S-Protected Cysteine Sulfoxide-Enabled Tryptophan-Selective Modification with Application to Peptide Lipidation

Abstract

Lipidation of peptides is a promising means of modification that can improve the therapeutic character of biologically active peptides. Here, a novel lipidation protocol for peptides is described. The C−H sulfenylation of indole in peptides using S-p-methoxybenzyl cysteine sulfoxide under acidic conditions in the presence of ammonium chloride, anisole, and triisopropylsilane enables late-stage tryptophan-selective peptide lipidation. This developed protocol has been used successfully for the lipidation of glucagon-like peptides. Oral glucose tolerance tests in wild-type mice indicated that the resulting lipidated peptides stimulate insulin secretion and exhibit a more long-lasting blood-glucose-lowering effect than a parent nonlipidated peptide.

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

“…Then, the addition of the Cys(Acm)(O)‐decorated lipid 15 (1.2 equiv.) in HFIP containing 4 M diisopropylamine (DA) ⋅ HCl [30c] into the stapling reaction mixture with additional stirring at 15 °C for 1 h allowed the Trp‐selective C−H sulfenylation to proceed, generating the lipidated/stapled peptides ( 16 a and 16 b ) in 34 % and 28 % isolated yields, respectively (Figures 6b and S20). Peptide mapping of the obtained peptides using chymotrypsin indicated that the desired expected modifications occurred on the Tyr and Trp residues (Figure S21).…”

“…Subsequently, in comparison with GLP‐1 (7–37) and non‐stapled lipidated GLP‐1 17 , [30c] the effect of the modifications in GLP‐1 peptides ( 16 a and 16 b ) was evaluated by an oral glucose tolerance test (OGTT) in wild‐type (WT) mice. After intraperitoneal administration of phosphate‐buffered saline (PBS) or the GLP‐1 peptides, insulin concentrations and blood glucose were measured during the OGTT (Figure 7).…”

Development of Naturally Inspired Peptide and Protein Chemistry

“…[107][108][109] We realized that S-protected Cys sulfoxides could be converted to the corresponding Cys(Cl) unit under acidic conditions in the presence of chloride anion in a redox-neutral manner. Under these conditions, S-p-methoxybenzyl Cys sulfoxide (Cys(MBzl) (O)) reacted efficiently with the Trp in peptide 121 to afford the tryptathionine-containing peptide 123 via an intermediate 122 110) (Fig. 30), and the success led to late-stage peptide lipidation.…”

“…30), and the success led to late-stage peptide lipidation. 111) In addition, regioselective disulfide formation using S-protected Cys sulfoxides has become available. Further research efforts for applying the sulfoxide chemistry to peptide/ protein science, including late-stage peptide/protein modification and syntheses of peptides containing multiple disulfides and side chain-bridged peptides, have continued in our group.…”

Advanced Insulin Synthesis by One-pot/stepwise Disulfide Bond Formation Enabled by Acid-activated S-Protected Cysteine Sulfoxide in the Presence of Chloride Anion

“…We report herein an advanced insulin synthesis that uses acidactivated S-protected cysteine sulfoxides for one-pot/stepwise disulfide bond formation as well as a subsequent lipidation sequence. [10]…”