Improved Stability and Tunable Functionalization of Parallel β‐Sheets via Multicomponent N‐Alkylation of the Turn Moiety

Abstract

In contrast to the myriad of methods available to produce α‐helices and antiparallel β‐sheets in synthetic peptides, just a few are known for the construction of stable, non‐cyclic parallel β‐sheets. Herein, we report an efficient on‐resin approach for the assembly of parallel β‐sheet peptides in which the N‐alkylated turn moiety enhances the stability and gives access to a variety of functionalizations without modifying the parallel strands. The key synthetic step of this strategy is the multicomponent construction of an N‐alkylated turn using the Ugi reaction on varied isocyano‐resins. This four‐component process assembles the orthogonally protected turn fragment and incorporates handles serving for labeling/conjugation purposes or for reducing peptide aggregation. NMR and circular dichroism analyses confirm the better‐structured and more stable parallel β‐sheets in the N‐alkylated peptides compared to the non‐functionalized variants.

Influence of N-Methylation and Conformation on Almiramide Anti-Leishmanial Activity

“…In cyclic peptides, N-methyl residues have also induced backbone f and ψ dihedral angles consistent with βand γ-turn conformers [49], as well as altered side chain χ geometry [50]. N-Alkylation of the central amide of the hairpin inducing D-Pro-Aib dipeptide has also been shown by variable temperature CD spectroscopy to reinforce the central turn conformer and enhance the stability of the folded β-sheet peptide [51]. Introduction of N-methyl residues within the peptide chain causes likely a shift from an extended sequence to a dynamic series of cisand transamide conformers exhibiting a preference for turn geometry, which in peptides 19-21 reduces activity.…”

Facile construction of peptidomimetics by sequential C–S/C–N bond activation of Ugi-adducts

“…7 Rivera reported an efficient on-resin approach for the assembly of parallel β-sheet peptides by using the Ugi-4CR on varied isocyano-resins. 8 However, the Ugi-4CR is limited to the synthesis of peptidomimetics bearing a secondary amide because of the use of isocyanides. 9 However, as peptidomimetics containing a primary amide exhibit diverse bioactivities, 1d,2 it is essential to develop rapid and efficient strategies for the preparation of diverse, complex and valuable peptidomimetics with a primary amide moiety.…”

On-Resin Ugi Reaction for C-Terminally Modified and Head-to-Tail Cyclized Antibacterial Peptides

“…For example, Jobin and co-workers achieved backbone anchoring and synthesis of cyclic peptides by a solid-phase Ugi reaction . On-resin Ugi reaction was also applied to the peptide fragment ligation, the synthesis of backbone N-substituted peptides, and the modification of peptides with heterocycle backbones through combinatorial chemistry . Recently, our group reported an on-resin, three-component Passerini reaction for the synthesis of nitroveratryl-caged peptides, the photolysis of which reveals a C-terminal carboxylic acid .…”