Transglutaminase surface recognition by peptidocalix[4]arene diversomers

A series of N-linked tetrakis(tetrapeptido)calix4]arene diversomers, 3A-P, has been synthesized by coupling of a cone calix4]arene tetracarboxylic acid chloride with tetrapeptides 1A-P obtained in a parallel fashion. The inhibition activity of 3A-P towards tissue and microbial transglutaminase was evaluated by in vitro assays with a labeled substrate. Kinetic analysis using one of the most active derivatives (3A) showed a noncompetitive inhibition with respect to the amino acceptor substrate and an uncompetitive inhibition with respect to amino donor substrate. Experimental results are in accordance with an inhibition due to a protein specific surface recognition on a region noncomprising the enzyme active site.