Dynamic Covalent Identification of an Efficient Heparin Ligand

Angewandte Chemie
Miriam CorredorIgnacio Alfonso

Abstract

Despite heparin being the most widely used macromolecular drug, the design of small-molecule ligands to modulate its effects has been hampered by the structural properties of this polyanionic polysaccharide. Now a dynamic covalent selection approach is used to identify a new ligand for heparin, assembled from extremely simple building blocks. The amplified molecule strongly binds to heparin (KD in the low μm range, ITC) by a combination of electrostatic, hydrogen bonding, and CH-π interactions as shown by NMR and molecular modeling. Moreover, this ligand reverts the inhibitory effect of heparin within an enzymatic cascade reaction related to blood coagulation. This study demonstrates the power of dynamic covalent chemistry for the discovery of new modulators of biologically relevant glycosaminoglycans.

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Citations

Jan 16, 2019·Chembiochem : a European Journal of Chemical Biology·Oscar Francesconi, Stefano Roelens
Jun 21, 2019·Chemical Communications : Chem Comm·Anna Serra-PontCiril Jimeno
Apr 30, 2020·Angewandte Chemie·Daniel CarbajoIgnacio Alfonso
Jun 27, 2020·Angewandte Chemie·Katharina AchaziGerd Multhaup
Sep 26, 2020·Chemical Communications : Chem Comm·Jordi SolàIgnacio Alfonso
Jul 15, 2020·Biomacromolecules·Jacek Janusz WalkowiakCarsten Werner
Jun 8, 2021·Chemical Science·Qiaoxian HuangRuibing Wang

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