Thermodynamics-Guided Design Reveals a Cooperative Hydrogen Bond in DC-SIGN-targeted Glycomimetics.

Autor:	Nemli DD; Institute for Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University Düsseldorf, Universitätsstraße 1, Düsseldorf 40225, Germany., Jiang X; Department of Pharmaceutical Sciences, Group Molecular Pharmacy, Pharmazentrum, University of Basel, Klingelbergstrasse 50, Basel CH-4056, Switzerland., Jakob RP; Department Biozentrum, Structural Area Focal Biology, University of Basel, Spitalstrasse 41, Basel 4056, Switzerland., Gloder LM; Institute for Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University Düsseldorf, Universitätsstraße 1, Düsseldorf 40225, Germany., Schwardt O; Department of Pharmaceutical Sciences, Group Molecular Pharmacy, Pharmazentrum, University of Basel, Klingelbergstrasse 50, Basel CH-4056, Switzerland., Rabbani S; Department of Pharmaceutical Sciences, Group Molecular Pharmacy, Pharmazentrum, University of Basel, Klingelbergstrasse 50, Basel CH-4056, Switzerland., Maier T; Department Biozentrum, Structural Area Focal Biology, University of Basel, Spitalstrasse 41, Basel 4056, Switzerland., Ernst B; Department of Pharmaceutical Sciences, Group Molecular Pharmacy, Pharmazentrum, University of Basel, Klingelbergstrasse 50, Basel CH-4056, Switzerland., Cramer J; Institute for Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University Düsseldorf, Universitätsstraße 1, Düsseldorf 40225, Germany.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 Aug 22; Vol. 67 (16), pp. 13813-13828. Date of Electronic Publication: 2024 May 21.
DOI:	10.1021/acs.jmedchem.4c00623
Abstrakt:	Due to the shallow and hydrophilic binding sites of carbohydrate-binding proteins, the design of glycomimetics is often complicated by high desolvation costs as well as competition with solvent. Therefore, a careful optimization of interaction vectors and ligand properties is required in the design and optimization of glycomimetics. Here, we employ thermodynamics-guided design to optimize mannose-based glycomimetics targeting the human C-type lectin receptor dendritic cell-specific intercellular adhesion molecule 3 grabbing nonintegrin (DC-SIGN), a pathogenic host factor in viral infections. By exploring ligand rigidification and hydrogen bond engineering, a monovalent glycomimetic with an unprecedented affinity for DC-SIGN in the low μM range was discovered. A matched molecular pair analysis based on microcalorimetric data revealed a stereospecific hydrogen bond interaction with Glu358/Ser360 as the origin of this cooperative and enthalpically dominated interaction. This detailed insight into the binding mechanism paves the way for an improvement of monovalent glycomimetics targeting DC-SIGN.
Databáze:	MEDLINE
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