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.

Residue‐Selective C−H Sulfenylation Enabled by Acid‐Activated S‐Acetamidomethyl Cysteine Sulfoxide with Application to One‐Pot Stapling and Lipidation Sequence

“…To suppress this alkylation, we evaluated the cationscavenging performance of a guanidinium salt, which can trap an iminium cation such as the Acm cation. [25] Among the guanidium salts that were examined, the guanidium trifluoromethanesulfonate (Gn • HOTf) soluble at a concentration < 0.2 M in the TMSOTf/TFA or TMSOTf/HFIP showed satisfactory results (entries 7 and 8, Figure 5e and f). Even, a decrease of TMSOTf in concentration to 0.1 M afforded the results comparable to those shown in entries 7 and 8 (Figure S8i and j).…”

Macrocyclization strategies for cyclic peptides and peptidomimetics

“…Tyrosine reacts in the ortho position via a C-nucleophilic attack of the iminium ion intermediate and a subsequent re-aromatization (Scheme 11). 66 Schiff bases (imines, hydrazones, and oximes) are used in dynamic covalent chemistry approaches due to their hydrolytic reversibility, with oximes being generally the most stable. Side-chain cyclization via oxime formation is achieved using noncanonical amino acids containing a 1,2-aminoalcohol, which is oxidized by NaIO 4 to an aldehyde (Scheme 12).…”

“…Tyrosine reacts in the ortho position via a C-nucleophilic attack of the iminium ion intermediate and a subsequent re-aromatization ( Scheme 11 ). 66 …”

Extendable stapling of unprotected peptides by crosslinking two amines with o-phthalaldehyde

“…The current toolbox for stapling native peptides could be greatly expanded by exploring other common amino acid residues as potential cross-linking anchors 24 – 28 . Useful methods for such noncysteine stapling are still very scarce 5 , 29 – 31 . Here, we show that the primary amino groups from two AA residues can undergo a condensation reaction with OPA as the linker, forming a class of underexplored isoindolinimine structures under mild aqueous conditions (Fig.…”