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From Oligosaccharides to Glycomimetics to Glycodrugs

English title From Oligosaccharides to Glycomimetics to Glycodrugs
Applicant Ernst Beat
Number 129935
Funding scheme Project funding (Div. I-III)
Research institution Institut für Molekulare Pharmazie Pharmazentrum Universität Basel
Institution of higher education University of Basel - BS
Main discipline Organic Chemistry
Start/End 01.04.2010 - 31.03.2013
Approved amount 578'596.00
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Keywords (16)

E-selectin; sialyl LewisX; selectin antagonists; bioactive conformation; fragment-based in situ combinatorial approach; myelin-associated glycoprotein (MAG); MAG antagonists; asialoglycoprotin receptor (ASGP-R); DC-SIGN; STD NMR; isothermal titration calorimetry (ITC); surface plasmon resonance (SPR); pharmacokinetics; pharmacodynamics; asialoglycoprotein receptor (ASGP-R);

Lay Summary (English)

Lead
Lay summary
Carbohydrates serve as versatile ligands in numerous biological processes. Many of them are of great pharmaceutical interest. However, this potential has not been fully exploited to date, because carbohydrates exhibit two inherent drawbacks. They generally show only modest pharmacodynamic (PD) properties, i.e. low affinities to their targets. In addition, their pharmacokinetic (PK) properties, such as bioavailability or plasma half-life, are typically unsatisfactory for therapeutic applications. With our research, we plan to contribute to the basics of carbohydrate-lectin interactions and thereby stimulate new pharmaceutical applications.We are focusing on four pharmaceutically important classes of carbohydrate receptors: Selectins (E- and P-selectin), siglecs (sialoadhesin, CD22, MAG), the asialoglycoprotein receptor (ASGP-R) and dendritic cell-specific ICAM-3 grabbing non-integrin (DC-SIGN). Although all four areas were intensively investigated in recent years, only isolated examples of high-affinity antagonists with drug-like properties have been reported so far.The improvement of the pharmacodynamic and pharmacokinetic properties will be addressed by (i) the identification of high-affinity antagonists by a novel fragment-based approach, (ii) the determination of kinetic and thermodynamic parameters of the glycomimetic/lectin interaction and (iii) the evaluation of the pharmacokinetic properties of new glycomimetics on our PADMET platform.The novel, fragment-based in situ combinatorial approach for the identification of high-affinity, low molecular weight antagonists was recently developed in our group. This new approach was successfully applied in our search of high-affinity E-selectin and MAG antagonists. It is planned to investigate its scope & limitation and to apply it to various other lectins, e.g. P-selectin, siglecs and DC-SIGN. Using NMR, Biacore and ITC, additional information of the ligand-receptor interaction will be acquired.To test the relevant PK properties of our high-affinity antagonists, a PADMET-platform (physicochemical properties, absorption, distribution, elimination, toxicity) was established and will be further extended. The panel of assays permits the PK characterization of newly synthesized antagonists and thus to consider PD and PK properties simultaneously.Our research will contribute to an extended understanding of the principles controlling carbohydrate-lectin interactions. In addition, the strategies developed for the design of glycomimetics with high-affinity and at the same time drug-like properties will contribute to the realization of the potential of this relatively untapped source of therapeutics.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Nanomolar E-Selectin Antagonists with Prolonged Half-Lives by a Fragment-Based Approach
Egger Jonas, Weckerle Celine, Cutting Brian, Schwardt Oliver, Rabbani Said, Lemme Katrin, Ernst Beat (2013), Nanomolar E-Selectin Antagonists with Prolonged Half-Lives by a Fragment-Based Approach, in JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 135(26), 9820-9828.
SIGLEC-4 (MAG) Antagonists: From the Natural Carbohydrate Epitope to Glycomimetics.
Schwardt Oliver, Kelm Soerge, Ernst Beat (2013), SIGLEC-4 (MAG) Antagonists: From the Natural Carbohydrate Epitope to Glycomimetics., Springer Verlag Online, Heidelberg.
Stabilization of branched oligosaccharides: Lewis(x) benefits from a nonconventional C-H···O hydrogen bond.
