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Dynamic Covalent Identification of an Efficient Heparin Ligand
Author(s) -
Corredor Miriam,
Carbajo Daniel,
Domingo Cecilia,
Pérez Yolanda,
Bujons Jordi,
Messeguer Angel,
Alfonso Ignacio
Publication year - 2018
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201806770
Subject(s) - chemistry , dynamic covalent chemistry , ligand (biochemistry) , covalent bond , heparin , macromolecule , combinatorial chemistry , small molecule , molecule , hydrogen bond , stereochemistry , supramolecular chemistry , biochemistry , organic chemistry , receptor
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 ( K D in the low μ m 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.