UC Santa Cruz

Agouti Signaling Peptide (ASIP) is a small disulfide-rich peptide, which acts as an inverse agonist at melanocortin receptor 1 (MC1R) and reduces the production of melanin. ASIP has recently been shown to increase melanoma treatment sensitivity. Here we develop strategies to improve ASIP potency by increasing its affinity and specificity to MC1R. We find no increase in binding for the constructs we synthesized. We then increase the stability of ASIP via head-to-tail cyclization using hydrazide intermediates to facilitate native chemical ligation. We find the imposed chemical restraint does not alter peptide structure or function as a melanocortin antagonist. We compared the stability of linear and cyclic ASIP in human serum, finding that cyclic ASIP has a slight increase in resistance to proteolysis. These studies have the potential to revolutionize the treatment of melanoma through the use of ASIP as a peptide therapeutic.