Protein Surface Recognition by Synthetic Receptors: A Route to Novel Submicromolar Inhibitors for α-Chymotrypsin

A family of synthetic receptors for protein surface recognition has been prepared. The receptors are based on a design in which four peptide loops are arrayed around a central calilx[4]arene core. By varying the sequence of the loop regions a range of differently functionalized receptor surfaces approximately 450 Å 2 in area can be prepared. From this family we have identified potent inhibitors of chymotrypsin that function by binding to the surface of the protein. The most potent of these ( 1 ) shows slow binding kinetics in an analogous manner to several of the natural protein proteinase inhibitors. Detailed kinetic analysis showed 1 to be a competitive inhibitor with K i and K i * values of 0.81 and 0.11 μM, respectively.