Advances in Merging Triazoles with Peptides and Proteins

Abstract

Five-membered heterocycles have found extensive use as peptide- and disulfide-bond mimics in peptidomimetics. The application of 1,4- and 1,5-substituted 1,2,3-triazoles has been particularly favored due to their ease of preparation by a variety of “click” methods including the copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) and the ruthenium-catalyzed azide–alkyne cycloaddition (RuAAC) reactions. These heterocycles are electronically similar to amide bonds and have provided both functional and structural analogues of biologically active peptides. One advantage of triazole ring amide surrogates is their stability toward natural enzyme activity. The quantitative and orthogonal nature of the CuAAC reaction has facilitated its use in peptide macrocyclization reactions. The CuAAC reaction is particularly useful to replace disulfide bonds in order to stabilize bioactive conformations of biologically active peptides. Metal-free cycloadditions promoted by ring strain (SPAAC) have been favored for labeling in living systems in which transition metals are poorly tolerated. A range of in vivo biomolecular “click” reactions have demonstrated the versatility of SPAAC reactions in living cells and even multicellular organisms. Although azides and alkynes can conveniently be introduced in peptides during synthesis, site-specific incorporation of these functional groups into proteins is more challenging. A variety of methods has been developed to make these reactive precursors, including residue-specific replacement and genetic code expansion. Recent developments of new ligands and catalysts for the CuAAC reaction have further contributed to the promising possibilities that triazoles provide for future applications in the peptide and protein field.