Depsipeptide Methodology for Solid-Phase Peptide Synthesis:  Circumventing Side Reactions and Development of an Automated Technique via Depsidipeptide Units^,

Abstract

The depsipeptide technique is a recently developed method for peptide synthesis which is applicable to difficult sequences when the synthetic difficulty arises because of aggregation phenomena. In the present work, application of the depsipeptide method to extremely difficult sequences has been demonstrated and a serious side reaction involving diketopiperazine formation uncovered and subsequently avoided by the appropriate use of the Bsmoc protecting group. Many other aspects of the technique have been investigated, such as the stability of the depsi units during assembly and workup procedures, the completeness of the O-acylation step, the occurrence of epimerization of the amino acid activated during O-acylation, and the nature of side products formed. In addition, the method was modified so as to allow for completely automated syntheses of long-chain depsipeptides without the need for any interruption by manual esterification procedures. Finally, the synthesis efficiency of the new depsipeptide technique was shown to be comparable to that of the well-known pseudoproline technique.

Peptide synthesis, characterization and 68Ga-radiolabeling of NOTA-conjugated ubiquicidin fragments for prospective infection imaging with PET/CT

“…Peptides with sequences that give rise to beta sheet secondary structures, and those with very hydrophobic regions are most prone to aggregation and are generally the most problematic to synthesize [23,[28][29][30][31][32]. Sequence analysis of UBI29-41, using the Garnier-Robson and Chou-Fasman algorithms, predicted an alpha helical secondary structure for this peptide rather than a beta sheet structure [6,33,34].…”

Total chemical synthesis of polypeptides and proteins: chemistry of ligation techniques and beyond

“…140 This avoids performing O-acylation on resin, which is cumbersome and racemization prone. Two useful routes were proposed to synthesize a depsidipeptide, Boc-Thr(Fmoc-Ala)-OH (Scheme 58), which was employed for an automated synthesis of the 31-mer Cterminal segment of a globular protein, crambin.…”

“…Out of the entire length of the peptide, the amide bond between Gly 25 and Ser 26 was isomerized into an ester bond and the rest of the sequence was assembled following standard protocols. After cleavage from the resin followed by deprotection of the Boc group from Ser 26 , the resulting click peptide O-acyl isoAb1e42 was easily purified through HPLC owing to its solubility in aqueous media (15 mg/ml 140 Stepwise procedures, purification techniques and methods to tackle the synthetic difficulties have been described, which adopt direct application of O/N acyl migration or pseudoproline-forming reactions for the efficient synthesis of peptides that otherwise induce unfavourable conformational constraints during chain assembly.…”

Switch‐Peptides: Design and Characterization of Controllable Super‐Amyloid‐Forming Host–Guest Peptides as Tools for Identifying Anti‐Amyloid Agents

“…Previously, we [5][6][7][8] and others [9][10][11][12] have shown that various steps along the amyloid formation pathway, including peptide/ protein misfolding, self-assembly, and amyloid formation and disassembly, can be triggered in a highly controllable manner through the incorporation of molecular switches into the amyloid-forming polypeptides, based on in situ intramolecular O! N acyl migration.…”

“…N acyl migration. [5][6][7][8][9][10][11][12][13][14][15][16] However, because of the special synthetic and purification skills required to prepare the full-length Ab switch-peptides, such peptides are not suitable for use in highthroughput screening assays. Therefore, the development of reliable model systems that are readily accessible and adaptable to automated HTS is of particular interest to understanding the mechanism of amyloid formation and facilitating the discovery of aggregation inhibitors of Ab and other amyloid-forming proteins.…”