The melanocortin receptors are a family of five (MC1-5R) G-protein coupled receptors that regulate a variety of biological functions including skin pigmentation, appetite, energy homeostasis and sexual function.¹ The melanocortin receptor subtypes have gained considerable interest from the pharmaceutical industry as MC4R is a potential therapeutic target for obesity and sexual dysfunction, while MC1R has more recently emerged as a potential target for skin cancer and inflammatory diseases.² The receptors are activated by binding of the melanocyte stimulating hormones (MSH) which contain a conserved minimal tetra-peptide pharmacophore (HFRW) that binds in turn-like conformation to the melanocortin receptors.³ To design novel melanocortin agonists, we choose the 14-mer cyclic peptide, sunflower trypsin inhibitor-1 as an ultra-stable framework to ‘graft’ in the HFRW melanocortin activating motif.⁴ Using this strategy and subsequent pharmacophore optimizations (D-amino acid substitution, N-methylation of peptide bonds, variation of macrocycle size) we have developed selective and potent (EC₅₀/IC₅₀ low pM) melanocortin receptor-1 agonists with potential application in the treatment of melanoma.