A Peptide Backbone Stapling Strategy Enabled by the Multicomponent Incorporation of Amide N‐Substituents

Abstract

The multicomponent backbone N‐modification of peptides on solid‐phase is presented as a powerful and general method to enable peptide stapling at the backbone instead of the side chains. This work shows that a variety of functionalized N‐substituents suitable for backbone stapling can be readily introduced by means of on‐resin Ugi multicomponent reactions conducted during solid‐phase peptide synthesis. Diverse macrocyclization chemistries were implemented with such backbone N‐substituents, including the ring‐closing metathesis, lactamization, and thiol alkylation. The backbone N‐modification method was also applied to the synthesis of α‐helical peptides by linking N‐substituents to the peptide N‐terminus, thus featuring hydrogen‐bond surrogate structures. Overall, the strategy proves useful for peptide backbone macrocyclization approaches that show promise in peptide drug discovery.

Macrocyclization strategies for cyclic peptides and peptidomimetics

“…To achieve stapling in solution, pseudodilution conditions were used by the slow addition of boronic acid and peptide to a solution of oxo-component. 340 A head-to-tail peptidomimetic can be generated in one step via the multicomponent reaction of an aldehyde, linear peptide, and (N-isocyanimino)triphenylphosphorane. 6 The resulting backbone contains a 1,3,4-oxadiazole, which was shown to stabilize a unique intramolecular hydrogen-bond network and enable a high passive membrane permeability in contrast to the analogous homodetic macrocycles.…”

“…To achieve stapling in solution, pseudo-dilution conditions were used by the slow addition of boronic acid and peptide to a solution of oxo-component. 340 …”

Designing stapled peptides to inhibit protein‐protein interactions: An analysis of successes in a rapidly changing field

“…Since many stapled peptides are designed to inhibit intracellular PPIs, they necessarily share common features with another class of peptide therapeutic, the cell‐penetrating peptides (CPPs). [ 15,18,36‐40 ] We cover some of the notable strategies that have been used to optimise the pharmacokinetic properties of stapled peptides sequences, enhance their activity and reduce their proteolysis. But whilst we have focussed this review on these enhancements, noting the expanding interest of pharmaceutical companies for novel peptides, [ 41 ] in some cases more “classical approaches” might provide a better alternative to stapling.…”

“…In parallel, the chemistry landscape for stapled peptides is continuously diversifying with a dozen "novel" linker chemistries reported in publications in 2019. [17][18][19][20][21][22][23] In some instances, only very subtle differences in the staple chemistry, or stereochemistry, trigger a significant change in the binding affinity, the pharmaceutical profile of the peptide, or give added functionality. [21,[24][25][26][27][28][29] Despite multiple publications and reviews describing reliable methods for the synthesis of stapled peptides [30][31][32][33][34][35] 35 ] and the commercialisation of the most common unnatural amino acids, their synthesis remains costly and until a few years ago, nonautomated.…”

“…Since many stapled peptides are designed to inhibit intracellular PPIs, they necessarily share common features with another class of peptide therapeutic, the cell-penetrating peptides (CPPs). [15,18,[36][37][38][39][40] We cover some of the notable strategies that have been used to optimise the pharmacokinetic properties of stapled peptides sequences, enhance their activity and reduce their proteolysis.…”