Inhibitors of selectin functions in the treatment of inflammatory skin disorders

Abstract

Selectins mediate tethering and rolling of leukocytes to the vascular endothelium, the first adhesive step in the recruitment of immune cells to inflamed tissues. Thus, selectins play a key role in the pathogenesis of common inflammatory skin disorders such as atopic dermatitis or psoriasis. As a consequence of their key functions, selectins have received much attention as potential target structures for new therapies. Indeed, a number of agents including small-molecule as well as peptide compounds interfering with selectin functions have been developed to treat inflammatory disorders. However, many of the selectin-directed compounds have not held up to the high expectations, in some cases due to overlapping and mutually compensating functions of selectins or suboptimal pharmacokinetic properties of the compounds, while other agents appear to be more promising candidates and have already entered clinical trials. Selectively targeting the functions of one or several selectins involved in the cascade of leukocyte recruitment promises exciting new therapeutic options, but, at the same time, bears considerable imponderables, which will be discussed in this review article.

Figure 1

Molecular interactions involved in lymphocyte extravasation in the skin (modified from von Andrian and Mackay 2000; Schön et al 2003). The upper part of the figure depicts key steps of interactions with the endothelial lining resulting in extravasation of lymphocytes. The bottom part shows selected adhesion molecules which mediate these events.