Search

Your search keyword '"Ernst, Beat"' showing total 532 results
Start Over Author "Ernst, Beat" Language english
532 results on '"Ernst, Beat"'

4. Strengthening an Intramolecular Non‐Classical Hydrogen Bond to Get in Shape for Binding.

Author

Varga, Norbert, Smieško, Martin, Jiang, Xiaohua, Jakob, Roman P., Wagner, Beatrice, Mühlethaler, Tobias, Dätwyler, Philipp, Zihlmann, Pascal, Rabbani, Said, Maier, Timm, Schwardt, Oliver, and Ernst, Beat

Subjects
ISOTHERMAL titration calorimetry, HYDROGEN bonding, PHARMACOKINETICS, ENTROPY, MOIETIES (Chemistry)
Abstract

In this research article, we report on the strengthening of a non‐classical hydrogen bond (C−H⋅⋅⋅O) by introducing electron withdrawing groups at the carbon atom. The approach is demonstrated on the example of derivatives of the physiological E‐selectin ligand sialyl Lewisx (1, sLex). Its affinity is mainly due to a beneficial entropy term, which is predominantly caused by the pre‐organization of sLex in its binding conformation. We have shown, that among the elements responsible for the pre‐organization, the stabilization by a non‐classical hydrogen bond between the H−C5 of l‐fucose and the ring oxygen O5 of the neighboring d‐galactose moiety is essential and yields 7.4 kJ mol−1. This effect could be further strengthened by replacing l‐fucose by 6,6,6‐trifluoro‐l‐fucose leading to an improved non‐classical H‐bond of 14.9 kJ mol−1, i.e. an improved pre‐organization in the bioactive conformation. For a series of glycomimetics of sLex (1), this outcome could be confirmed by high field NMR‐shifts of the H−C5Fuc, by X‐ray diffraction analysis of glycomimetics co‐crystallized with E‐selectin as well as by isothermal titration calorimetry. Furthermore, the electron‐withdrawing character of the CF3‐group beneficially influences the pharmacokinetic properties of sLex mimetics. Thus, acid‐stability, a prerequisite for gastrointestinal stability, could be substantially improved. [ABSTRACT FROM AUTHOR]

Published
2024
Full Text
View/download PDF

11. Tetra‐ and Hexavalent Siglec‐8 Ligands Modulate Immune Cell Activation.

Author

Conti, Gabriele, Bärenwaldt, Anne, Rabbani, Said, Mühlethaler, Tobias, Sarcevic, Mirza, Jiang, Xiaohua, Schwardt, Oliver, Ricklin, Daniel, Pieters, Roland J., Läubli, Heinz, and Ernst, Beat

Subjects
LIGAND binding (Biochemistry), LIGANDS (Chemistry), CARBOHYDRATE-binding proteins, BINDING sites, MAST cells, PROTEIN binding, LECTINS
Abstract

Carbohydrate‐binding proteins are generally characterized by poor affinities for their natural glycan ligands, predominantly due to the shallow and solvent‐exposed binding sites. To overcome this drawback, nature has exploited multivalency to strengthen the binding by establishing multiple interactions simultaneously. The development of oligovalent structures frequently proved to be successful, not only for proteins with multiple binding sites, but also for proteins that possess a single recognition domain. Herein we present the syntheses of a number of oligovalent ligands for Siglec‐8, a monomeric I‐type lectin found on eosinophils and mast cells, alongside the thermodynamic characterization of their binding. While the enthalpic contribution of each binding epitope was within a narrow range to that of the monomeric ligand, the entropy penalty increased steadily with growing valency. Additionally, we observed a successful agonistic binding of the tetra‐ and hexavalent and, to an even larger extent, multivalent ligands to Siglec‐8 on immune cells and modulation of immune cell activation. Thus, triggering a biological effect is not restricted to multivalent ligands but could be induced by low oligovalent ligands as well, whereas a monovalent ligand, despite binding with similar affinity, showed an antagonistic effect. [ABSTRACT FROM AUTHOR]

