Total synthesis of snake toxin α-bungarotoxin and its analogues by hydrazide-based native chemical ligation

Nicotinic acetylcholine receptors(nAChRs) play important roles in intercellular communications of nerve cells. α-Bungarotoxins(αBtx) is a moderator for the nAChRs. Chemical synthesis provides a promising way to access aBtx and their analogues. Here, we reported a new method for a-bungarotoxin by combining Fmoc-SPPS and peptide hydrazide based ligation strategy. The two-segment ligation method may enable efficient synthesis of aBtx analogues. These synthetic toxin peptides are useful tools for development of imaging or therapeutic reagents.

Total synthesis of TRADD death domain with arginine N-GlcNAcylation by hydrazide-based native chemical ligation

TNFR1-associated death domain protein(TRADD)with arginine N-GlcNAcylation is a novel and structurally unique posttranslational modification(PTM)glycoprotein that blocks the formation of death-inducing signaling complex(DISC),orchestrating host nuclear factorκB(NF-κB)signaling in entero-pathogenic Escherichia coli(EPEC)-infected cells.This particular glycosylated modification plays an extremely vital role for the effective colonization and pathogenesis of pathogens in the gut.Herein we describe the total synthesis of TRADD death domain(residues 195-312)with arginine235 NGlcNAcylation(Arg-GIcNAc TRADD(195-312)).Two longish peptidyl fragments of the wild-type primary sequence were obtained by robust,microwave-assisted,highly efficient,solid-phase peptide synthesis(SPPS),the N-GlcNAcylated sector was built by total synthesis and attached specifically to resinbound peptide with an unprotected ornithine residue via silver-promoted on-resin guanidinylation,ArgGlcNAc TRADD(195-312)was constructed by hydrazide-based native chemical ligation(NCL).The facile synthetic strategy is expected to be generally applicable for the rapid synthesis of other proteins with Arg-GIcNAc modification and to pave the way for the related chemically biological study.