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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
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6. 158 Structure-guided design of derivatives of the complement inhibitor compstatin with improved species specificity profiles

Author

Anita Vogt, Stephanie, primary, Aschwanden, Roman, additional, Lamers, Christina, additional, John Lander, Alexander, additional, Schwardt, Oliver, additional, Geisbrecht, Brian, additional, Meyer zu Schwabedissen, Henriette, additional, Lill, Markus, additional, Lambris, John D., additional, Smiesko, Martin, additional, and Ricklin, Daniel, additional

Published
2023
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8. SIGLEC-4 (MAG) Antagonists: From the Natural Carbohydrate Epitope to Glycomimetics

Author

Schwardt, Oliver, Kelm, Soerge, Ernst, Beat, Bayley, Hagan, Series editor, Houk, Kendall N., Series editor, Hughes, Greg, Series editor, Hunter, Christopher A., Series editor, Ishihara, Kazuaki, Series editor, Krische, Michael J, Series editor, Lehn, J.-M., Series editor, Luque, Rafael, Series editor, Olivucci, Massimo, Series editor, Siegel, Jay S., Series editor, Thiem, Joachim, Series editor, Venturi, Margherita, Series editor, Wong, Chi-Huey, Series editor, Wong, Henry N.C., Series editor, You, Shu-Li, Series editor, Wing-Wah Yam, Vivian, Series editor, Gerardy-Schahn, Rita, editor, Delannoy, Philippe, editor, and von Itzstein, Mark, editor

Published
2015
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10. Tetra- and Hexavalent Siglec-8 Ligands Modulate Immune Cell Activation

Author

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

Published
2023

11. Impact of OATP2B1 on Pharmacokinetics of Atorvastatin Investigated in rSlco2b1-Knockout and SLCO2B1-Knockin Rats

Author

Kinzi, Jonny, Hussner, Janine, Seibert, Isabell, Vythilingam, Mirubagini, Vonwyl, Celina, Gherardi, Clarisse, Detampel, Pascal, Schwardt, Oliver, Ricklin, Daniel, and Meyer zu Schwabedissen, Henriette E.

Abstract

The organic anion transporting polypeptide (OATP) 2B1 is considered an emerging drug transporter that is found expressed in pharmacokinetically relevant organs such as the liver, small intestine, and kidney. Despite its interaction with various substrate drugs, the understanding of its in vivo relevance is still limited. In this study, we first validated the interaction of atorvastatin with rat OATP2B1 using transiently transfected HeLa cells. Moreover, we characterized our rSlco2b1-knockout and SLCO2B1-knockin rats for mRNA, protein expression, and localization of OATP2B1 in the liver, small intestine, and kidney. The transporter showed the highest expression in the liver followed by the small intestine. In humanized rats, human OATP2B1 is localized on the sinusoidal membrane of hepatocytes. In enterocytes of wild-type and humanized rats, the transporter was detected in the luminal membrane with the vast majority being localized subapical. Subsequently, we assessed atorvastatin pharmacokinetics in male wild-type, rSlco2b1-knockout, and SLCO2B1-knockin rats after a single-dose administration (orally and intravenously). Investigating the contribution of rat OATP2B1 or human OATP2B1 to oral atorvastatin pharmacokinetics revealed no differences in concentration-time profiles or pharmacokinetic parameters. However, when comparing the pharmacokinetics of atorvastatin after intravenous administration in SLCO2B1-humanized rats and knockout animals, notable differences were observed. In particular, the systemic exposure (area under the curve) decreased by approximately 40% in humanized animals, whereas the clearance was 57% higher in animals expressing human OATP2B1. These findings indicate that human OATP2B1 influences pharmacokinetics of atorvastatin after intravenous administration, most likely by contributing to the hepatic uptake.SIGNIFICANCE STATEMENTWild-type, rSlco2b1-knockout, and SLCO2B1-humanized Wistar rats were characterized for the expression of rat and human SLCO2B1/OATP2B1. Pharmacokinetic studies of atorvastatin over 24 hours were conducted in male wild-type, rSlco2b1-knockout, and SLCO2B1-humanized rats. After a single-dose intravenous administration, a lower systemic exposure and an increase in clearance were observed in SLCO2B1-humanized rats compared with knockout animals indicating a contribution of OATP2B1 to the hepatic clearance.

