Insightful Improvement in the Design of ...
Document type :
Article dans une revue scientifique: Article original
Permalink :
Title :
Insightful Improvement in the Design of Potent Uropathogenic E. coli FimH Antagonists
Author(s) :
Mousavifar, Leila [Auteur]
Université du Québec à Montréal = University of Québec in Montréal [UQAM]
Sarshar, Meysam [Auteur]
Bridot, Clarisse [Auteur]
Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement (RID-AGE) - U1167
Scribano, Daniela [Auteur]
Ambrosi, Cecilia [Auteur]
Palamara, Anna Teresa [Auteur]
Vergoten, Gérard [Auteur]
Roubinet, Benoît [Auteur]
Landemarre, Ludovic [Auteur]
Bouckaert, Julie [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Roy, René [Auteur]
Université du Québec à Montréal = University of Québec in Montréal [UQAM]
Sarshar, Meysam [Auteur]
Bridot, Clarisse [Auteur]
Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement (RID-AGE) - U1167
Scribano, Daniela [Auteur]
Ambrosi, Cecilia [Auteur]
Palamara, Anna Teresa [Auteur]
Vergoten, Gérard [Auteur]
Roubinet, Benoît [Auteur]
Landemarre, Ludovic [Auteur]
Bouckaert, Julie [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Roy, René [Auteur]
Journal title :
Pharmaceutics
Abbreviated title :
Pharmaceutics
Volume number :
15
Pages :
527
Publisher :
MDPI AG
Publication date :
2023-02-04
ISSN :
1999-4923
English keyword(s) :
uropathogenic Escherichia coli (UPEC)
FimH
antagonists
mannosides
glycocomimetics
crystallography
adhesion inhibition
bladder cells
molecular dynamic simulations
FimH
antagonists
mannosides
glycocomimetics
crystallography
adhesion inhibition
bladder cells
molecular dynamic simulations
HAL domain(s) :
Sciences du Vivant [q-bio]
English abstract : [en]
Selective antiadhesion antagonists of Uropathogenic Escherichia coli (UPEC) type-1 Fimbrial adhesin (FimH) are attractive alternatives for antibiotic therapies and prophylaxes against acute or recurrent urinary tract ...
Show more >Selective antiadhesion antagonists of Uropathogenic Escherichia coli (UPEC) type-1 Fimbrial adhesin (FimH) are attractive alternatives for antibiotic therapies and prophylaxes against acute or recurrent urinary tract infections (UTIs) caused by UPECs. A rational small library of FimH antagonists based on previously described C-linked allyl α-D-mannopyranoside was synthesized using Heck cross-coupling reaction using a series of iodoaryl derivatives. This work reports two new members of FimH antagonist amongst the above family with sub nanomolar affinity. The resulting hydrophobic aglycones, including constrained alkene and aryl groups, were designed to provide additional favorable binding interactions with the so-called FimH “tyrosine gate”. The newly synthesized C-linked glycomimetic antagonists, having a hydrolytically stable anomeric linkage, exhibited improved binding when compared to previously published analogs, as demonstrated by affinity measurement through interactions by FimH lectin. The crystal structure of FimH co-crystallized with one of the nanomolar antagonists revealed the binding mode of this inhibitor into the active site of the tyrosine gate. In addition, selected mannopyranoside constructs neither affected bacterial growth or cell viability nor interfered with antibiotic activity. C-linked mannoside antagonists were effective in decreasing bacterial adhesion to human bladder epithelial cells (HTB-9). Therefore, these molecules constituted additional therapeutic candidates’ worth further development in the search for potent anti-adhesive drugs against infections caused by UPEC.Show less >
Show more >Selective antiadhesion antagonists of Uropathogenic Escherichia coli (UPEC) type-1 Fimbrial adhesin (FimH) are attractive alternatives for antibiotic therapies and prophylaxes against acute or recurrent urinary tract infections (UTIs) caused by UPECs. A rational small library of FimH antagonists based on previously described C-linked allyl α-D-mannopyranoside was synthesized using Heck cross-coupling reaction using a series of iodoaryl derivatives. This work reports two new members of FimH antagonist amongst the above family with sub nanomolar affinity. The resulting hydrophobic aglycones, including constrained alkene and aryl groups, were designed to provide additional favorable binding interactions with the so-called FimH “tyrosine gate”. The newly synthesized C-linked glycomimetic antagonists, having a hydrolytically stable anomeric linkage, exhibited improved binding when compared to previously published analogs, as demonstrated by affinity measurement through interactions by FimH lectin. The crystal structure of FimH co-crystallized with one of the nanomolar antagonists revealed the binding mode of this inhibitor into the active site of the tyrosine gate. In addition, selected mannopyranoside constructs neither affected bacterial growth or cell viability nor interfered with antibiotic activity. C-linked mannoside antagonists were effective in decreasing bacterial adhesion to human bladder epithelial cells (HTB-9). Therefore, these molecules constituted additional therapeutic candidates’ worth further development in the search for potent anti-adhesive drugs against infections caused by UPEC.Show less >
Language :
Anglais
Audience :
Internationale
Popular science :
Non
Administrative institution(s) :
Université de Lille
CNRS
CNRS
Research team(s) :
Computational Molecular Systems Biology
Submission date :
2023-04-04T14:20:31Z
2023-04-05T07:04:34Z
2023-04-05T07:04:34Z
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