Conformational Studies of ß-Azapeptoid Foldamers: A New Class of Peptidomimetics with Confined Dihedrals.

Controlling amide bond geometries and the secondary structures of ß-peptoids is a challenging task as they contain several rotatable single bonds in their backbone. Herein, we describe the synthesis and conformational properties of novel "ß-azapeptoids" with confined dihedrals. We discuss how the acylhydrazide sidechains in these molecules enforce trans amide geometries (ω ~180°) via steric and stereoelectronic effects. We also show that the Θ(Cα -Cß ) and Ψ(OC-Cα ) backbone torsions of ß-azapeptoids occupy a narrow range (170-180°) that can be rationalized by the staggered conformational preference of the backbone methylene carbons and a novel backbone nO →σ*Cß-N interaction discovered in this study. However, the ϕ (Cß -N) torsion remains freely rotatable and, depending on ϕ, the sidechains can be parallel, perpendicular, and anti-parallel relative to each other. In fact, we observed parallel and perpendicular relative orientations of sidechains in the crystal geometries of ß-azapeptoid dimers. We show that ϕ of ß-azapeptoids can be controlled by incorporating a bulky substituent at the backbone ß-carbon, which could provide complete control over all the backbone dihedrals. Finally, we show that the ϕ and Ψ dihedrals of ß-azapeptoids resemble that of a PPII helix and they retain PPII structure when incorporated in Host-guest proline peptides.

Sidechain-Backbone Tetrel Bonding Interactions Provide a General Mechanism for trans-Peptoid Stabilization.

Cis-trans isomerization of amide bonds impedes de novo design of folded peptoids (poly-N-substituted glycines) with precise secondary structures and affects peptoid-biomolecule binding affinity. Herein, from X-ray, NMR and DFT studies of azapeptoids, we have discovered a tetrel bonding interaction that stabilizes trans-peptoids. We show that peptoids having α-heteroatoms and N-aryl groups in the sidechain adopt trans-amide geometries due to the presence of a nX /πAr →σ*Cα-N tetrel bonding interaction between the sidechain α-heteroatom lone pair (nX ) or π-electrons (πAr ) and the σ* orbital of the backbone Cα -N bond. Further, CD spectroscopic studies of oligo-proline host-guest model peptides showed that azapeptoid residues stabilize polyproline II helical conformation. These data indicate that the sidechain-backbone tetrel bonding could be leveraged to design peptoids with precise secondary structures for a wide range of biological and material applications.

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

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.