Published
2024
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12. 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
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13. Sialic Acid Derivatives Inhibit SiaT Transporters and Delay Bacterial Growth

Author

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

Published
2022
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14. 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
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18. A Remote Secondary Binding Pocket Promotes Heteromultivalent Targeting of DC-SIGN

Author

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

Published
2021
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22. Sweet Drugs for Bad Bugs: A Glycomimetic Strategy against the DC-SIGN-Mediated Dissemination of SARS-CoV-2

Author

Cramer, Jonathan, primary, Lakkaichi, Adem, additional, Aliu, Butrint, additional, Jakob, Roman P., additional, Klein, Sebastian, additional, Cattaneo, Ivan, additional, Jiang, Xiaohua, additional, Rabbani, Said, additional, Schwardt, Oliver, additional, Zimmer, Gert, additional, Ciancaglini, Matias, additional, Abreu Mota, Tiago, additional, Maier, Timm, additional, and Ernst, Beat, additional

Published
2021
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23. Selective Monovalent Galectin‐8 Ligands Based on 3‐Lactoylgalactoside

Author

Girardi, Benedetta, primary, Manna, Martina, additional, Van Klaveren, Sjors, additional, Tomašič, Tihomir, additional, Jakopin, Žiga, additional, Leffler, Hakon, additional, Nilsson, Ulf J., additional, Ricklin, Daniel, additional, Mravljak, Janez, additional, Schwardt, Oliver, additional, and Anderluh, Marko, additional

Published
2021
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26. Sweet Drugs for Bad Bugs: A Glycomimetic Strategy against the DC-SIGN-Mediated Dissemination of SARS-CoV-2

Author

Cramer, Jonathan, Lakkaichi, Adem, Aliu, Butrint, Jakob, Roman P, Klein, Sebastian, Cattaneo, Ivan, Jiang, Xiaohua, Rabbani, Said, Schwardt, Oliver, Zimmer, Gert, Ciancaglini, Matias, Abreu Mota, Tiago, Maier, Timm, and Ernst, Beat

Subjects
630 Agriculture, 570 Life sciences, biology, 590 Animals (Zoology), 500 Science, 610 Medicine & health
Abstract

The C-type lectin receptor DC-SIGN is a pattern recognition receptor expressed on macrophages and dendritic cells. It has been identified as a promiscuous entry receptor for many pathogens, including epidemic and pandemic viruses such as SARS-CoV-2, Ebola virus, and HIV-1. In the context of the recent SARS-CoV-2 pandemic, DC-SIGN-mediated virus dissemination and stimulation of innate immune responses has been implicated as a potential factor in the development of severe COVID-19. Inhibition of virus binding to DC-SIGN, thus, represents an attractive host-directed strategy to attenuate overshooting innate immune responses and prevent the progression of the disease. In this study, we report on the discovery of a new class of potent glycomimetic DC-SIGN antagonists from a focused library of triazole-based mannose analogues. Structure-based optimization of an initial screening hit yielded a glycomimetic ligand with a more than 100-fold improved binding affinity compared to methyl ��-d-mannopyranoside. Analysis of binding thermodynamics revealed an enthalpy-driven improvement of binding affinity that was enabled by hydrophobic interactions with a loop region adjacent to the binding site and displacement of a conserved water molecule. The identified ligand was employed for the synthesis of multivalent glycopolymers that were able to inhibit SARS-CoV-2 spike glycoprotein binding to DC-SIGN-expressing cells, as well as DC-SIGN-mediated trans-infection of ACE2+ cells by SARS-CoV-2 spike protein-expressing viruses, in nanomolar concentrations. The identified glycomimetic ligands reported here open promising perspectives for the development of highly potent and fully selective DC-SIGN-targeted therapeutics for a broad spectrum of viral infections.

