Targeting selectin functions in the therapy of psoriasis.
As leukocytes play a primary role in the immunopathogenesis of psoriasis, it is a reasonable assumption that preventing those cells from localizing to the sites of cutaneous inflammation can stop the disease process. Selectins, a family of three single-chain transmembrane adhesion molecules, which bind to carbohydrate moieties displayed on other cells, are pivotally involved in the initial steps of leukocyte recruitment, i.e. tethering and rolling along the endothelial lining of blood vessels. Thus, compounds impairing selectin functions have been developed to treat inflammatory disorders, such as psoriasis. Potential strategies to interfere with selectin functions include direct inhibition through monoclonal antibodies or small-molecule compounds, transcriptional regulation of selectin expression, and modulation of the post-transcriptional glycosylation of selectin ligands. More than a dozen different compounds targeting selectin functions are currently under development, several of which have shown promising effects on leukocyte recruitment and the therapy of inflammatory conditions under experimental conditions. However, based on preclinical and early clinical investigations, it appears that in some cases specifically targeting the function of single selectins may not be sufficient to effectively interrupt the inflammatory cascade. This is, at least in part, due to considerable redundancies and overlaps in the functions of the selectins, a notion that is corroborated by the apparently more pronounced therapeutic efficacy of some compounds with broader activity against several selectins. Overall, while targeting selectin functions promises rather selective and pathogenesis-based therapeutic approaches against psoriasis, the clinical value of such strategies, alone or in combination with other therapies, remains to be seen.
Schön
Michael P
MP
Rudolf Virchow Center, DFG Center for Experimental Biomedicine, and Department of Dermatology and Venereology, University of Würzburg, Germany. michael.schoen@virchow.uni-wuerzburg.de
Drewniok
Claudia
C
Boehncke
W-Henning
WH
D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D011565:Psoriasis / Q000188:drug therapy* / Q000378:metabolism*; D019087:Selectins / Q000737:chemistry / Q000378:metabolism*
D019087:Selectins