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Issue 20, 2020
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Precipitation-free high-affinity multivalent binding by inline lectin ligands

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Abstract

Multivalent ligand–protein interactions are a key concept in biology mediating, for example, signalling and adhesion. Multivalent ligands often have tremendously increased binding affinities. However, they also can cause crosslinking of receptor molecules leading to precipitation of ligand–receptor complexes. Plaque formation due to precipitation is a known characteristic of numerous fatal diseases limiting a potential medical application of multivalent ligands with a precipitating binding mode. Here, we present a new design of high-potency multivalent ligands featuring an inline arrangement of ligand epitopes with exceptionally high binding affinities in the low nanomolar range. At the same time, we show with a multi-methodological approach that precipitation of the receptor is prevented. We distinguish distinct binding modes of the ligands, in particular we elucidate a unique chelating binding mode, where four receptor binding sites are simultaneously bridged by one multivalent ligand molecule. The new design concept of inline multivalent ligands, which we established for the well-investigated model lectin wheat germ agglutinin, has great potential for the development of high-potency multivalent inhibitors as future therapeutics.

Graphical abstract: Precipitation-free high-affinity multivalent binding by inline lectin ligands

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Supplementary files

Article information


Submitted
25 Mar 2020
Accepted
27 Apr 2020
First published
27 Apr 2020

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2020,11, 5227-5237
Article type
Edge Article

Precipitation-free high-affinity multivalent binding by inline lectin ligands

P. Rohse, S. Weickert, M. Drescher and V. Wittmann, Chem. Sci., 2020, 11, 5227
DOI: 10.1039/D0SC01744B

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