Published
2023
Full Text
View/download PDF

14. Prodruggability of carbohydrates--oral FimH antagonists

Author

Schonemann, Wojciech, Kleeb, Simon, Datwyler, Philipp, Schwardt, Oliver, and Ernst, Beat

Subjects
Urinary tract infections -- Care and treatment, Antagonists (Biochemistry) -- Health aspects, Bioavailability -- Observations, Chemistry
Abstract

Abstract: The bacterial lectin FimH is a promising therapeutic target for the nonantibiotic prevention and treatment of urinary tract infections. In this communication, an ester prodrug approach is described to [...]

Published
2016
Full Text
View/download PDF

17. A Structural-Reporter Group to Determine the Core Conformation of Sialyl Lewis x Mimetics.

Author

Wagner, Beatrice, Binder, Florian P. C., Jiang, Xiaohua, Mühlethaler, Tobias, Preston, Roland C., Rabbani, Said, Smieško, Martin, Schwardt, Oliver, and Ernst, Beat

Subjects
SPATIAL orientation, FUCOSE, MOIETIES (Chemistry), GALACTOSE
Abstract

The d-GlcNAc moiety in sialyl Lewisx (sLex, 1) acts predominantly as a linker to position the d-Gal and the l-Fuc moieties in the bioactive spatial orientation. The hypothesis has been made that the NHAc group of GlcNAc pushes the fucose underneath the galactose and, thus, contributes to the stabilization of the bioactive conformation of the core of sLex (1). To test this hypothesis, GlcNAc mimetics consisting of (R,R)-1,2-cyclohexanediols substituted with alkyl and aryl substituents adjacent to the linking position of the fucose moiety were synthesized. To explore a broad range of extended and spatially demanding R-groups, an enzymatic approach for the synthesis of 3-alkyl/aryl-1,2-cyclohexanediols (3b-n) was applied. These cyclohexanediol derivatives were incorporated into the sLex mimetics 2b-n. For analyzing the relationship of affinity and core conformation, a 1H NMR structural-reporter-group concept was applied. Thus, the chemical shift of H-C5Fuc proved to be a sensitive indicator for the degree of pre-organization of the core of this class of sLex mimetics and therefore could be used to quantify the contribution of the R-groups. [ABSTRACT FROM AUTHOR]

Published
2023
Full Text
View/download PDF

33. Sialic Acid Derivatives Inhibit SiaT Transporters and Delay Bacterial Growth.

Author

Bozzola, Tiago, Scalise, Mariafrancesca, Larsson, Christer U., Newton-Vesty, Michael C., Rovegno, Caterina, Mitra, Ankita, Cramer, Jonathan, Wahlgren, Weixiao Yuan, Radhakrishnan Santhakumari, Partha, Johnsson, Richard E., Schwardt, Oliver, Ernst, Beat, Friemann, Rosmarie, Dobson, Renwick C. J., Indiveri, Cesare, Schelin, Jenny, Nilsson, Ulf J., and Ellervik, Ulf

Published
2022
Full Text
View/download PDF

37. The price of flexibility – a case study on septanoses as pyranose mimetics† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c7sc04289b

Author

Sager, Christoph P., Fiege, Brigitte, Zihlmann, Pascal, Vannam, Raghu, Rabbani, Said, Jakob, Roman P., Preston, Roland C., Zalewski, Adam, Maier, Timm, Peczuh, Mark W., and Ernst, Beat

Subjects
Chemistry, fungi, food and beverages, health care economics and organizations
Abstract

