Cross-resistance studies and thermostability assays revealed that LPCRW_0005 has a similar mechanism of action to the capsid binder pleconaril. Elucidation of the crystal structure of the HRV14/LPCRW_0005 complex revealed the existence of multiple hydrophobic and polar interactions between the VP1 pocket and LPCRW_0005. CONCLUSIONS: LPCRW_0005 is a novel inhibitor of HRV14 replication that acts as a capsid binder. The compound has a chemical structure that is markedly smaller than that of other capsid binders. Structural studies show that LPCRW_0005, in contrast to pleconaril, leaves the toe end of the pocket in VP1 empty. This suggests that extended analogues of LPCRW_0005 that fill the full cavity could be more potent inhibitors of rhinovirus replication. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com. |
Publisher version (URL): | http://dx.doi.org/10.1093/jac/dku200 |
URI: | http://hdl.handle.net/10261/124193 |
DOI: | http://dx.doi.org/10.1093/jac/dku200 |
Identifiers: | doi: 10.1093/jac/dku200 issn: 1098-6596 |
Appears in Collections: | (IBMB) Artículos |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
accesoRestringido.pdf | 15,38 kB | Adobe PDF | ![]() View/Open |
Show full item record
Review this work
Review this work
WARNING: Items in Digital.CSIC are protected by copyright, with all rights reserved, unless otherwise indicated.