Design and synthesis of multiple-loop receptors based on a calix[4]arene scaffold for protein surface recognition

We have recently reported a synthetic protein binding agent with fourfold symmetry containing four identical peptide loops attached to the four phenyl groups of a calix[4]arene core. One of these first generation derivatives not only bound strongly to cytochrome c but also blocked its ability to interact with protein partners or simple reducing agents. In developing second generation protein binding agents with better affinity and selectivity, we required a synthetic approach that would lead to a less symmetrical arrangement of the peptide loops around the core calix[4]arene scaffold. We herein report an important step in the wider application of this strategy with the preparation of a series of unsymmetrical receptors in which two different loops are attached to the core calixarene.