Application of copper(i) catalyzed azide–alkyne [3+2] cycloaddition to the synthesis of template-assembled multivalent peptide conjugates

Abstract

Here we describe the facile generation of tetravalent peptide conjugates via a copper(I) catalyzed azide-alkyne cycloaddition (CuAAC) using a cyclic peptide template as a versatile conjugation scaffold. This stable and rigid framework is a conformationally constrained cyclic beta-sheet decorated with spatially defined alkyne moieties that serve as selectively addressable coupling sites. The proposed method allows for the effective coupling of unprotected peptide monomers in water at room temperature within comparatively short reaction times. The resulting conjugates display the ligands in an oriented manner, thus allowing for multivalent interactions with given target molecules, which may contribute to enhanced affinity and specificity. In addition, the selected scaffold offers an orthogonal coupling site for the incorporation of fluorescent labels or radioligands.

Two Rapid Catalyst-Free Click Reactions for In Vivo Protein Labeling of Genetically Encoded Strained Alkene/Alkyne Functionalities

“…1,2 Early focus of click chemistry centered on the Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) reaction. 3,4 The CuAAC reaction is highly bioorthogonal due to the biologically inert nature of the azide and alkyne functional groups. Applications of this reaction in chemical biology include activity-based protein profiling and selective biomolecule labeling.…”

Use of Click Chemistry for Obtaining an Antimicrobial Chimeric Peptide Containing the LfcinB and Buforin II Minimal Antimicrobial Motifs

“…In order to establish the optimal experimental conditions for the Cu AAC reaction, it was necessary to standardize (i) amounts of precursors and catalysts, (ii) solvents and their proportions, (iii) reaction time, and (iv) temperature. It has been reported that polar solvents favor the generation of the triazole ring. In attempting to carry out this reaction in polar aprotic solvents such as DMF, ring generation was not observed .…”

1,2,3‐Triazole: Multifunktionswerkzeuge für die Peptidchemie

“…Diese Strategie macht es nicht nur möglich, effektiv Fluoreszenz‐ oder Radioreportermoleküle anzuknüpfen, sondern auch größere biomolekulare Strukturen kontrolliert aufzubauen. So lassen sich auf Gerüstmolekülen wie cyclischen Dekapeptiden oder organisch‐anorganischen Hybridplattformen Peptidliganden in mehrfacher Ausfertigung präsentieren (Abbildung 2) 35 Solch multivalente Strukturen zeigen gegenüber den einzelnen Liganden oft verbesserte Bindeeigenschaften.…”

“…So kann die Bindung an Oberflächen mit vielen Zielmolekülen (beispielsweise mit Zellmembranen) durch mehrere gleichzeitige Interaktionen signifikant gesteigert werden (Avidität). Sehr umfassend wurde diese Strategie zur oligovalenten Präsentation von RGD‐Peptiden angewandt 35 Das RGD‐Motiv zeigen lineare oder cyclische Peptide, die mit der Aminosäuresequenz Arginin‐Glycin‐Asparaginsäure Integrinrezeptoren binden und inhibieren können.…”