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);
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.
Schwardt Oliver, Kelm Soerge, Ernst Beat (2013), SIGLEC-4 (MAG) Antagonists: From the Natural Carbohydrate Epitope to Glycomimetics.
, Springer Verlag Online, Heidelberg.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.