Zierke Mirko, Smieško Martin, Rabbani Said, Aeschbacher Thomas, Cutting Brian, Allain Frédéric H-T, Schubert Mario, Ernst Beat (2013), Stabilization of branched oligosaccharides: Lewis(x) benefits from a nonconventional C-H···O hydrogen bond., in Journal of the American Chemical Society, 135(36), 13464-72.
Anti-Adhesion Therapy for Urinary Tract Infections - A Balanced PK/PD-Profile Proved to be Key for Success
X. Jiang D. Abgottspon S. Kleeb S. Rabbani M. Scharenberg M. Wittwer M. Haug O. Schwardt B. (2012), Anti-Adhesion Therapy for Urinary Tract Infections - A Balanced PK/PD-Profile Proved to be Key for Success, in J. Med. Chem., 55(10), 4700-4713.
Conformational Constraints: Nature Does It Best with Sialyl Lewisx
Titz Alexander, Marra Alberto, Cutting Brian, Smiesko Martin, Papandreou George, Dondoni Alessandro, Ernst Beat (2012), Conformational Constraints: Nature Does It Best with Sialyl Lewisx, in EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, (28), 5534-5539.
Cutaneous iontophoretic delivery of CGP69669A, a silalyl Lewisx mimetic, in vitro
Taís Gratieri Beatrice Wagner Dhaval Kalaria Beat Ernst and Yogeshvar N. Kalia (2012), Cutaneous iontophoretic delivery of CGP69669A, a silalyl Lewisx mimetic, in vitro, in Experimental Dematology, 21, 226-228.
Development and validation of a HPAE-PAD method for the quantification of CGP69669A, a sialyl Lewisx mimetic, in skin permeation studies.
Taís Gratieri Beatrice Wagner Dhaval Kalaria Beat Ernst and Yogeshvar N. Kalia (2012), Development and validation of a HPAE-PAD method for the quantification of CGP69669A, a sialyl Lewisx mimetic, in skin permeation studies., in Biomed. Chromatogr., 26(4), 507-511.
FimH Antagonists: Structure-Activity and Structure-Property Relationships for Biphenyl α-D-Mannopyranosides
Lijuan Pang Simon Kleeb Katrin Lemme Said Rabbani Meike Scharenberg Adam Zalewski Florentina S (2012), FimH Antagonists: Structure-Activity and Structure-Property Relationships for Biphenyl α-D-Mannopyranosides, in ChemMedChem, 7(8), 1404-1422.
From a Library of MAG Antagonists to Nanomolar CD22 Ligands.
Stefanie Mesch Katrin Lemme Matthias Wittwer Hendrik Koliwer-Brandl Oliver Schwardt Sørge Kel (2012), From a Library of MAG Antagonists to Nanomolar CD22 Ligands., in ChemMedChem, 7, 134-143.
In vivo evaluation of FimH antagonists - a novel class of antimicrobials for the treatment of urinary tract infection.
Abgottspon Daniela, Ernst Beat (2012), In vivo evaluation of FimH antagonists - a novel class of antimicrobials for the treatment of urinary tract infection., in Chimia, 66(4), 166-9.
Pre-organization of the Core Structure of E-Selectin Antagonists
Daniel Schwizer John T. Patton Brian Cutting Martin Smieško Beatrice Wagner Ako Kato Céline (2012), Pre-organization of the Core Structure of E-Selectin Antagonists, in Chem. Eur. J., 18, 1342-1351.
Sialyl Lewis(x): a "pre-organized water oligomer"?
Binder Florian P C, Lemme Katrin, Preston Roland C, Ernst Beat (2012), Sialyl Lewis(x): a "pre-organized water oligomer"?, in Angewandte Chemie (International ed. in English), 51(29), 7327-31.
Design, synthesis and biological evaluation of mannosyl triazoles as FimH antagonists
O. Schwardt S. Rabbani M. Hartmann D. Abgottspon M. Wittwer S. Kleeb A. Zalewski et al. (2011), Design, synthesis and biological evaluation of mannosyl triazoles as FimH antagonists, in Bioorg. Med. Chem., 19, 6454-6473.
E- and P-Selectin: Differences, Similarities and Implications for the Design of P-Selectin Antagonists
Binder Florian P. C., Ernst Beat (2011), E- and P-Selectin: Differences, Similarities and Implications for the Design of P-Selectin Antagonists, in CHIMIA, 65(4), 210-213.
Epitope structure of the carbohydrate recognition domain of asialoglycoprotein receptor to a monoclonal antibody revealed by high resolution proteolytic excision mass spectrometry.
R. Stefanescu R. Born A. Moise B. Ernst M. Przybylski (2011), Epitope structure of the carbohydrate recognition domain of asialoglycoprotein receptor to a monoclonal antibody revealed by high resolution proteolytic excision mass spectrometry., in J. Am. Soc Mass Spectr., 22(1), 148-157.
High affinity sialoside ligands of myelin associated glycoprotein.
Y. Zeng C. Rademacher C.M. Nycholat S. Futakawa K. Lemme B. Ernst J.C. Paulson (2011), High affinity sialoside ligands of myelin associated glycoprotein., in Bioorg. Med. Chem. Lett., 21(17), 5045-5049.

