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 Angstrom(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 (I) 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 mu M, respectively.