Institut für Laboratoriumsmedizin, Klinische Chemie und Pathobiochemie 

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Inhibitors for Selectins

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Background

Fig. 1: Leukocyte extravasation. The process of leukocyte migration from the vessel lumen to the sur­roun­ding tissue is a closely orchestrated cascade of cell interactions with the en­do­thelium. Each step consists of a cha­rac­teristic pattern of receptors, their ligands, cytokines and che­mo­attrac­tants.

Extravasation of leukocytes into the targeted tissue is a desired process during inflammation and homing. In contrast, in acute inflammatory diseases with excessive immune response and autoimmune diseases, it comes to an uncontrolled migration of leukocytes into the affected tissue. In the case of autoimmune diseases (e.g. Crohn's disease or rheumatiod arthritis) endogenous structures are recognized by the immune system as foreign. In acute inflammatory or chronic inflammatory diseases with excessive immune response these pa­tho­lo­gi­cally increase in migration of leukocytes is due to an excess of pathogens / noxious sub­stances, such as Bacteria (pneumonia) and viruses (myocarditis) or toxins (chronic obstructive pulmonary disease, COPD) and uncontrolled enzyme re­ac­tions (pancreatitis). The reason is that the inflam­mation-causing toxicants exceed the bandwidth of the regulation of the immune response with the result that the excessive emigration of leukocytes not only eliminate the noxious substances, but leads to additional tissue damage.

The members of the selectin family (L-, P- and E-selectin) mediate the capturing, rolling and slow rolling of the leukocytes. Therefore, they are good candidates to engage in the process of leukocyte ex­tra­va­sation. 

Aims

Fig. 2: Different interactions of the selectins. L-selectin (blue) interacts with ligands on the en­do­thelium and on other leu­ko­cytes. During inflammation, P-selectin (purple) and E-selectin (grey) are both up­regulated from the en­do­thelium and bind ligands on the leukocytes.

Characterisation of known and design of novel selectin inhibitors which reduce leukocyte adhesion to develope new the­ra­peutics.

Examples for different inhibitors

  • Polymers, e.g. polyglycerol sulfate
  • Aptamers
  • Functionalized nanoparticles
  • Small molecules, e.g. Efomycin M
  • Antibodies

Examples

Rolling cells with and without inhibitor

untreated cells

5 MB  

 cells with inhibitor 100n M D13UF

3 MB