New modalities in conformationally constrained peptides for potency, selectivity and cell permeation.

There has been a resurgence of interest in peptide pharmaceuticals as they have an advantage of potency, selectivity and less toxicity compared with small-molecule therapeutics. The main draw back of peptides is lack of stability to biological media. Constraining a peptide has been one of the approaches to improving in vivo stability of the peptides. Several new modalities in constraining peptides have been developed over recent years and this review highlights some of the new developments. The newer cyclization 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. As chemists further understand the rules governing cell permeability, oral absorption and enhancing stability of peptides, we can expect to see more peptides entering clinic for many unmet medical needs.