Furan-Based Locked Z-Vinylogous γ-Amino Acid Stabilizing Protein α-Turn in Water-Soluble Cyclic α₃γ Tetrapeptides

Abstract

Described here is the design, synthesis, and conformational analysis of cyclic tetrapeptides (CTPs) with α3γ architecture containing a furan-based locked Z-vinylogous amino acid (Vaa). This unnatural amino acid locks into a γ-turn that induces type IαRS-turn in the CTPs. Stabilized by a 13-membered intramolecular H-bond, these CTPs show robust conformation in water and aprotic solvent irrespective of the sequence of tripeptide consisting of α-amino acids used.

Non‐classical Helices with cis Carbon–Carbon Double Bonds in the Backbone: Structural Features of α,γ‐Hybrid Peptide Foldamers

“…[14] Grison et al and others also reported turn mimetics using Z-vinylogous amino acids. [15] Recently,w ed emonstrated the design of stable b-hairpins,t hree-stranded b-sheets,a nd miniature bmeander mimetics ( Figure 1) through selective incorporation of E-vinylogous residues into hybrid peptides. [16] Furthermore,w eh ave shown an unusual planar structure from 1:1 alternating a-residues and E-vinylogous residues ( Figure 1).…”

Bicyclic Pyrrolidine-Isoxazoline γ Amino Acid: A Constrained Scaffold for Stabilizing α-Turn Conformation in Isolated Peptides

“…Our results indicated that (+)-(3a R 6a S )- 1 enantiomer, in combination with glycine, is effective in stabilizing the α-turn conformation in peptides (Figure 1). This structural motif occurs quite often in many key sites of proteins, such as enzyme active site, and metal binding domains (Wintjens et al, 1996), although few molecules are known to mimic or stabilize it on isolated peptides (Kelso et al, 2004; Hoang et al, 2011; Krishna et al, 2014; Wang et al, 2018.). Our results make thus the unnatural γ-amino acid 1 of particular interest for future development of bioactive peptidomimetics.…”

The Role of N‐Methyl Squaramides in a Hydrogen‐Bonding Strategy to Fold Peptidomimetic Compounds

“…Alternatively, α‐turns are unusual secondary structures in proteins that enable 13‐membered hydrogen‐bonded rings to be stabilized by internal hydrogen bonds that correspond to tighter structures as β‐turns. Although they have a unique role in relevant bioactive peptides, there are just a few examples of synthetic modules mimicking α‐turns because of the difficulty of reproducing its features in synthetic modules . Therefore, access to modules that could mimic the formation of α‐ and β‐turns in bioactive peptidomimetic compounds is of significant interest.…”

“…Although they have au nique role in relevant bioactive peptides, there are just af ew examples of synthetic modules mimicking a-turns because of the difficultyo fr eproducingi ts features in synthetic modules. [15,16] Therefore, access to modules that could mimict he formation of a-a nd b-turns in bioactive peptidomimetic compounds is of significant interest. Many different scaffolds mimic b-turn fragments.…”

“…tert-Butyl ((S)-1-(((S)-1-(cyclohexylamino)-1-oxo-3-phenylpropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate(16):C ompound 16 was synthesized according to the general procedure for amino acid coupling, using N-Boc-l-valine (265 mg, 1.22 mmol) and phenylalanine-cyclohexylamide (300 mg, 1.22 mmol) in DMF (10 mL). CH 2 Cl 2 (50 mL) was added to the reaction mixture, and the resulting solution was washed with HCl 1 m (3 50 mL), H 2 O (50 mL) and brine (50 mL), dried over MgSO4 and concentrated.…”