Fucosylated ubiquitin and orthogonally glycosylated mutant A28C: conceptually new ligands for <i>Burkholderia ambifaria</i> lectin (BambL)

Kuhaudomlarp, Sakonwan; Cerofolini, Linda; Santarsia, Sabrina; Gillon, Émilie; Fallarini, Silvia; Lombardi, Grazia; Denis, Maxime; Giuntini, Stefano; Valori, Carolina; Fragai, Marco; Dondoni, Alessandro; Nativi, Cristina

doi:10.1039/d0sc03741a

Cited by 8 publications

(7 citation statements)

References 36 publications

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“…Interestingly, a discrepancy between two carbohydrate‐binding sites in the interaction with the complex carbohydrates, but not with MeFuc, has been reported for BambL recently. [9a] Given the lack in affinity change with 2FF, we propose that inhibition of secondary site could potentially down‐regulate the affinity of BambL by tuning the orthosteric site between two monomers, but not within a monomer. However, the hexameric structure of BambL complicates the identification of allosteric pathway since the symmetry‐related sites are close to each other and chemical shifts can be affected by two binding events.…”

Section: Resultsmentioning

confidence: 95%

Druggable Allosteric Sites in β‐Propeller Lectins

et al. 2021

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Carbohydrate-binding proteins (lectins) are auspicious targets in drug discovery to combat antimicrobial resistance;h owever,t heir non-carbohydrate drug-like inhibitors are still unavailable.Here,wepresent adruggable pocket in a b-propeller lectin BambL from Burkholderia ambifaria as ap otential target for allosteric inhibitors.T his site was identified employing 19 FNMR fragment screening and acomputational pocket prediction algorithm SiteMap.T he structure-activity relationship study revealed the most promising fragment with ad issociation constant of 0.3 AE 0.1 mM and al igand efficiency of 0.3 kcal mol À1 HA À1 that affected the orthosteric site.T his effect was substantiated by site-directed mutagenesis in the orthosteric and secondary pockets.F uture drug-discovery campaigns that aim to develop small molecule inhibitors can benefit from allosteric sites in lectins as an ew therapeutic approach against antibiotic-resistant pathogens.

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Section: Resultsmentioning

confidence: 95%

Druggable Allosteric Sites in β‐Propeller Lectins

et al. 2021

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“…Fucose-binding lectins expressed by life-threatening pathogens such as B. cenocepacia or A. fumigatus have attracted attention in view of their potential implications in respiratory infections. 19,21,22,28,29 The role of the recently identified FleA lectin in A. fumigatus pathogenesis is however still unclear. Published studies suggest that FleApromoted binding may actually attenuates A. fumigatus virulence, by improving mucocilliary clearance, macrophage killing, and/or inhibition of conidia germination to hyphae.…”

Section: Discussionmentioning

confidence: 99%

Hexavalent thiofucosides to probe the role of the Aspergillus fumigatus lectin FleA in fungal pathogenicity

et al. 2021

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“…Another study employed ubiquitin as scaffold protein for multivalent presentation of aryl α-O-fucoside 49 to address the fucose-binding Burkholderia ambifaria lectin BamL. [37] B. ambifaria is a Gram-negative opportunistic bacterium causing infections of the respiratory tract and is particularly dangerous for CF patients. [38] Its fucose-binding lectin BamL is the key virulence factor and associates as a trimer with two binding sites per monomer.…”

Section: Proteins As Multivalent Scaffoldsmentioning

confidence: 99%

Novel Approaches To Design Glycan‐Based Antibacterial Inhibitors

Behren

Westerlind

2022

Eur J Org Chem

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The interactions between bacterial lectins and carbohydrates on the host cell surface can mediate bacterial adhesion, invasion, and immune evasion. Multivalency plays a key role in these binding events. However, additional molecular mechanisms greatly impact multivalent binding recognition. To develop specific and effective bacterial inhibitors, a deeper understanding of the complex underlying mechanisms of bacterial adhesion processes is necessary. By interfering with bacterial adhesion, synthetic multivalent glycoconjugates do not only have the potential to improve or replace antibiotic treatments, but also represent useful tools to study carbohydrate-pathogen interactions. In this review, we highlight a few recent advances in the synthesis and application of synthetic glycan-based scaffolds to uncover the nature of glycan-bacteria interactions and to design efficient bacterial inhibitors.

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Fucosylated ubiquitin and orthogonally glycosylated mutant A28C: conceptually new ligands for Burkholderia ambifaria lectin (BambL)

Abstract: Two orthogonal, metal free click reactions, enabled to glycosylate ubiquitin and its mutant A28C forming two protein scaffolds with high affinity for BambL, a lectin from the human pathogen Burkholderia...

Cited by 8 publications

References 36 publications

Druggable Allosteric Sites in β‐Propeller Lectins

Druggable Allosteric Sites in β‐Propeller Lectins

Hexavalent thiofucosides to probe the role of the Aspergillus fumigatus lectin FleA in fungal pathogenicity

Novel Approaches To Design Glycan‐Based Antibacterial Inhibitors

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