Cargando…
Precipitation-free high-affinity multivalent binding by inline lectin ligands
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...
Autores principales: | , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Royal Society of Chemistry
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159369/ https://www.ncbi.nlm.nih.gov/pubmed/34122979 http://dx.doi.org/10.1039/d0sc01744b |
_version_ | 1783700070433030144 |
---|---|
author | Rohse, Philipp Weickert, Sabrina Drescher, Malte Wittmann, Valentin |
author_facet | Rohse, Philipp Weickert, Sabrina Drescher, Malte Wittmann, Valentin |
author_sort | Rohse, Philipp |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8159369 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | The Royal Society of Chemistry |
record_format | MEDLINE/PubMed |
spelling | pubmed-81593692021-06-11 Precipitation-free high-affinity multivalent binding by inline lectin ligands Rohse, Philipp Weickert, Sabrina Drescher, Malte Wittmann, Valentin Chem Sci Chemistry 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. The Royal Society of Chemistry 2020-04-27 /pmc/articles/PMC8159369/ /pubmed/34122979 http://dx.doi.org/10.1039/d0sc01744b Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by-nc/3.0/ |
spellingShingle | Chemistry Rohse, Philipp Weickert, Sabrina Drescher, Malte Wittmann, Valentin Precipitation-free high-affinity multivalent binding by inline lectin ligands |
title | Precipitation-free high-affinity multivalent binding by inline lectin ligands |
title_full | Precipitation-free high-affinity multivalent binding by inline lectin ligands |
title_fullStr | Precipitation-free high-affinity multivalent binding by inline lectin ligands |
title_full_unstemmed | Precipitation-free high-affinity multivalent binding by inline lectin ligands |
title_short | Precipitation-free high-affinity multivalent binding by inline lectin ligands |
title_sort | precipitation-free high-affinity multivalent binding by inline lectin ligands |
topic | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159369/ https://www.ncbi.nlm.nih.gov/pubmed/34122979 http://dx.doi.org/10.1039/d0sc01744b |
work_keys_str_mv | AT rohsephilipp precipitationfreehighaffinitymultivalentbindingbyinlinelectinligands AT weickertsabrina precipitationfreehighaffinitymultivalentbindingbyinlinelectinligands AT dreschermalte precipitationfreehighaffinitymultivalentbindingbyinlinelectinligands AT wittmannvalentin precipitationfreehighaffinitymultivalentbindingbyinlinelectinligands |