Novel approaches to the design of bioavailable melanotropins.

INTRODUCTION: The melanocortin system is a primordial and critical system for survival, involved in a wide variety of physiological functions. It includes melanocortin receptors (MCRs) and melanotropin ligands (MCLs). MCRs are important drug targets that can regulate several key physiological processes. Extensive efforts have been made to develop peptide and peptidomimetics targeting melanocortin receptors including MC1R, MC3R, MC4R and MC5R. Most research is focused on developing potent and selective melanotropins. However, developing bioavailable melanotropins remains challenging. Areas covered: Herein, the authors summarize promising strategies for developing bioavailable MCLs by using cyclized N-methylated melanotropins, and using cyclotide and tetrapeptide as templates. They discuss their unique advantages in oral availability and targeting MCRs in the central nervous system or in peripheral tissues. Finally, they discuss the observed differences in thepharmacology of MCRs between in vitro and in vivo tests. Expert opinion: N-methylated cyclized melanotropins have great potential to become bio- available drugs targeting MCRs in the brain, while MCR-grafted cyclotides tend to target MCRs in peripheral tissue. A better understanding of the biased signaling process is a new challenge and opportunity for the future discovery of bioavailable MCLs.