Synthesis of Disulfide Surrogate Peptides through a Serine/Threonine Ligation-Assisted Diaminodiacid Strategy

Abstract

We report a new serine/threonine ligation (STL)assisted diaminodiacid (DADA) strategy for the flexible construction of disulfide surrogates by the option of more abundant -Aa-Ser/Thr-ligation sites. The practicality of this strategy was evidenced by the synthesis of the intrachain disulfide surrogate of C-type natriuretic peptide and the interchain disulfide surrogate of insulin.

Synthesis of disulfide-rich C-terminal Cys-containing peptide acids through a photocleavable side-chain anchoring strategy

“…To further demonstrate the utility of 1 , we applied it to the synthesis of human C-type natriuretic peptide 22 ( hCNP 22 ), which consists of 22 amino acids with one disulfide bond (Cys6–Cys22). 5 b ,15 Specifically, 1 was inserted at Cys 22 through SPPS and peptide 5 was cleaved from the resin using TFA (Fig. 4a).…”

Oxidation and Phenolysis of Peptide/Protein C-Terminal Hydrazides Afford Salicylaldehyde Ester Surrogates for Chemical Protein Synthesis

“…The high abundance of N-terminal residues (Ser/Thr/Cys/Val) in native proteins and the good compatibility with the C-terminal residues in the SAL esters (with Lys, Glu, and Asp as exceptions) provide multiple choices for ligation sites. , In recent years, C-to-N − and N-to-C sequential STL strategies and the combined application of STL with NCL , have been developed through selective protection of N-terminal residues and the design of C-terminal SAL ester surrogates. With these developments, STL has been widely applied to obtain various protein and cyclic peptide products. − As a further advancement, protein semisynthesis is considered crucial for maximizing the synthetic efficiency. While expressed protein segments with N-terminal residues for STL/CPL (i.e., Ser/Thr) can be readily obtained, − the preparation of expressed proteins with C-terminal SAL esters, however, remains a significant challenge.…”

Synthesis of A11Cys–B11Cys Disulfide Surrogates of H2 Relaxin through an Intermolecular Native Chemical Ligation-Assisted Diaminodiacid Strategy

“…Replacing the disulfide bonds with metabolically stable surrogates through chemical synthesis could improve the stability of ISPs. − Through the side-chain assembly strategy, insulin disulfide surrogates with enhanced thermal stability or resistant against insulin-degrading enzyme (IDE) had been obtained. We recently developed a more flexible diaminodiacid − (DADA)-based single-shot solid-phase synthesis strategy to replace the terminal interchain disulfide bond (A24 Cys –B23 Cys ) of H2 relaxin, and several analogs with improved stability or enhanced selectivity were obtained . Then we were interested in the construction of another H2 relaxin analog by replacing the interchain disulfide bond A11 Cys –B11 Cys .…”