Strategies to Control the Cis-Trans Isomerization of Peptoid Amide Bonds.

Abstract

Peptoids are oligomers of N-substituted glycine units. They structurally resemble peptides but, unlike natural peptides, the side chains of peptoids are present on the amide nitrogen atoms instead of the α-carbons. The N-substitution improves cell-permeability of peptoids and enhance their proteolytic stability over natural peptides. Therefore, peptoids are ideal peptidomimetic candidates for drug discovery, especially for intracellular targets. Unfortunately, most peptoid ligands discovered so far possess moderate affinity towards their biological targets. The moderate affinity of peptoids for biomacromolecules is linked to their conformational flexibility, which causes substantial entropic loss during the peptoid-biomacromolecule binding process. The conformational flexibility of peptoids is caused by the lack of backbone chirality, absence of hydrogen bond donors (NH) in their backbone to form CO⋅⋅⋅HN hydrogen bonds and the facile cis-trans isomerization of their tertiary amide bonds. In recent years, many investigators have shown that the incorporation of specific side chains with unique steric and stereoelectronic features can favourably shift the cis-trans equilibria of peptoids towards one of the two isomeric forms. Such strategies are helpful to design homogenous peptoid oligomers having well defined secondary structures. Herein, we discuss the strategies developed over the years to control the cis-trans isomerization of peptoid amide bonds.