Intrinsically Photoswitchable α/β Peptides toward Two‐State Foldamers

Abstract

A simple, unsaturated, E-Z photoisomerizable β-amino acid, (Z)-3-aminoprop-2-enoic acid, has been introduced into peptide foldamers through a one-pot chemical coupling, based on Pd/Cu-catalyzed olefin oxidative amidation, between two peptide segments carrying, respectively, a -Gly-NH residue at the C-terminus and an acryloyl group at the N-terminus. Reversible conversion between the Z and E configurations of the 3-aminoprop-2-enoic linkage was achieved photochemically. A crystallographic analysis on two model compounds shed light on the consequences, in terms of 3D structure and self-association properties, brought about by the different configuration of the unsaturated linkage. As a proof of concept, E-Z photoisomerization of a 3-aminoprop-2-enoic acid residue, inserted as the junction between two conformationally distinct peptide domains (one helical while the other β-sheet promoter), allowed supramolecular self-association to be reversibly turned on/off.

A ribosomally synthesized and post-translationally modified peptide containing a β-amino acid and a macrocyclic motif

“…It has been found that Aaa (Δ Z βAla) residue in a peptide allows formation of an N-H••O = C intra-residue H-bond which closes a 6-membered pseudo ring system, allowing the peptide to form a well-de ned 3D architecture of the attened β sheet 29 . Recent studies demonstrated that foldamers containing Δ Z βAla/Δ E βAla units display interesting conformational, electronic, and supramolecular aggregation properties that can be modulated by selective E-Z photoisomerization [30][31][32] .…”

The Diverse World of Foldamers: Endless Possibilities of Self-Assembly

“…Photoswitchable α–Δβ foldamers containing single [ 248 ] or multiple (up to four) units of Δ Z β-Ala (( Z )-3-aminoprop-2-enoic acid, the C α,β -unsaturated analog of β-Ala) [ 249 ] were studied in water and acetonitrile, respectively. The singly Δ Z β-Ala-substituted peptide Cbz-(Ala-Aib) 2 -Ala-Gly-Δ Z β-Ala-Lys-Leu-Val-Phe-Phe-OH was irradiated at 290–320 nm in water, and the stable hydrogel was submitted to TEM analysis with uranyl acetate staining.…”

“…On the contrary, in the Z isomer, the intraresidue N-H···O=C interaction of Δ Z β-Ala, experimentally demonstrated by single-crystal XRD and 1 H NMR in CD 3 CN solution, simultaneously led to the loss of two potential intermolecular hydrogen bonds and to a bent overall structure, for which no higher aggregations of dimers should be possible. In fact, after 10 min irradiation at 254 nm of hydrogel containing 95% E isomer, the equilibration to a 6:4 E / Z mixture led to an almost complete fiber dissociation and hydrogel destruction [ 248 ].…”

Photoresponsive Prion‐Mimic Foldamer to Induce Controlled Protein Aggregation

“…Foldamer structures allow chemists to broaden and expand the limited range of structural components that body up natural proteins, and foldamers have been designed to carry out protein‐like functions of binding, catalysis and signal relay [22] . We recently succeeded in introducing the simplest unsaturated ( E ‐ Z photoisomerizable) β‐amino acid, namely ( Z )‐3‐aminoprop‐2‐enoic acid (Δ Z βAla), into peptide foldamers [23, 24] . The reversible conversion between the Δ Z βAla and Δ E βAla configurations, achieved photochemically, was accompanied by remarkable consequences on the 3D‐structure of the peptides.…”

“…[22] We recently succeeded in introducing the simplest unsaturated (E-Z photoisomerizable) b-amino acid, namely (Z)-3-aminoprop-2-enoic acid (D Z bAla), into peptide foldamers. [23,24] The reversible conversion between the D Z bAla and D E bAla configurations, achieved photochemically, was accompanied by remarkable consequences on the 3D-structure of the peptides. This allowed their molecular self-association through intermolecular hydrogen bonding to be spatiotemporally turned on-off.…”