On the Cyclization of Non‐cyclic Peptides for Biological Applications: Inspiration from Naturally Cyclic Peptides

Abstract

Peptides are unique class of biomolecules for pharmaceutics and industries, given their structural features that can be applied to many approaches. Although their advantages are known, they suffer from some limitations that need to be overcome. Some disadvantages are peptidic conformations’ flexibility and susceptibility to proteolytic degradation. Research has been in a constant endeavor to provide solutions. The discovery of cyclic peptides in plants opened the door for new insights into peptide‐based applications. These peptides display high stability to physical and chemical conditions. They possess a wide range of biological activities. In addition, cyclic peptides shows enhanced activities compared to linear peptides. Thus, the idea of non‐cyclic peptide cyclization can be of great use in eliminating issues and improving peptide capabilities. Inspired by the naturally found cyclic peptides, many approaches for synthetic cyclization have been proposed. The current review provides an overall discussion of the available methods for cyclization, applications, and characterization techniques. The present review offers a unique source for colleagues newly exposed to the subject and on the verge of entering the field of cyclic peptides by providing an initiating step covering the essential points needed to be considered around peptide cyclization.

Zilucoplan: A Newly Approved Macrocyclic Peptide for Treatment of Anti-Acetylcholine Receptor Positive Myasthenia Gravis

“…Another strategy adopted to increase the stability of these molecules is cyclization [4]. Cyclic peptides show both enhanced pharmacokinetic and pharmacodynamic properties compared to linear peptides [63]. Cyclization decreases conformational changes of the molecule, by reduction of spatial vibrations, and increases the surface area for interaction with the biological target, improving the binding affinity and selectivity.…”

Recent Advances in Metal-Free Peptide Stapling Strategies

“…Depending on the sites of cyclization, the strategies for forming cyclic peptides can be categorized into head-to-tail, head-to-side chain, side chain-to-tail, and side chain-to-side chain cyclization. The latter plays a key role in achieving secondary conformations (α-helices or β-sheets) necessary for creating “stapled peptides” . The α-helices are commonly situated on the interfaces of PPIs, so it is possible to reasonably design α-helical peptides that disturb such PPIs …”

“…The latter plays a key role in achieving secondary conformations (α-helices or β-sheets) necessary for creating "stapled peptides". 4 The α-helices are commonly situated on the interfaces of PPIs, so it is possible to reasonably design α-helical peptides that disturb such PPIs. 5 In recent years, alongside the numerous classical cyclization strategies, significant progress has been made in new stapling strategies such as bicyclization, photoisomerization, reversible cyclization, ultra-rapid cyclization, etc., some of which even realize the stapling and further late-stage functionalization simultaneously.…”