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Enhancing Potency and Selectivity of a DC‐SIGN Glycomimetic Ligand by Fragment‐Based Design: Structural Basis
Author(s) -
Medve Laura,
Achilli Silvia,
GuzmanCaldentey Joan,
Thépaut Michel,
Senaldi Luca,
Le Roy Aline,
Sattin Sara,
Ebel Christine,
Vivès Corinne,
MartinSantamaria Sonsoles,
Bernardi Anna,
Fieschi Franck
Publication year - 2019
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201903391
Subject(s) - dc sign , chemistry , ligand (biochemistry) , selectivity , sign (mathematics) , lectin , stereochemistry , biophysics , combinatorial chemistry , biochemistry , biology , receptor , mathematics , mathematical analysis , genetics , antigen , dendritic cell , catalysis
Abstract Chemical modification of pseudo‐dimannoside ligands guided by fragment‐based design allowed for the exploitation of an ammonium‐binding region in the vicinity of the mannose‐binding site of DC‐SIGN, leading to the synthesis of a glycomimetic antagonist (compound 16 ) of unprecedented affinity and selectivity against the related lectin langerin. Here, the computational design of pseudo‐dimannoside derivatives as DC‐SIGN ligands, their synthesis, their evaluation as DC‐SIGN selective antagonists, the biophysical characterization of the DC‐SIGN/ 16 complex, and the structural basis for the ligand activity are presented. On the way to the characterization of this ligand, an unusual bridging interaction within the crystals shed light on the plasticity and potential secondary binding sites within the DC‐SIGN carbohydrate recognition domain.