4pdw: Difference between revisions
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''' | ==A benzonitrile analogue inhibits rhinovirus replication== | ||
<StructureSection load='4pdw' size='340' side='right' caption='[[4pdw]], [[Resolution|resolution]] 3.00Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4pdw]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human_rhinovirus_14 Human rhinovirus 14] and [http://en.wikipedia.org/wiki/Rhinovirus_b Rhinovirus b]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4PDW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4PDW FirstGlance]. <br> | |||
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2XK:4-[(4,5-DIMETHOXY-2-NITROPHENYL)ACETYL]BENZONITRILE'>2XK</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene><br> | |||
<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4pdw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4pdw OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4pdw RCSB], [http://www.ebi.ac.uk/pdbsum/4pdw PDBsum]</span></td></tr> | |||
<table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
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 (EC50 of 2 +/- 1 muM). 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. | |||
A novel benzonitrile analogue inhibits rhinovirus replication.,Lacroix C, Querol-Audi J, Roche M, Franco D, Froeyen M, Guerra P, Terme T, Vanelle P, Verdaguer N, Neyts J, Leyssen P J Antimicrob Chemother. 2014 Jun 19. pii: dku200. PMID:24948704<ref>PMID:24948704</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Human rhinovirus 14]] | |||
[[Category: Rhinovirus b]] | |||
[[Category: Franco, D.]] | |||
[[Category: Froeyen, M.]] | |||
[[Category: Guerra, P.]] | |||
[[Category: Lacroix, C.]] | |||
[[Category: Leyssen, P.]] | |||
[[Category: Neyts, J.]] | |||
[[Category: Querol-Audi, J.]] | |||
[[Category: Roche, M.]] | |||
[[Category: Terme, T.]] | |||
[[Category: Vanelle, P.]] | |||
[[Category: Verdaguer, N.]] | |||
[[Category: Benzonitrile inhibitor]] | |||
[[Category: Virus]] | |||
Revision as of 11:23, 2 July 2014
A benzonitrile analogue inhibits rhinovirus replicationA benzonitrile analogue inhibits rhinovirus replication
Structural highlights
Publication Abstract from PubMedOBJECTIVES: 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 (EC50 of 2 +/- 1 muM). 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. A novel benzonitrile analogue inhibits rhinovirus replication.,Lacroix C, Querol-Audi J, Roche M, Franco D, Froeyen M, Guerra P, Terme T, Vanelle P, Verdaguer N, Neyts J, Leyssen P J Antimicrob Chemother. 2014 Jun 19. pii: dku200. PMID:24948704[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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