Rational Design of a DNA‐Scaffolded High‐Affinity Binder for Langerin

Bachem, Gunnar; Wamhoff, Eike‐Christian; Silberreis, Kim; Kim, Dong-Yoon; Baukmann, Hannes; Fuchsberger, Felix F.; Dernedde, Jens; Rademacher, Christoph; Seitz, Oliver

doi:10.1002/anie.202006880

Cited by 25 publications

(22 citation statements)

References 65 publications

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“…However, many challenges remain, and various aspects of this field still require exploration. First, numerous biological molecules capable of bivalent or multivalent interactions have not yet been explored in regard to their use in the design of biosensors [130][131][132][133][134][135]. Second, precisely designed nanostructures are required for biosensors, particularly those used for detecting viruses; this is because they express unique patterns of antigen arrays.…”

Section: Discussionmentioning

confidence: 99%

Biosensors Based on Bivalent and Multivalent Recognition by Nucleic Acid Scaffolds

et al. 2022

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Several biological macromolecules adopt bivalent or multivalent interactions to perform various cellular processes. In this regard, the development of molecular constructs presenting multiple ligands in a specific manner is becoming crucial for the understanding of multivalent interactions and for the detection of target macromolecules. Nucleic acids are attractive molecules to achieve this goal because they are capable of forming various, structurally well-defined 2D or 3D nanostructures and can bear multiple ligands on their structures with precisely controlled ligand–ligand distances. Thanks to the features of nucleic acids, researchers have proposed a wide range of bivalent and multivalent binding agents that strongly bind to target biomolecules; consequently, these findings have uncovered new biosensing strategies for biomolecule detection. To date, various bivalent and multivalent interactions of nucleic acid architectures have been applied to the design of biosensors with enhanced sensitivity and target accuracy. In this review, we describe not only basic biosensor designs but also recently designed biosensors operating through the bivalent and multivalent recognition of nucleic acid scaffolds. Based on these designs, strategies to transduce bi- or multivalent interaction signals into readable signals are discussed in detail, and the future prospects and challenges of the field of multivalence-based biosensors are explored.

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Section: Discussionmentioning

confidence: 99%

Biosensors Based on Bivalent and Multivalent Recognition by Nucleic Acid Scaffolds

et al. 2022

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“…Under physiological conditions, glycan-receptor interactions take place in multivalent fashion, conveying avidity and selectivity to the otherwise transient and promiscuous nature of monovalent glycan recognition. , Analogously, multivalency has been exploited to target CLRs or used in various assay systems to mimic and study these complex interactions. − In addition to common homomultivalent targeting approaches, typically directed toward the primary CBS, simultaneously engaging secondary binding pockets represents a promising concept. The incentive here is to leverage avidity effects and to achieve higher receptor specificity, bypassing the overlapping glycan recognition profiles of lectins.…”

Section: Introductionmentioning

confidence: 99%

A Remote Secondary Binding Pocket Promotes Heteromultivalent Targeting of DC-SIGN

et al. 2021

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Dendritic cells (DC) are antigen-presenting cells coordinating the interplay of the innate and the adaptive immune response. The endocytic C-type lectin receptors DC-SIGN and Langerin display expression profiles restricted to distinct DC subtypes and have emerged as prime targets for next-generation immunotherapies and anti-infectives. Using heteromultivalent liposomes copresenting mannosides bearing aromatic aglycones with natural glycan ligands, we serendipitously discovered striking cooperativity effects for DC-SIGN+ but not for Langerin+ cell lines. Mechanistic investigations combining NMR spectroscopy with molecular docking and molecular dynamics simulations led to the identification of a secondary binding pocket for the glycomimetics. This pocket, located remotely of DC-SIGN’s carbohydrate bindings site, can be leveraged by heteromultivalent avidity enhancement. We further present preliminary evidence that the aglycone allosterically activates glycan recognition and thereby contributes to DC-SIGN-specific cell targeting. Our findings have important implications for both translational and basic glycoscience, showcasing heteromultivalent targeting of DCs to improve specificity and supporting potential allosteric regulation of DC-SIGN and CLRs in general.

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“… 76 Bachem et al used DNA-PNA scaffolds to precisely space and cluster glycans to selectively engage Langerin with 1150-fold increased affinity in comparison to the free ligand. 77 In addition to precisely targeting 3D presentation to gain affinity, the presentation of glycans can affect a sensing outcome (which is not necessarily proportional to affinity). For example, SARS-CoV-2 spike protein binding in a flow-through assay was dependent on the length of polymeric linkers, connecting Neu5NAc to gold nanoparticles, 49 and polymer chain length and chemistry tuned the outputs in gold nanoparticle aggregation assays ( Figure 5 B).…”

Section: D Presentationmentioning

confidence: 99%

“…Both lectins bind to the mannose, but selectivity was achieved due to the spacing differences in the Langerin homotrimer, in comparison to the DC-SIGN homotetramer (Figure A) . Bachem et al used DNA-PNA scaffolds to precisely space and cluster glycans to selectively engage Langerin with 1150-fold increased affinity in comparison to the free ligand . In addition to precisely targeting 3D presentation to gain affinity, the presentation of glycans can affect a sensing outcome (which is not necessarily proportional to affinity).…”

Section: D Presentationmentioning

confidence: 99%

Toward Glycomaterials with Selectivity as Well as Affinity

Richards

Gibson

2021

JACS Au

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Multivalent glycosylated materials (polymers, surfaces, and particles) often show high affinity toward carbohydrate binding proteins (e.g., lectins) due to the nonlinear enhancement from the cluster glycoside effect. This affinity gain has potential in applications from diagnostics, biosensors, and targeted delivery to anti-infectives and in an understanding of basic glycobiology. This perspective highlights the question of selectivity, which is less often addressed due to the reductionist nature of glycomaterials and the promiscuity of many lectins. The use of macromolecular features, including architecture, heterogeneous ligand display, and the installation of non-natural glycans, to address this challenge is discussed, and examples of selectivity gains are given.

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Rational Design of a DNA‐Scaffolded High‐Affinity Binder for Langerin

Cited by 25 publications

References 65 publications

Biosensors Based on Bivalent and Multivalent Recognition by Nucleic Acid Scaffolds

Biosensors Based on Bivalent and Multivalent Recognition by Nucleic Acid Scaffolds

A Remote Secondary Binding Pocket Promotes Heteromultivalent Targeting of DC-SIGN

Toward Glycomaterials with Selectivity as Well as Affinity

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