Macrocyclic α helical peptide therapeutic modality: A perspective of learnings and challenges

Macrocyclic alpha-helical peptides have emerged as a compelling new therapeutic modality to tackle targets confined to the intracellular compartment. Within the scope of hydrocarbon-stapling there has been significant progress to date, including the first stapled alpha-helical peptide to enter into clinical trials. The principal design concept of stapled alpha-helical peptides is to mimic a cognate (protein) ligand relative to binding its target via an alpha-helical interface. However, it was the proclivity of such stapled alpha-helical peptides to exhibit cell permeability and proteolytic stability that underscored their promise as unique macrocyclic peptide drugs for intracellular targets. This perspective highlights key learnings as well as challenges in basic research with respect to structure-based design, innovative chemistry, cell permeability and proteolytic stability that are essential to fulfill the promise of stapled alpha-helical peptide drug development. (C) 2018 Published by Elsevier Ltd.