Macrocyclic α Helical Peptide Therapeutic Modality: A Perspective of Learnings and Challenges

Publication date: Available online 16 March 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Tomi K. Sawyer, Anthony Partridge, Hung Yi Kristal Kaan, Yu-Chi Juang, Shuhui Lim, Charles Johannes, Tsz Ying Yuen, Chandra Verma, Srinivasaraghavan Kannan, Pietro Aronica, Tan Yaw Sing, Brad Sherborne, Sookhee Ha, Jerome Hochman, Shiying Chen, Laura Surdi, Andrea Peier, Berengere Sauvagnat, Peter Dandliker, Chris Brown, Simon Ng, Fernando Ferrer, David P. Lane
Macrocyclic α-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 α-helical peptide to enter into clinical trials. The principal design concept of stapled α-helical peptides is to mimic a cognate (protein) ligand relative to binding its target via an α-helical interface. However, it was the proclivity of such stapled α-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 α-helical peptide drug development.

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