On‐Chip Screening of a Glycomimetic Library with C‐Type Lectins Reveals Structural Features Responsible for Preferential Binding of Dectin‐2 over DC‐SIGN/R and Langerin

Medve, Laura; Achilli, Silvia; Serna, Sonia; Zuccotto, Fabio; Varga, Norbert; Thépaut, Michel; Civera, Monica; Vivès, Corinne; Fieschi, Franck; Reichardt, Niels; Bernardi, Anna

doi:10.1002/chem.201802577

Cited by 14 publications

(11 citation statements)

References 71 publications

(54 reference statements)

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“…Together with the Bernardi group, we have recently shown how microarrays can be used to screen small glycomimetics in a more systematic approach, which has allowed us to identify compounds presenting selectivity for Dectin‐2 over DC‐SIGN C‐type lectins. However, in this case each glycomimetic had to be synthesized individually in solution prior to its immobilization onto the array for analysis …”

Section: Introductionmentioning

confidence: 99%

Rapid On‐Chip Synthesis of Complex Glycomimetics from N‐Glycan Scaffolds for Improved Lectin Targeting

Cioce

Thépaut

Fieschi

et al. 2020

Chemistry A European J

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C-type lectinr eceptor (CLR)c arbohydrate binding proteinsf ound on immune cells with important functions in pathogen recognition as well as self and non-self-differentiation are increasingly moving into the focus of drug developers as targets for the immune therapy of cancer autoimmune diseases and inflammation and to improvet he efficacy of vaccines. The development of molecules with increaseda ffinitya nd selectivity over the natural glycanb inders has largely focused on the synthesis of mono and disaccharidem imetics but glycana rray bindinge xperiments have shown increased binding selectivity and affinity for selected larger oligosaccharides that are able to engage in additionalf avorable interactions beyondt he primary binding site. Here, aplatform for the rapid preparation and screening of N-glycanm imetics on microarrays is presented that turns ap anel of complex glycan core structures into structurally diverse glycomimetics by ac ombination of enzymatic glycosylation with an onnatural donor and subsequent cycloaddition with ac ollection of alkynes. All surface-basedr eactions were monitored by MALDI-TOF MS to assess conversion and purityo fs pot compositions. Screening the collectiono f3 74 N-glycomimetics against the plant lectin WFAa nd the 2 humani mmune lectins MGL ECD and LangerinE CD producedanumber of high affinity binders as lead structures for more selectivelectin targeting probes.

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Section: Introductionmentioning

confidence: 99%

Rapid On‐Chip Synthesis of Complex Glycomimetics from N‐Glycan Scaffolds for Improved Lectin Targeting

Cioce

Thépaut

Fieschi

et al. 2020

Chemistry A European J

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“…In the FP competition method, we measured the binding of hexasaccharide 17 and the protein in solution, while in the sugar immobilized experiment, we observed the direct interaction between the growth factor and a multivalent functionalized surface. As previously shown, the format of the interaction experiment can strongly influence the calculated affinity values [4,43,44]. Thus, the multivalent presentation of the fluorinated oligosaccharide on the microplate provided much higher binding affinities, in comparison with the solution-phase results.…”

Section: Resultsmentioning

confidence: 93%

Synthesis of a Fluorous-Tagged Hexasaccharide and Interaction with Growth Factors Using Sugar-Coated Microplates

2019

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Here, we report the synthesis of a sulfated, fully protected hexasaccharide as a glycosaminoglycan mimetic and the study of its interactions with different growth factors: midkine, basic fibroblast growth factor (FGF-2) and nerve growth factor (NGF). Following a fluorous-assisted approach, monosaccharide building blocks were successfully assembled and the target oligosaccharide was prepared in excellent yield. The use of more acid stable 4,6-O-silylidene protected glucosamine units was crucial for the efficiency of this strategy because harsh reaction conditions were needed in the glycosylations to avoid the formation of orthoester side products. Fluorescence polarization experiments demonstrated the strong interactions between the synthesized hexamer, and midkine and FGF-2. In addition, we have developed an alternative assay to analyse these molecular recognition events. The prepared oligosaccharide was non-covalently attached to a fluorous-functionalized microplate and the direct binding of the protein to the sugar-immobilized surface was measured, affording the corresponding KD,surf value.

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“…Certainly, langerin features a more reduced and particular specificity than related lectins such as DC-SIGN or Dectin. [200] It cannot recognize Le A and Le X antigens and presents a limited ability to target inner Man residues in highly branched scaffolds, in part due to the two protruding charged lysine side chains near the calcium site. These two side chains have been actually exploited for the design of bulky and positive substituents which can preclude binding to langerin while still targeting DC-SIGN, thereby improving the selectivity for the latter.…”

Section: Langerinmentioning

confidence: 99%

Molecular Recognition in C‐Type Lectins: The Cases of DC‐SIGN, Langerin, MGL, and L‐Sectin

et al. 2020

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Carbohydrates play a pivotal role in intercellular communication processes. In particular, glycan antigens are key for sustaining homeostasis, helping leukocytes to distinguish damaged tissues and invading pathogens from healthy tissues. From a structural perspective, this cross-talk is fairly complex, and multiple membrane proteins guide these recognition processes, including lectins and Toll-like receptors. Since the beginning of this century, lectins have become potential targets for therapeutics for controlling and/or avoiding the progression of pathologies derived from an incorrect immune outcome, including infectious processes, cancer, or autoimmune diseases. Therefore, a detailed knowledge of these receptors is mandatory for the development of specific treatments. In this review, we summarize the current knowledge about four key C-type lectins whose importance has been steadily growing in recent years, focusing in particular on how glycan recognition takes place at the molecular level, but also looking at recent progresses in the quest for therapeutics.

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On‐Chip Screening of a Glycomimetic Library with C‐Type Lectins Reveals Structural Features Responsible for Preferential Binding of Dectin‐2 over DC‐SIGN/R and Langerin

Cited by 14 publications

References 71 publications

Rapid On‐Chip Synthesis of Complex Glycomimetics from N‐Glycan Scaffolds for Improved Lectin Targeting

Rapid On‐Chip Synthesis of Complex Glycomimetics from N‐Glycan Scaffolds for Improved Lectin Targeting

Synthesis of a Fluorous-Tagged Hexasaccharide and Interaction with Growth Factors Using Sugar-Coated Microplates

Molecular Recognition in C‐Type Lectins: The Cases of DC‐SIGN, Langerin, MGL, and L‐Sectin

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