Identification of New L-Fucosyl and L-Galactosyl Amides as Glycomimetic Ligands of TNF Lectin Domain of BC2L-C from Burkholderia cenocepacia
Articolo
Data di Pubblicazione:
2023
Citazione:
Identification of New L-Fucosyl and L-Galactosyl Amides as Glycomimetic Ligands of TNF Lectin Domain of BC2L-C from Burkholderia cenocepacia / S. Mazzotta, G. Antonini, F. Vasile, E. Gillon, J. Lundstrøm, A. Varrot, L. Belvisi, A. Bernardi. - In: MOLECULES. - ISSN 1420-3049. - 28:3(2023), pp. 1494.1-1494.18. [10.3390/molecules28031494]
Abstract:
The inhibition of carbohydrate-lectin interactions is being explored as an efficient approach
to anti adhesion therapy and biofilm destabilization, two alternative antimicrobial strategies that
are being explored against resistant pathogens. BC2L-C is a new type of lectin from Burkholderia
cenocepacia that binds (mammalian) fucosides at the N-terminal domain and (bacterial) mannosides at
the C-terminal domain. This double carbohydrate specificity allows the lectin to crosslink host cells
and bacterial cells. We have recently reported the design and generation of the first glycomimetic
antagonists of BC2L-C, β-C- or β-N-fucosides that target the fucose-specific N-terminal domain
(BC2L-C-Nt). The low water solubility of the designed N-fucosides prevented a full examination of
this promising series of ligands. In this work, we describe the synthesis and biophysical evaluation of
new L-fucosyl and L-galactosyl amides, designed to be water soluble and to interact with BC2L-C-Nt.
The protein–ligand interaction was investigated by Saturation Transfer Difference NMR, Isothermal
Titration Calorimetry and crystallographic studies. STD-NMR experiments showed that both fucosyl
and galactosyl amides compete with α-methyl fucoside for lectin binding. A new hit compound
was identified with good water solubility and an affinity for BC2L-C-Nt of 159 μM (ITC), which
represents a one order of magnitude gain over α-methyl fucoside. The x-ray structure of its complex
with BC2L-C-Nt was solved at 1.55 Å resolution.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
lectins; fucosides; N-glycosides; crystallography; glycomimetics; antiadhesive therapy
Elenco autori:
S. Mazzotta, G. Antonini, F. Vasile, E. Gillon, J. Lundstrøm, A. Varrot, L. Belvisi, A. Bernardi
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