Recent Advances in the Synthesis of Peptoid Macrocycles

Abstract

Over the past two decades, developing medical applications for peptides has, and continues to be a highly active area of research. At present there are over 60 peptide‐based drugs on the market and more than 140 in various stages of clinical trials. The interest in peptide‐based therapeutics arises from their biocompatibility and their ability to form defined secondary and tertiary structures, resulting in a high selectivity for complex targets. However, there are significant challenges associated with the development of peptide‐based therapeutics, namely peptides are readily metabolised in vivo. Peptoids are an emerging class of peptidomimetic and they offer an alternative to peptides. Peptoids are comprised of N‐substituted glycines where side‐chains are located on the nitrogen atom of the amide backbone rather than the α‐carbon as is the case in peptides. This change in structure confers a high degree of resistance to proteolytic degradation but the absence of any backbone hydrogen bonding means that peptoids exhibit a high degree of conformational flexibility. Cyclisation has been explored as one possible route to rigidify peptoid structures, making them more selective, and, therefore more desirable as potential therapeutics. This review outlines the various strategies that have been developed over the last decade to access new types of macrocyclic peptoids.

DNA origami protection and molecular interfacing through engineered sequence-defined peptoids

“…The ether side chain, like in the Nte monomers, has been shown in previous peptoid studies to exhibit antifouling and surface passivation properties. That can prevent surface adsorption of biomolecules in physiological environments and inhibit enzymatic degradation of DNA origamis due to proteases and nucleases (44,46,53,54).…”

“…In this work, we demonstrate that peptoid-based coating provides a tunable platform for protecting DNA nanostructures in a broad range of bioactive environments. Peptoids, comprising N-substituted glycines, are an emerging class of peptidomimetic molecules that offer biocompatibility, low-cost synthesis, high chemical flexibility, and designable sequences and performances (42)(43)(44). In a recent study, Xuan et al (45) demonstrated that peptoid architectures could be engineered at the atomic level, resulting in a variety of atomically defined structural arrangements.…”

“…In a recent study, Xuan et al (45) demonstrated that peptoid architectures could be engineered at the atomic level, resulting in a variety of atomically defined structural arrangements. Compared to peptides, peptoids possess high conformational flexibility and confer a high degree of resistance to proteolytic degradation (44,46), due to the side chains located on the nitrogen of the amide backbone instead of the α-carbon. These tunable properties, as well as their intrinsic biocompatibility, offer an attractive property for drug/gene delivery and cellular-imaging applications (47)(48)(49)(50).…”

Branched peptides as bioactive molecules for drug design

“…A, Different strategies for the improvement of peptide stability to proteolytic cleavage. The images are schematic representations of molecules constructed by: d amino‐acids (empty circles); unnatural amino‐acids (full squares and pentagons); cyclization through the use of disulfide bonds obtained by cysteines oxidation (black circles); structural constraints given by the presence of amino‐acids like, for example, proline or histidine (curved line on full circles); peptidomimetics, where for example, the nitrogen atom of the amide backbone is used rather than the α‐carbon as in the case of peptides (thick ribbon); branched peptides where two or four identical peptides are linked together by an amino acidic core (empty squares). B, Schematic representation of nanocarriers used to link drugs, including peptides, for the improvement of bioavailability.…”

A facile on‐bead method for fully symmetric tetra‐substituted DOTA derivatizations using peptoid moieties

“…Therefore, we report here an innovative and facile method to carry out symmetrical tetra modifications around the DOTA scaffold using the unique active site distribution patterns of commercially available resins. We once again chose peptoids as our main source of modifying moieties due to the facile and straightforward chemistry involved with peptoid synthesis …”