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.
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
Journal of the American Chemical Society, 2013, 135 (26), pp 9820–9828 | doi: 10.1021/ja4029582Further Information
Closing the carbon loop
08.12.2016 | University of Pittsburgh
Newly discovered bacteria-binding protein in the intestine
08.12.2016 | University of Gothenburg
In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.
Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...
Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
08.12.2016 | Life Sciences
08.12.2016 | Physics and Astronomy
08.12.2016 | Materials Sciences