Macrocyclization of Peptide Side Chains by the Ugi Reaction: Achieving Peptide Folding and Exocyclic N-Functionalization in One Shot

Abstract

The cyclization of peptide side chains has been traditionally used to either induce or stabilize secondary structures (β-strands, helices, reverse turns) in short peptide sequences. So far, classic peptide coupling, nucleophilic substitution, olefin metathesis, and click reactions have been the methods of choice to fold synthetic peptides by means of macrocyclization. This article describes the utilization of the Ugi reaction for the side chain-to-side chain and side chain-to-termini macrocyclization of peptides, thus enabling not only access to stable folded structures but also the incorporation of exocyclic functionalities as N-substituents. Analysis of the NMR-derived structures revealed the formation of helical turns, β-bulges, and α-turns in cyclic peptides cross-linked at i, i + 3 and i, i + 4 positions, proving the folding effect of the multicomponent Ugi macrocyclization. Molecular dynamics simulation provided further insights on the stability and molecular motion of the side chain cross-linked peptides.

Designing helical peptide inhibitors of protein–protein interactions

“…For example, Vasco et al demonstrated that the Ugi reaction operating on modified side chains can both stabilize an α-turn and introduce exocyclic N-functionalization at the resulting lactam bridge. [17] In another example, the acetone-linked bridge reported by Assem et al has been shown to enhance helical secondary structure when introduced between peptide side-chain nucleophiles such as thiols. [18] In addition to stabilizing helical structures, the ketone moiety in the linker can be modified with diverse molecular tags by oxime ligation.…”

A gold mine for drug discovery: Strategies to develop cyclic peptides into therapies

“…Very recently, several multicomponent reactions have also been used as stapling approaches to lock peptide conformations into alpha‐helical structures, such as Ugi reaction (Figure A), Ugi‐Smiles reaction (Figure B), A 3 ‐coupling reaction (Figure C), petasis reaction (Figure D),etc. Many representational multicomponent stapling strategies have been described in Figure .…”

Multicomponent Peptide Stapling as a Diversity‐Driven Tool for the Development of Inhibitors of Protein–Protein Interactions

“…As depicted in Scheme , besides RCM, one‐component stapling techniques (that is, the peptide as the only component) currently include the traditional construction of lactam and disulfide bridges as well as others based on oxime and thioether bond formation or the Ugi cyclization between Lys and Asp/Glu side chains . On the other hand, there is an increasing interest in two‐component stapling approaches (Scheme A), in which eventually biorthogonal processes, such as the click Cu I ‐catalyzed alkyne–azide cycloaddition and dithiol (Cys) bis‐alkylation, introduce a stapling linker capable to stabilize the α‐helical structure, with the former one also enabling the functionalization of the staple moiety.…”

“…This strategy could be potentially more efficient for the rapid optimization of the linker, since parallel syntheses and biological screening can be undertaken using a single peptide sequence and varying the length, flexibility, and hydrophobicity of the linker. Multi‐component reactions (MCRs) are excellent diversity‐generating tools and have recently emerged as powerful stapling tools capable to lock specific peptide conformations and simultaneously diversify the staple moiety by variation of endo ‐ and exo ‐cyclic moieties during the multicomponent formation of the side chain cross‐linker …”