The folding propensity of α/sulfono-γ-AA peptidic foldamers with both left- and right-handedness

Abstract

The discovery and application of new types of helical peptidic foldamers have been an attractive endeavor to enable the development of new materials, catalysts and biological molecules. To maximize their application potential through structure-based design, it is imperative to control their helical handedness based on their molecular scaffold. Herein we first demonstrate the generalizability of the solid-state right-handed helical propensity of the 413-helix of L-α/L-sulfono-γ-AA peptides that as short as 11-mer, using the high-resolution X-ray single crystallography. The atomic level folding conformation of the foldamers was also elucidated by 2D NMR and circular dichroism under various conditions. Subsequently, we show that the helical handedness of this class of foldamer is controlled by the chirality of their chiral side chains, as demonstrated by the left-handed 413-helix comprising 1:1 D-α/D-sulfono-γ-AA peptide. In addition, a heterochiral coiled-coil-like structure was also revealed for the first time, unambiguously supporting the impact of chirality on their helical handedness. Our findings enable the structure-based design of unique folding biopolymers and materials with the exclusive handedness or the racemic form of the foldamers in the future.

Determination of the critical chain length for macromolecular crystallization using structurally flexible polyketones

“…However, single crystal X-ray diffraction (SCXRD) analysis of the as-obtained crystals gave a highly disordered structure along the oligomer chain with remarkably large R 1 values (>0.20). As observed for some oligomer crystals having other repeating units, 14,54–57 such a disordering can be attributable to aperiodic ordering of oligomer chains to give pseudo infinite chain structures. To improve the diffraction data quality, we examined crystal annealing at various temperatures.…”

α/Sulfono-γ-AApeptide Hybrid Analogues of Glucagon with Enhanced Stability and Prolonged In Vivo Activity

“…Our α/sulfono-γ-AApeptide hybrids design was based on glucagon–NH 2 and started with the introduction of sulfono-γ-AA residues from the C terminus of glucagon (Table and Figure A) . As alternative α-amino acid and L-sulfono-γ-AA hybrid peptide in a 1:1 repeat pattern forms a robust 4 13 helical structure (pitch: 5.5 Å) similar to α-helix (right-handed 4 13 helix, pitch 5.4 Å), − the replacement of three neighboring amino acids with one amino acid and one sulfono-γ-AA residue was expected to retain the helix structure in glucagon (Figure B). In addition, it is widely known that inclusion of addition unnatural amino acids and long PEG and fatty acid chains (Figure C) was also manifested to enhance the stability and activity. , The activity of these α/sulfono-γ-AApeptide hybrids 1–10 (Table ) was first determined using a cAMP response element (CRE)-driven luciferase reporter in human embryonic kidney (HEK) (HEK293) cells stably expressing human GCGR obtained with O8 as the control (Figure ).…”

“…Among recent advances, backbone modification has emerged as an effective strategy using unnatural residues such as β-amino acids − or oligoureas , to replace a few α-amino acid residues in short-acting bioactive peptides in order to achieve enhanced resistance to proteolytic degradation, more favorable pharmacokinetic (PK) properties, and retain biological activity in vivo. As proteolytically stable peptidomimetics, sulfono-γ-AApeptides (Figure ) exhibit remarkable capability of mimicking the helical domain of proteins and modulating a range of medicinally relevant protein–protein interactions (PPIs). − Indeed, helical sulfono-γ-AApeptides, including left-handed − and right-handed homogeneous sulfono-γ-AApeptides, as well as left-handed and right-handed 1:1 heterogeneous α/sulfono-γ-AApeptides, ,− have been demonstrated as suitable backbones for mimicking the helical domain of bioactive peptides owing to their robust helical folding propensity and close similarity to α-helix; however, the replacement of just a few canonical amino acid residues in the long bioactive peptides with unnatural sulfono-γ-AA residues remains rather underexplored …”

Helical sulfono-γ-AApeptides with predictable functions in protein recognition

“…3A and B). 34,36,38 The side chains of this type of peptide were almost perpendicular to the helical axis and point away from the peptide axis. The series of crystal structures we have obtained clearly reveal the neat and uniform 13-hydrogen bond pattern between the backbone carbonyl group of each residue and the amide N–H of the fourth residue with a distance of 1.95–2.11 Å.…”

“…27–33 As a class of proteolytically stable peptidomimetics, sulfono-γ-AApeptides and their related peptide hybrids exhibit unique folding stability by adopting a series of robust helical structures with well-defined hydrogen bond patterns. 34–39 This type of unnatural peptidomimetics has the following advantages: (1) half of the side chains are derived from the chiral groups of canonical amino acids, whereas the other half of the side chains are introduced by sulfonyl chlorides, providing an enormous chemical diversity. (2) They can form well-defined and stable secondary structures analogous to that of an α-helix, enabling the mimicry of the structures of natural peptides or proteins and maintaining or even improving the functions of their natural counterparts.…”