Issue 8, 2021

Macrocyclization strategies for cyclic peptides and peptidomimetics

Abstract

Peptides are a growing therapeutic class due to their unique spatial characteristics that can target traditionally “undruggable” protein–protein interactions and surfaces. Despite their advantages, peptides must overcome several key shortcomings to be considered as drug leads, including their high conformational flexibility and susceptibility to proteolytic cleavage. As a general approach for overcoming these challenges, macrocyclization of a linear peptide can usually improve these characteristics. Their synthetic accessibility makes peptide macrocycles very attractive, though traditional synthetic methods for macrocyclization can be challenging for peptides, especially for head-to-tail cyclization. This review provides an updated summary of the available macrocyclization chemistries, such as traditional lactam formation, azide–alkyne cycloadditions, ring-closing metathesis as well as unconventional cyclization reactions, and it is structured according to the obtained functional groups. Keeping peptide chemistry and screening in mind, the focus is given to reactions applicable in solution, on solid supports, and compatible with contemporary screening methods.

Graphical abstract: Macrocyclization strategies for cyclic peptides and peptidomimetics

Supplementary files

Article information

Article type
Review Article
Submitted
10 mar 2021
Accepted
01 jun 2021
First published
29 jun 2021
This article is Open Access
Creative Commons BY license

RSC Med. Chem., 2021,12, 1325-1351

Macrocyclization strategies for cyclic peptides and peptidomimetics

C. Bechtler and C. Lamers, RSC Med. Chem., 2021, 12, 1325 DOI: 10.1039/D1MD00083G

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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