Development Oral Available Melanotropins Based on the Cyclic Peptide Framework of Sunflower Trypsin Inhibitor-1

摘要

The melanocortin system involves numerous physiological functions and is associated with many diseases such as skin cancer, obesity and diabetes, sexual dysfunction, neuropathic pain, inflammatory diseases etc. Our primary interests have been focusing on the human melanocortin 1 and 4 receptors (hMClR, hMC4R) due to their direct involvement in the regulation of feeding behavior, energy homeostasis, as well as inflammatory diseases. Nevertheless, the full scope of physiological functions of these receptors is still poorly understood. There has been a resurgence of interest in peptide pharmaceuticals recently as they have an advantage of potency, selectivity and less toxicity compared with small-molecule therapeutics. The main drawback of peptides is lack of stability in biological media. Using cycloids and N-Methylation have been useful options to improve in vivo stability of the peptides [1]. Several new modalities in constraining peptides have been developed over recent years and this work highlights some of the new developments in our lab [2,3]. The newer grafted and methylation strategies have rendered, in some cases, oral activity, cell permeability, improved potency at the target receptor, selectivity against receptor subtypes and improved stability to enzymes. Further understanding rules governing cell permeability, oral absorption and enhancing stability of peptides can help peptides to enter the clinic for many unmet medical needs.