Collaboration

Group / person Country
Types of collaboration
Scripps Research Institute United States of America (North America)
- Publication
University of Konstanz Germany (Europe)
- Publication
University of Geneva Switzerland (Europe)
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Annual Research Meeting Poster Structural Evidence for an Induced Fit of E-selectin upon Small Molecule Ligand Binding 23.01.2013 Universität Basel, Switzerland Preston Roland; Ernst Beat;
ISMC 2012 Poster Development of Orally Available FimH Antagonists for the Treatment of Urinary Tract Infections 02.09.2012 Berlin, Germany Ernst Beat; Kleeb Simon;
26th International Carbohydrate Symposium Talk given at a conference Anti-Adhesion Therapy - A Balanced SAR Proved to be Key for Success 22.07.2012 Madrid, Spain Ernst Beat;
26th International Carbohydrate Symposium Poster Insights into the GlycoCode - Structural Analysis of Carbohydrates in Solution 22.07.2012 Madrid, Spain Ernst Beat;
Annual Research Meeting Poster The Role of Galactose in Lex-type Ligands Binding to DC-SIGN 14.02.2012 Universität Basel, Switzerland Ernst Beat; Mayer Katharina;
Annual Research Meeting Poster X-Ray Crystallography of E-selectin-Antagonist Complexes 14.02.2012 Universität Basel, Switzerland Preston Roland; Ernst Beat;
Annual Research Meeting Poster Development of Orally Available FimH Antagonists for the Treatment of Urinary Tract Infections 14.02.2012 Universität Basel, Switzerland Ernst Beat; Kleeb Simon;
Scripps, La Jolla Talk given at a conference Discovery of Antagonists for Lectin Targets by a Fragment-based Approach 23.09.2011 La Jolla, CA, USA, United States of America Ernst Beat;
Siemens Molecular Imaging Talk given at a conference Discovery of Antagonists for Lectin Targets by a Fragment-based Approach 21.09.2011 Los Angeles, United States of America Ernst Beat;
Swiss Pharma Science Day Poster Development of Orally Available FimH Antagonists for the Treatment of Urinary Tract Infections 31.08.2011 Bern, Switzerland Ernst Beat; Kleeb Simon;
Swiss Pharma Science Day Poster Binding Characterization of the S128R E-Selectin Mutant 31.08.2011 Bern, Switzerland Ernst Beat; Preston Roland;
CSIC Madrid Talk given at a conference Discovery of Antagonists for Lectin Targbets by a Fragment-based Approach 28.04.2011 Madrid, Spain Ernst Beat;
MedChem Europe Munich Talk given at a conference Fragment-based Lead Discovery for Lectin Targets 28.03.2011 München, Germany Ernst Beat;
Annual Research Meeting Poster STD-NMR reveals distinct binding-modes for substituted Lewis structures to DC-SIGN 02.02.2011 Universität Basel, Switzerland Mayer Katharina; Ernst Beat;
Annual Research Meeting Poster Ester Prodrugs: How the Chemical Structure Influences the Hydrolysis Rate 02.02.2011 Universität Basel, Switzerland Ernst Beat; Kleeb Simon;
Annual Research Meeting Poster Binding Characterization of the S128R E-selectin Mutant 02.02.2011 Universität Basel, Switzerland Preston Roland; Ernst Beat;
Annual Meeting Society of Glycobiology Poster Binding Characterization of the S128R Mutant E-selectin 07.11.2010 Tampa, United States of America Preston Roland; Ernst Beat;