Published
2021
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29. A Potent Mimetic of the Siglec-8 Ligand 6'-Sulfo-Sialyl Lewisx

Author

Kroezen, Blijke S., Conti, Gabriele, Girardi, Benedetta, Cramer, Jonathan, Jiang, Xiaohua, Rabbani, Said, Müller, Jennifer, Kokot, Maja, Luisoni, Enrico, Ricklin, Daniel, Schwardt, Oliver, and Ernst, Beat

Subjects
respiratory system
Abstract

Siglec-8 is a promising target for the treatment of eosinophil- and mast cell-associated diseases such as asthma. Based on pharmacophore analysis of 6’-sulfo-sialyl Lewisx, a specific Siglec-8 ligand identified in glycan array screening, potent glycomimetics were developed. While maintaining the neuraminic acid core, a carbocyclic replacement of the Gal moiety and the introduction of a sulfonamide led to a 20-fold improvement of affinity.

Published
2020

33. Drug Discovery Today

Author

Schwardt, Oliver, primary, Cutting, Brian, additional, Kolb, Hartmuth, additional, and Ernst, Beat, additional

Published
2012
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36. A Potent Mimetic of the Siglec‐8 Ligand 6’‐Sulfo‐Sialyl Lewisx

Author

Kroezen, Blijke S., primary, Conti, Gabriele, additional, Girardi, Benedetta, additional, Cramer, Jonathan, additional, Jiang, Xiaohua, additional, Rabbani, Said, additional, Müller, Jennifer, additional, Kokot, Maja, additional, Luisoni, Enrico, additional, Ricklin, Daniel, additional, Schwardt, Oliver, additional, and Ernst, Beat, additional

Published
2020
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41. Front Cover: Improvement of Aglycone π‐Stacking Yields Nanomolar to Sub‐nanomolar FimH Antagonists (ChemMedChem 7/2019)

Author

Schönemann, Wojciech, primary, Cramer, Jonathan, additional, Mühlethaler, Tobias, additional, Fiege, Brigitte, additional, Silbermann, Marleen, additional, Rabbani, Said, additional, Dätwyler, Philipp, additional, Zihlmann, Pascal, additional, Jakob, Roman P., additional, Sager, Christoph P., additional, Smieško, Martin, additional, Schwardt, Oliver, additional, Maier, Timm, additional, and Ernst, Beat, additional

Published
2019
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42. Improvement of Aglycone π‐Stacking Yields Nanomolar to Sub‐nanomolar FimH Antagonists

Author

Schönemann, Wojciech, primary, Cramer, Jonathan, additional, Mühlethaler, Tobias, additional, Fiege, Brigitte, additional, Silbermann, Marleen, additional, Rabbani, Said, additional, Dätwyler, Philipp, additional, Zihlmann, Pascal, additional, Jakob, Roman P., additional, Sager, Christoph P., additional, Smieško, Martin, additional, Schwardt, Oliver, additional, Maier, Timm, additional, and Ernst, Beat, additional

Published
2019
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50. FimH Antagonists: Bioisosteres To Improve the in Vitro and in Vivo PK/PD Profile

Author

Kleeb, Simon, primary, Pang, Lijuan, additional, Mayer, Katharina, additional, Eris, Deniz, additional, Sigl, Anja, additional, Preston, Roland C., additional, Zihlmann, Pascal, additional, Sharpe, Timothy, additional, Jakob, Roman P., additional, Abgottspon, Daniela, additional, Hutter, Aline S., additional, Scharenberg, Meike, additional, Jiang, Xiaohua, additional, Navarra, Giulio, additional, Rabbani, Said, additional, Smiesko, Martin, additional, Lüdin, Nathalie, additional, Bezençon, Jacqueline, additional, Schwardt, Oliver, additional, Maier, Timm, additional, and Ernst, Beat, additional

Published
2015
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