From Oligosaccharides to Glycomimetics
Third-party funded project
Project title From Oligosaccharides to Glycomimetics
Principal Investigator(s) Ernst, Beat
Organisation / Research unit Departement Pharmazeutische Wissenschaften / Molekulare Pharmazie (Ernst)
Project start 01.04.2010
Probable end 31.03.2013
Status Completed
Abstract

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.

Keywords E-selectin, sialyl Lewisx, selectin antagonists, bioactive conformation, fragment-based in situ combinatorial approach, myelin-associated glycoprotein (MAG), MAG antagonists, asialoglycoprotein receptor (ASGP-R)
Financed by Swiss National Science Foundation (SNSF)
   

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23/01/2021