Cooperative Stapling of Native Peptides at Lysine and Tyrosine or Arginine with Formaldehyde

Abstract

Stapling of peptides by intramolecular crosslinking of two neighboring amino acid side chains offers an important tool to modulate the structure and properties of peptides. In comparison to the stapling of artificially engineered peptide substrates, methods for stapling native peptides are more desirable for easier accessibility and genetic encodability. However, the existing strategy for selectivity control in the stapling of native peptides is relatively limited: the site of anchoring is often dominated by Cys, and the means for achieving the position selectivity among the same type of residues at different locations is lacking. We have developed a simple and powerful strategy for stapling native peptides at lysine residues with formaldehyde by the cooperation of nearby tyrosine or arginine residues. The stapling reactions can proceed with high efficiency and residue selectivity under mild conditions, and generate linchpins with distinct physiochemical properties. The new method for peptide stapling enables unique control of position‐selectivity for substrates bearing multiple reaction sites by reactivity that can be readily built in the peptide sequence.

Head-to-tail cyclization for the synthesis of naturally occurring cyclic peptides on organophosphorus small-molecular supports

“…3 To date, scientists have persisted to improve and develop novel strategies for peptide cyclization. 4…”

Peptide macrocyclisation via late-stage reductive amination

“…Aldehyde condensation chemistry has also been explored in macrocyclisation approaches which exploit various side chain functionalities. [36][37][38][39][40] The use of dialdehyde linkers-based primarily off of the phthalaldehyde scaffold-as linchpin reagents 41 capable of trapping peptides bearing two nucleophilic sites has emerged as a particularly valuable strategy (Scheme 1C). An early example exploited the reactivity of peptide-derived hydroxylamines and hydrazines for dynamic covalent cross-linking, 42 with more recent studies demonstrating the robust functionalisation of native peptide substrates.…”

Solid‐Phase Peptide Macrocyclization and Multifunctionalization via Dipyrrin Construction

“…[6] To this end, a repertoire of peptide macrocyclization and stapling approaches has been developed and diversified over the past decade. [7] Cross-couplings, [8] click reactions, [9] C À H activations/functionalizations, [10] ring-closing olefin metathesis reactions, [11] Diels-Alder cycloaddi-tions, [12] multicomponent Ugi/Petasis-type reactions, [13] and ligation-mediated cyclizations, [14] among others, [15] have been established in site-specific fashions employing a variety of anchoring residues/terminal groups. [16] New structural-functional moieties can be introduced into the backbones of peptide macrocycles via certain above-mentioned approaches as the staple linkers, which can be manipulated to optimize the cyclopeptide ring size/rigidity, and furnish new handling sites for small-molecule drug and fluorescent dye conjugations to access unprecedented chemotypes and become powerful tools to probe PPIs and orchestrate therapeutic applications.…”