1,4-Disubstituted 1,2,3-Triazoles as Amide Bond Surrogates for the Stabilisation of Linear Peptides with Biological Activity

Abstract

Peptides represent an important class of biologically active molecules with high potential for the development of diagnostic and therapeutic agents due to their structural diversity, favourable pharmacokinetic properties, and synthetic availability. However, the widespread use of peptides and conjugates thereof in clinical applications can be hampered by their low stability in vivo due to rapid degradation by endogenous proteases. A promising approach to circumvent this potential limitation includes the substitution of metabolically labile amide bonds in the peptide backbone by stable isosteric amide bond mimetics. In this review, we focus on the incorporation of 1,4-disubstituted 1,2,3-triazoles as amide bond surrogates in linear peptides with the aim to increase their stability without impacting their biological function(s). We highlight the properties of this heterocycle as a trans-amide bond surrogate and summarise approaches for the synthesis of triazole-containing peptidomimetics via the Cu(I)-catalysed azide-alkyne cycloaddition (CuAAC). The impacts of the incorporation of triazoles in the backbone of diverse peptides on their biological properties such as, e.g., blood serum stability and affinity as well as selectivity towards their respective molecular target(s) are discussed.

Macrocyclization strategies for cyclic peptides and peptidomimetics

“…Furthermore, the dipolarity of the triazole compares well to the amide's (Scheme 32, right). [262][263][264] The 1,2,3-triazole has been used to stabilize secondary structures or other motifs, including α-helices 265,266 3 10 -helices, 262,267 β-hairpins, 268 and disulfides. 21,269 The reaction has been used extensively for, among others, bioconjugation and materials science, with comprehensive reviews available.…”

“…21,269 The reaction has been used extensively for, among others, bioconjugation and materials science, with comprehensive reviews available. 12,263,264,270 Despite its widespread usage, the detailed reaction mechanism has been challenging to establish. The current consensus 260 is that the catalytic cycle is initiated by the coordination of the Cu I -species to the alkyne, followed by the tethering of the azide to the complex.…”

“…271 Likewise, alkynes are commercially available or can be synthetically accessed by, for instance, the Corey-Fuchs reaction or Seyferth-Gilbert homologation. 264 When a short spacer on the C-terminus is desired for headto-tail cyclization, it is possible to introduce a C-terminal propargylamine by using a silyl-based alkyne modifying (SAM)-resin. 272,273 CuAAC does not require protecting groups and can be performed on-resin 267,271,[274][275][276][277][278] as well as in solution, 262,[265][266][267][268][269][279][280][281][282][283][284][285][286][287][288][289][290][291][292][293][294][295] which is more common and proceeds under mild conditions.…”

1,5-Disubstituted 1,2,3-Triazoles as Amide Bond Isosteres Yield Novel Tumor-Targeting Minigastrin Analogs

“…[16][17][18][19][20] The systematic replacement of amide bonds by 1,4-Tz (termed a triazole scan) has been used as a tool to probe the contribution of the backbone to the stability and the activity of biologically relevant peptides similar to an N-methyl amide scan. 21 So far, this approach has been applied to enkephalin, 22 angiotensin, 23 bombesin, [24][25][26] neurotensin, 27,28 and minigastrin. 29,30 Examples of peptidomimetics based on 1,5-disubstituted 1,2,3triazoles (1,5-Tz) are scarce.…”

1,2,3-Triazoles as Biomimetics in Peptide Science

“…An important example of peptide mimicry in medicinal chemistry is the replacement of the amide with a heterocyclic bioisostere such as the 1,2,3-triazole moiety [ 22 , 23 ].…”