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Synthesis of β-d-galactopyranoside-Presenting Glycoclusters, Investigation of Their Interactions with Pseudomonas aeruginosa Lectin A (PA-IL) and Evaluation of Their Anti-Adhesion Potential

L. Malinovská, S. Thai Le, M. Herczeg, M. Vašková, J. Houser, E. Fujdiarová, J. Komárek, P. Hodek, A. Borbás, M. Wimmerová, M. Csávás,

. 2019 ; 9 (11) : . [pub] 20191101

Jazyk angličtina Země Švýcarsko

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc20025524

Pseudomonas aeruginosa is an opportunistic human pathogen associated with cystic fibrosis. This bacterium produces, among other virulence factors, a soluble d-galactose-specific lectin PA-IL (LecA). PA-IL plays an important role in the adhesion to the host cells and is also cytotoxic. Therefore, this protein is an interesting therapeutic target, suitable for inhibition by carbohydrate-based compounds. In the current study, β-d-galactopyranoside-containing tri- and tetravalent glycoclusters were synthesized. Methyl gallate and pentaerythritol equipped with propargyl groups were chosen as multivalent scaffolds and the galactoclusters were built from the above-mentioned cores by coupling ethylene or tetraethylene glycol-bridges and peracetylated propargyl β-d-galactosides using 1,3-dipolar azide-alkyne cycloaddition. The interaction between galactoside derivatives and PA-IL was investigated by several biophysical methods, including hemagglutination inhibition assay, isothermal titration calorimetry, analytical ultracentrifugation, and surface plasmon resonance. Their ability to inhibit the adhesion of P. aeruginosa to bronchial cells was determined by ex vivo assay. The newly synthesized multivalent galactoclusters proved to be significantly better ligands than simple d-galactose for lectin PA-IL and as a result, two representatives of the dendrimers were able to decrease adhesion of P. aeruginosa to bronchial cells to approximately 32% and 42%, respectively. The results may provide an opportunity to develop anti-adhesion therapy for the treatment of P. aeruginosa infection.

Citace poskytuje Crossref.org

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$a Malinovská, Lenka $u Central European Institute of Technology, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic. malinovska@mail.muni.cz. National Centre for Biomolecular Research, Faculty of Science, Masaryk University, Kotlářská 2, 611 37 Brno, Czech Republic. malinovska@mail.muni.cz.
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$a Synthesis of β-d-galactopyranoside-Presenting Glycoclusters, Investigation of Their Interactions with Pseudomonas aeruginosa Lectin A (PA-IL) and Evaluation of Their Anti-Adhesion Potential / $c L. Malinovská, S. Thai Le, M. Herczeg, M. Vašková, J. Houser, E. Fujdiarová, J. Komárek, P. Hodek, A. Borbás, M. Wimmerová, M. Csávás,
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$a Pseudomonas aeruginosa is an opportunistic human pathogen associated with cystic fibrosis. This bacterium produces, among other virulence factors, a soluble d-galactose-specific lectin PA-IL (LecA). PA-IL plays an important role in the adhesion to the host cells and is also cytotoxic. Therefore, this protein is an interesting therapeutic target, suitable for inhibition by carbohydrate-based compounds. In the current study, β-d-galactopyranoside-containing tri- and tetravalent glycoclusters were synthesized. Methyl gallate and pentaerythritol equipped with propargyl groups were chosen as multivalent scaffolds and the galactoclusters were built from the above-mentioned cores by coupling ethylene or tetraethylene glycol-bridges and peracetylated propargyl β-d-galactosides using 1,3-dipolar azide-alkyne cycloaddition. The interaction between galactoside derivatives and PA-IL was investigated by several biophysical methods, including hemagglutination inhibition assay, isothermal titration calorimetry, analytical ultracentrifugation, and surface plasmon resonance. Their ability to inhibit the adhesion of P. aeruginosa to bronchial cells was determined by ex vivo assay. The newly synthesized multivalent galactoclusters proved to be significantly better ligands than simple d-galactose for lectin PA-IL and as a result, two representatives of the dendrimers were able to decrease adhesion of P. aeruginosa to bronchial cells to approximately 32% and 42%, respectively. The results may provide an opportunity to develop anti-adhesion therapy for the treatment of P. aeruginosa infection.
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$a Thai Le, Son $u Department of Pharmaceutical Chemistry, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary. le.thai.son@pharm.unideb.hu. Doctoral School of Pharmaceutical Sciences, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary. le.thai.son@pharm.unideb.hu.
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$a Herczeg, Mihály $u Department of Pharmaceutical Chemistry, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary. herczeg.mihaly@science.unideb.hu. Research Group for Oligosaccharide Chemistry of Hungarian Academy of Sciences, Egyetem tér 1, H-4032 Debrecen, Hungary. herczeg.mihaly@science.unideb.hu.
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$a Vašková, Michaela $u Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, 128 40 Prague 2, Czech Republic. michael.vaskova@gmail.com.
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$a Houser, Josef $u Central European Institute of Technology, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic. houser@mail.muni.cz. National Centre for Biomolecular Research, Faculty of Science, Masaryk University, Kotlářská 2, 611 37 Brno, Czech Republic. houser@mail.muni.cz.
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$a Fujdiarová, Eva $u National Centre for Biomolecular Research, Faculty of Science, Masaryk University, Kotlářská 2, 611 37 Brno, Czech Republic. eva.fujdiarova@mail.muni.cz.
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$a Komárek, Jan $u Central European Institute of Technology, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic. honzakomarek@mail.muni.cz. National Centre for Biomolecular Research, Faculty of Science, Masaryk University, Kotlářská 2, 611 37 Brno, Czech Republic. honzakomarek@mail.muni.cz.
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$a Hodek, Petr $u Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, 128 40 Prague 2, Czech Republic. petr.hodek@natur.cuni.cz.
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$a Wimmerová, Michaela $u Central European Institute of Technology, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic. michaw@chemi.muni.cz. National Centre for Biomolecular Research, Faculty of Science, Masaryk University, Kotlářská 2, 611 37 Brno, Czech Republic. michaw@chemi.muni.cz. Department of Biochemistry, Faculty of Science, Masaryk University, Kotlářská 2, 611 37 Brno, Czech Republic. michaw@chemi.muni.cz.
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$a Csávás, Magdolna $u Department of Pharmaceutical Chemistry, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary. csavas.magdolna@science.unideb.hu.
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