Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

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

10.07.2013
Uni Basel Researchers have identified a new class of selectin antagonists as lead structures for anti-inflammatory drugs. Their results were recently published in the Journal of the American Chemical Society.

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

Reto Caluori | Universität Basel
Further information:
http://www.unibas.ch
http://dx.doi.org/10.1021/ja4029582

More articles from Life Sciences:

nachricht Nanoparticle Exposure Can Awaken Dormant Viruses in the Lungs
16.01.2017 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt

nachricht Cholera bacteria infect more effectively with a simple twist of shape
13.01.2017 | Princeton University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Designing Architecture with Solar Building Envelopes

Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.

As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...

Im Focus: How to inflate a hardened concrete shell with a weight of 80 t

At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).

Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...

Im Focus: Bacterial Pac Man molecule snaps at sugar

Many pathogens use certain sugar compounds from their host to help conceal themselves against the immune system. Scientists at the University of Bonn have now, in cooperation with researchers at the University of York in the United Kingdom, analyzed the dynamics of a bacterial molecule that is involved in this process. They demonstrate that the protein grabs onto the sugar molecule with a Pac Man-like chewing motion and holds it until it can be used. Their results could help design therapeutics that could make the protein poorer at grabbing and holding and hence compromise the pathogen in the host. The study has now been published in “Biophysical Journal”.

The cells of the mouth, nose and intestinal mucosa produce large quantities of a chemical called sialic acid. Many bacteria possess a special transport system...

Im Focus: Newly proposed reference datasets improve weather satellite data quality

UMD, NOAA collaboration demonstrates suitability of in-orbit datasets for weather satellite calibration

"Traffic and weather, together on the hour!" blasts your local radio station, while your smartphone knows the weather halfway across the world. A network of...

Im Focus: Repairing defects in fiber-reinforced plastics more efficiently

Fiber-reinforced plastics (FRP) are frequently used in the aeronautic and automobile industry. However, the repair of workpieces made of these composite materials is often less profitable than exchanging the part. In order to increase the lifetime of FRP parts and to make them more eco-efficient, the Laser Zentrum Hannover e.V. (LZH) and the Apodius GmbH want to combine a new measuring device for fiber layer orientation with an innovative laser-based repair process.

Defects in FRP pieces may be production or operation-related. Whether or not repair is cost-effective depends on the geometry of the defective area, the tools...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

Nothing will happen without batteries making it happen!

05.01.2017 | Event News

 
Latest News

Multiregional brain on a chip

16.01.2017 | Power and Electrical Engineering

New technology enables 5-D imaging in live animals, humans

16.01.2017 | Information Technology

Researchers develop environmentally friendly soy air filter

16.01.2017 | Power and Electrical Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>