Right-Handed Helical Foldamers Consisting of De Novo d-AApeptides

Abstract

New types of foldamer scaffolds are formidably challenging to design and synthesize, yet highly desirable as structural mimics of peptides/proteins with a wide repertoire of functions. In particular, the development of peptidomimetic helical foldamers holds promise for new biomaterials, catalysts, and drug molecules. Unnatural L-sulfono-γ-AApeptides were recently developed and shown to have potential applications in both biomedical and material sciences. However, D-sulfono-γ-AApeptides, the enantiomers of L-sulfono-γ-AApeptides, have never been studied due to the lack of high-resolution three-dimensional structures to guide structure-based design. Herein, we report the first synthesis and X-ray crystal structures of a series of 2:1 L-amino acid/D-sulfono-γ-AApeptide hybrid foldamers, and elucidate their folded conformation at the atomic level. Single-crystal X-ray crystallography indicates that this class of oligomers folds into well-defined right-handed helices with unique helical parameters. The helical structures were consistent with data obtained from solution 2D NMR, CD studies, and molecular dynamics simulations. Our findings are expected to inspire the structure-based design of this type of unique folding biopolymers for biomaterials and biomedical applications.

Inhibition of β-catenin/B cell lymphoma 9 protein−protein interaction using α-helix–mimicking sulfono-γ-AApeptide inhibitors

“…As a new class of proteolytically stable peptidomimetics, γ-AApeptides have emerged as effective peptidomimetics that play important roles in chemical biology and biomedical sciences (17)(18)(19). Specifically, sulfono-γ-AApeptides have been shown to have excellent folding stability to adopt a series of helical structures with a well-defined hydrogen-bonding pattern (20)(21)(22)(23)(24). In sulfono-γ-AApeptides, one-half of the side chains are introduced by sulfonyl chlorides, providing enormous chemical diversity ( Fig.…”

De Novo Left‐Handed Synthetic Peptidomimetic Foldamers

“…γ‐AApeptides (N‐ a cetylated‐N‐ a minoethyl amino acid oligomers, stemming from a chiral peptide nucleic acid (PNA) backbone) are receiving increasing attention as a new class of peptidomimetics owing to their enormous chemical diversity imparted by arbitrary side chains and their resistance to proteolytic degradation (Figure a) . More recently, we reported the crystal structures of de novo heterogeneous 2:1 α/ d ‐sulfono‐γ‐AA hybrid oligomers capable of adopting right‐handed 4.5 16‐14 helical conformations, as well as heterogeneous 1:1 α/ l ‐sulfono‐γ‐AA hybrid oligomers that form right‐handed 4 13 helices, thus demonstrating that peptidomimetics containing γ‐AApeptide units can be unique heterogeneous foldamers. However, crystal structures of homogeneous sulfono‐γ‐AApeptides, which would be much more significant, as the folding conformation of sulfono‐γ‐AApeptides could be elucidated, were not yet obtained.…”

“…To exclude the potential impact of side chains on the folding propensity, initially l ‐methyl‐sulfono‐γ‐AA with a chlorobenzene sulfonyl group was chosen (Figure b). All together four oligomers (oligomers 1 a , b and 2 a , b ) were synthesized by solid‐phase Fmoc chemistry according to the protocol reported previously . To test the generality of forming foldamers, the side chains on the oligomeric sequences included cationic NH 2 , anionic COOH, and hydrophobic 4‐chlorobenzenesulfonyl residues (oligomers 3 a , b , 4 a , b ,and 5 a ).…”

“…After a series of attempts, we first obtained single crystals of 1 a suitable for X‐ray diffraction analysis at a resolution of 1.1 Å from a mixture of acetonitrile and H 2 O. Surprisingly, unlike classic α‐helices or recently developed 4.5 16‐14 and 4 13 helices based on heterogeneous backbones, this homogeneous l ‐sulfono‐γ‐AA oligomer adopts an unprecedented left‐handed helical structure with a four‐helical fold with a radius of 2.8 Å and a helical pitch of 5.1 Å (Figure a). The helix possesses four distinct helical faces, with side chains aligned at 90° intervals to form a rectangular shape when viewed down the helix axis.…”

Oligomers of α‐ABpeptoid/β3‐peptide hybrid

“…These desirable features may allow them to serve as an important tool in various biological applications. Indeed, a myriad of peptidomimetic foldamers have been developed including β‐ and γ‐peptides, oligoureas, oligopyrrolidines, γ‐AApeptides, α‐aminoxy acids, azapeptides, oligotriazoles, aromatic oligoamides, and peptoids …”