Researchers Make Progress on Selectin Antagonists, Prerequisite to Anti-Inflammatory Drugs

The selectins belonging to the C-type lectins were identified in the early 1990s. There are numerous reports that underscore their biological significance. In diseases in which cell adhesion, extravasation of cells from the bloodstream or the migration of specific lymphocytes is implicated in the pathology, they present attractive therapeutic targets. Sialyl Lewisx (sLex) is the minimal carbohydrate epitope recognized by E-selectin.

As typical for carbohydrate-lectin interactions, the sLex/E-selectin interaction is characterized by low affinity and a short half-life in the range of seconds, one reason for this being the shallow and solvent-accessible binding site of E-selectin. While this behavior is necessary for selectin's physiological function, it is a challenge for the development of selectin antagonists for therapeutic applications.

Such low affinity poses challenges for researchers who would like to develop selectin antagonists as anti-inflammatory drugs. Researchers have turned to the use of mimetic compounds, which lack the disadvantageous pharmacodynamic and pharmacokinetic properties of carbohydrates. Although numerous contributions presenting mimetic structures with considerably improved affinities have been published, E-selectin antagonists with high affinities and slower dissociation rates are still required.

Promising Fragments Identified

In a recent article published in the Journal of the American Chemical Society, the research group of Professor Beat Ernst at the University of Basel describes a fragment-based approach guided by nuclear magnetic resonance, which led to the identification of fragments binding to a second site in close proximity to the sLex binding site. The best fragments were connected to a mimic of sLex via triazole linkers of different length, and evaluated by surface plasmon resonance. This generated a range of new compounds with markedly improved affinity to E-selectin.

Detailed analysis of the five most promising candidates revealed antagonists with KD values ranging from 30 to 89 nM. In addition, half-lives of several minutes were observed for the complex of E-selectin with the fragment-based selectin antagonists. This new class of selectin antagonists exhibits a promising starting point for the development of selectin-based anti-inflammatory drugs.

Broader Applications

With their article, the authors contribute valuable information to the selectin field, in which Prof. Ernst and his team have been active for many years. In collaboration with GlycoMimetics, Inc., they have recently successfully promoted a selectin antagonist to clinical trials. Furthermore, similar fragment-based approaches can be applied to other lectin targets, which notoriously resist the identification of monovalent high-affinity ligands.

Original Citation
Jonas Egger, Céline Weckerle, Brian Cutting, Oliver Schwardt, Said Rabbani, Katrin Lemme, and Beat Ernst
Nanomolar E-Selectin Antagonists with Prolonged Half-Lives by a Fragment-Based Approach

Journal of the American Chemical Society, 2013, 135 (26), pp 9820–9828 | doi: 10.1021/ja4029582

Further Information
Prof. Dr. Beat Ernst, University of Basel, Department of Pharmaceutical Sciences, Klingelbergstrasse 50, 4056 Basel, Switzerland, Tel. +41 61 267 15 51, email: beat.ernst@unibas.ch