Awards

Title Year
Runner-up Metrohm Prize for Oral Presentations EPFL in Lausanne im Rahmen des Fall Meetings der Schweizerischen Chemischen Gesellschaft Session of Medicinal Chemistry & Chemical Biology 2013

Associated projects

Number Title Start Funding scheme
144183 The Bacterial Lectin FimH - High and Low Affinity States 01.10.2012 Project funding (Div. I-III)
120628 Carbohydrate-Lectin Interactions: Pharmacodynamic/Pharmacokinetic Aspects 01.04.2008 Project funding (Div. I-III)
133859 Purchase of a laser scanning microscope / LSM710 Carl Zeiss 01.12.2010 R'EQUIP
120628 Carbohydrate-Lectin Interactions: Pharmacodynamic/Pharmacokinetic Aspects 01.04.2008 Project funding (Div. I-III)
146202 From Oligosaccharides to Glycomimetics to Glycodrugs 01.04.2013 Project funding (Div. I-III)

Abstract

Carbohydrates serve as versatile ligands in numerous biological processes. Many of them are of great pharmaceutical interest, e.g. in the treatment of viral, parasitic, mycotic and bacterial infections, inflammatory diseases, as well as a broad range of human cancers. However, this potential has not been fully exploited to date, because carbohydrates exhibit two inherent drawbacks in respect to their therapeutic potential. They generally show only modest pharmacodynamic (PD) properties, i.e. low affinities to their targets. In addition, their pharmacokinetic (PK) properties, such as bioavailability or plasma half-life, are typically unsatisfactory for therapeutic applications. Finally, although tremendously improved novel glycosylation protocols and solid phase approaches have become available, oligosaccharides are still manufactured only by cumbersome multistep syntheses. With our research, we plan to contribute to the basics of carbohydrate-lectin interactions and thereby stimulate new pharmaceutical applications.We are focusing on four pharmaceutically important classes of carbohydrate receptors: Selectins (E- and P-selectin), siglecs (sialoadhesin, CD22, MAG), the asialoglycoprotein receptor (ASGP-R) and dendritic cell-specific ICAM-3 grabbing non-integrin (DC-SIGN). Although all four areas were intensively investigated in recent years, only isolated examples of high-affinity antagonists with drug-like properties have been reported so far.The improvement of the PD and PK properties will be addressed by (i) the identification of high-affinity antagonists by a novel fragment-based approach, (ii) the determination of kinetic and thermodynamic parameters of the glycomimetic/lectin interaction and (iii) the evaluation of the pharmacokinetic properties of new glycomimetics in the PADMET platform.The novel, fragment-based in situ combinatorial approach for the identification of high-affinity, low molecular weight antagonists was recently developed in our group. It is especially suited in cases where there is little or no structural information on the binding sites. This new approach was successfully applied in our search of high-affinity E-selectin and MAG antagonists. It is planned to investigate its scope & limitation and to apply it to various other lectins, e.g. P-selectin, siglecs and DC-SIGN. Using NMR, surface plasmon resonance and isothermal titration calorimetry (ITC), additional information of the ligand-receptor interaction will be acquired.To test the relevant pharmacokinetic properties of our high-affinity antagonists, a PADMET-platform (physicochemical properties, absorption, distribution, elimination, toxicity) was established and will be further extended. The panel of assays permits the pharmacokinetic characterization of newly synthesized antagonists and thus to consider PD and PK properties simultaneously.Our research will contribute to an extended understanding of the principles controlling carbohydrate-lectin interactions. In addition, the strategies developed for the design of glycomimetics with high-affinity and at the same time drug-like properties will contribute to the realization of the potential of this relatively untapped source of therapeutics.
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