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.In addition,the diverse applications of peptide are due to their distinctive properties,including ease of synthesis and characterization,introduction of chemical diversity by novel amino acid substitution,and modulation of 3D structure by chemical modification.The application of peptides as drugs stems from their key roles in many target recognition and signal transduction pathways,which makes them an attractive avenue to target diseases.However,the major drawback of many peptides is lack of stability in biological media.In this context,cyclization and N-methylation of peptides have become useful approaches for improving in vivo stability of peptides.These two strategies have rendered,in some cases,oral bioavailability,cell permeability,improved potency at the target receptor,selectivity against receptor subtypes and improved stability to enzymes.Several new modalities in constraining peptides also have been developed over recent years and this work highlights some of these developments.Further understanding the rules governing cell permeability,oral absorption and stability for enzymatic degradation of peptides can help peptides to enter the clinical phases for many unmet medical needs.