Document Detail


Susceptibility of coxsackievirus B3 laboratory strains and clinical isolates to the capsid function inhibitor pleconaril: antiviral studies with virus chimeras demonstrate the crucial role of amino acid 1092 in treatment.
MedLine Citation:
PMID:  16150864     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVES: At present, most promising compounds to treat enterovirus-induced diseases are broad-spectrum capsid function inhibitors which bind into a hydrophobic pocket in viral capsid protein 1 (VP1). Coxsackievirus B3 (CVB3) Nancy was the only prototypic enterovirus strain shown to be pleconaril-resistant. This study was designed to better understand the polymorphism of the hydrophobic pocket in CVB3 laboratory strains and clinical isolates and its implications for treatment with the capsid function inhibitor pleconaril. METHODS: Pleconaril susceptibility was determined in cytopathic effect-inhibitory, plaque reduction or virus yield assays. Sequence analysis of the genome region coding for VP1 and/or subsequent alignment of amino acids lining the hydrophobic pocket of five CVB3 laboratory strains and 20 clinical isolates were carried out. Virus chimeras and computational analysis were used to prove the role of amino acid 1092. RESULTS AND CONCLUSIONS: Despite high conservation of pocket amino acids, polymorphism was detected at positions 1092, 1094 and 1180. Neither Pro-1094-->Thr nor Val-1180-->Ile altered efficacy of pleconaril treatment. But the amino acid at position 1092 was strongly associated with susceptibility of CVB3 to the capsid inhibitor. Whereas leucine was involved in resistance, isoleucine and valine were detected in pleconaril-susceptible CVB3. Results from antiviral assays with hybrid viruses demonstrate the crucial role of amino acid 1092 in pleconaril susceptibility. A resistant cDNA-generated CVB3 became pleconaril-susceptible after accepting parts from the genome region encoding Ile-1092 into its capsid. Computational analysis suggests that conformational changes in the hydrophobic pocket occur when leucine is substituted for isoleucine or valine and that this change leads to susceptibility to pleconaril.
Authors:
Michaela Schmidtke; Elke Hammerschmidt; Susanne Schüler; Roland Zell; Eckhard Birch-Hirschfeld; Vadim A Makarov; Olga B Riabova; Peter Wutzler
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2005-09-08
Journal Detail:
Title:  The Journal of antimicrobial chemotherapy     Volume:  56     ISSN:  0305-7453     ISO Abbreviation:  J. Antimicrob. Chemother.     Publication Date:  2005 Oct 
Date Detail:
Created Date:  2005-09-28     Completed Date:  2006-01-11     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  7513617     Medline TA:  J Antimicrob Chemother     Country:  England    
Other Details:
Languages:  eng     Pagination:  648-56     Citation Subset:  IM    
Affiliation:
Institute of Virology and Antiviral Therapy, Medical Centre of the Friedrich Schiller University Jena, Hans Knoell Str. 2, D-07740 Jena, Germany. michaela.schmidtke@med.uni-jena.de
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Substitution / genetics
Animals
Antiviral Agents / pharmacology*
CHO Cells
Capsid / drug effects*,  physiology
Capsid Proteins / antagonists & inhibitors,  chemistry*,  genetics,  metabolism*
Cell Line
Cricetinae
Dose-Response Relationship, Drug
Drug Resistance, Viral
Enterovirus B, Human / classification,  drug effects*,  genetics*,  isolation & purification
Enterovirus Infections / virology
Humans
Hydrophobicity
Oxadiazoles / pharmacology*
Polymorphism, Genetic
Chemical
Reg. No./Substance:
0/Antiviral Agents; 0/Capsid Proteins; 0/Oxadiazoles; 0/pleconaril

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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