Interacting with lectins, mannose can be mimicked with seven-membered ring analogues but at the price of a substantial entropy penalty., Seven-membered ring mimetics of mannose were studied as ligands for the mannose-specific bacterial lectin FimH, which plays an essential role in the first step of urinary tract infections (UTI). A competitive binding assay and isothermal titration calorimetry (ITC) experiments indicated an approximately ten-fold lower affinity for the seven-membered ring mannose mimetic 2-O-n-heptyl-1,6-anhydro-d-glycero-d-galactitol (7) compared to n-heptyl α-d-mannopyranoside (2), resulting exclusively from a loss of conformational entropy. Investigations by solution NMR, X-ray crystallography, and molecular modeling revealed that 7 establishes a superimposable H-bond network compared to mannoside 2, but at the price of a high entropic penalty due to the loss of its pronounced conformational flexibility. These results underscore the importance of having access to the complete thermodynamic profile of a molecular interaction to “rescue” ligands from entropic penalties with an otherwise perfect fit to the protein binding site.

Published
2017

41. EUROCarbDB: An open-access platform for glycoinformatics

Author

von der Lieth, Claus-Wilhelm, Freire, Ana Ardá, Blank, Dennis, Campbell, Matthew P, Ceroni, Alessio, Damerell, David R, Dell, Anne, Dwek, Raymond A, Ernst, Beat, Fogh, Rasmus, Frank, Martin, Geyer, Hildegard, Geyer, Rudolf, Harrison, Mathew J, Henrick, Kim, Herget, Stefan, Hull, William E, Ionides, John, Joshi, Hiren J, Kamerling, Johannis P, Leeflang, Bas R, Lütteke, Thomas, Lundborg, Magnus, Maass, Kai, Merry, Anthony, Ranzinger, René, Rosen, Jimmy, Royle, Louise, Rudd, Pauline M, Schloissnig, Siegfried, Stenutz, Roland, Vranken, Wim F, Widmalm, Göran, and Haslam, Stuart M

Published
2011
Full Text
View/download PDF

42. Substrate specificity of fucosyl transferase III: an efficient synthesis of sialyl [Lewis.sup.x]-, sialyl [Lewis.sup.a]- derivatives and mimetics thereof

Author

Ernst, Beat, Wagner, Bea, Baisch, Gabi, Katopodis, Andreas, Winkler, Tammo, and Ohrlein, Reinhold

Subjects
Butane, Glycols, Catalysts -- Composition, Carbohydrates, Chemical research -- Analysis
Abstract

Fucosyl transferase III (FucT III) has previously been characterized as the most general enzyme of the FucT family, as judged from its ability to catalyze the transfer of fucose to both Gal[beta](1-3)GlcNAc and Gal[beta](1-4)GlcNAc, In order to explore the synthetic potential of FucT III for the enzymatic synthesis of sialyl [Lewis.sup.x] and sialyl [Lewis.sup.a] derivatives, its substrate specificity has been probed using a number of natural substrate mimetics. A remarkable range of acceptor substrates was found when N-acetyl glucosamine was replaced by D-glucal, (R,R)-1,2-cyclohexanediol and (R,R)-butan-2,3-diol. Although the reaction rates were low compared to the reaction with the natural substrates, they proved to be sufficient for the synthesis of preparative amounts. Key words: fucosyl transferase III, sialyl [Lewis.sup.a], sialyl [Lewis.sup.x], carbohydrate mimetics.

Published
2000

45. A Remote Secondary Binding Pocket Promotes Heteromultivalent Targeting of DC-SIGN.

Author

Wawrzinek, Robert, Eike-Christian Wamhoff, Lefebre, Jonathan, Rentzsch, Mareike, Bachem, Gunnar, Domeniconi, Gary, Schulze, Jessica, Fuchsberger, Felix F., Hengxi Zhang, Modenutti, Carlos, Schnirch, Lennart, Marti, Marcelo A., Schwardt, Oliver, Bräutigam, Maria, Guberman, Mónica, Hauck, Dirk, Seeberger, Peter H., Seitz, Oliver, Titz, Alexander, and Ernst, Beat

Published
2021
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results