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.
Highlights
Acetic acid, displacement using a primary amine.[9a]. There are other, less commonly used methods of peptoid synthesis, for example, solid phase monomer synthesis,[11] and solution phase methods such as ringopening polymerisation of N-substituted N-carboxyanhydride monomers[12] and Ugi 4-component reactions,[13] but these are beyond the scope of this review, except for when specific examples have played a key role in accessing macrocyclic peptoids
Cyclic peptoids have been shown in several cases to improve cell penetration and to enhance antimicrobial activity when compared to their linear precursors.[22]
Since 2007, efforts have been underway to synthesise smaller (3- to 5-mer) cyclic peptoids, but the yields obtained were often relatively low, for the trimers(< 20 %) or conditions were not optimised.[21,30]. Accessing this type of peptoid is desirable given that small cyclic tetra-peptides have been shown to act as histone deacetylase inhibitors (HDIs).[31]
Summary
Vivo half-life means that for peptides oral administration is very rarely possible, further limiting their utility as drugs. To overcome these barriers, molecules resembling peptides are being developed by many groups in both academia and industry. Molecules resembling peptides are being developed by many groups in both academia and industry These molecules are often referred to as peptidomimetics and among these are a class of compounds known as peptoids (Figure 1).[8]
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