Design of cyclized selective melanotropins

This article describes the development of cyclic peptides for G‐protein coupled receptors to enable structure‐function knowledge and the design of novel therapeutics. One important property of cyclic peptides is that they tend to be resistant to the digestion, enabling them to survive in the human digestive tract. This trait makes them very important as drug leads or as scaffolds which, in theory, can be engineered to incorporate a peptide domain of medicinal value. This is especially important for delivery of peptides that would be destroyed without such implementation. The melanocortin system is the focus of this article, and includes melanotropin ligands and melanocortin receptors. We examine two strategies to constrain the melanotropin peptide backbone. The first is based on global constraint of peptides by cyclization using various kinds of linkers. In the second approach we describe the use of a natural cyclized template, the cyclotide, to graft the melanotropin phamacophore, ‐His‐Phe‐Arg‐Trp‐, to obtain selective drug leads. In these examples the conserved melanocyte stimulating hormone pharmacophore is examined and the modified peptides were synthesized by solid phase methodology. Biological studies confirmed the production of selective, potent and in some cases orally available ligands.