T cell migration, essential for immune surveillance and response, is mediated by the integrin LFA-1. Cathepsin X, a cysteine carboxypeptidase, is involved in the regulation of T cell migration by interaction with LFA-1. We show that sequential cleavage of C-terminal amino acids from the cytoplasmic beta2 tail of LFA-1, by cathepsin X , enhances binding of the adaptor protein talin to LFA-1 and triggers formation of the latter's high-affinity form. Analysis of LFA-1 by conformation-specific mAb showed that cathepsin X modulates LFA-1 affinity, promoting formation of high-affinity from intermediate-affinity LFA-1 but not the initial activation of LFA-1 from a bent to extended form. Cathepsin X post-translational modifications may thus represent a mechanism of LFA-1 fine-tuning that enables the trafficking of T cells.
COBISS.SI-ID: 2988913
Aberrant cathepsin B activity is associated with various diseases, however, despite extensive research, there are no cathepsinB inhibitors in clinical use. Here, nitroxoline, an established antimicrobial agent, is identified as a potent, reversible inhibitor of cathepsin B, and is thus a potential drug candidate for the treatment of diseases in which cathepsin B activity plays a role.
COBISS.SI-ID: 3024241
We present the discovery of 6-substituted 4-benzylthio-1,3,5-triazin-2(1H)-ones as inhibitors of cathepsin B, starting from screening of a library of variously 2,4,6-trisubstituted 1,3,5-triazines and 1,3,5-triazin-2(1H)-ones on three different human cathepsins. The synthesis and enzymatic evaluation of a focused library of new 1,3,5-triazin-2(1H)-ones is also described. The detailed kinetics analyses have shown that these compounds can act as reversible, partial mixed-type inhibitors of cathepsin B, with Ki and Ki' values in the low micromolar range. The inhibitory activities of selected compounds were also assessed against two related cysteine proteases, cathepsinH and cathepsin L, to estimate their selectivity
COBISS.SI-ID: 3068017