Issue 4, 2017

Artificial disulfide-rich peptide scaffolds with precisely defined disulfide patterns and a minimized number of isomers

Abstract

Disulfide-rich peptides are emerging as potential templates for drug design applications. However, the synthesis and reengineering of disulfide-rich peptides are challenging, owing to the complexity of the oxidative folding process involving a number of diverse isomeric structures. Novel disulfide-rich peptide scaffolds that are not besieged by their disulfide isomers are still greatly desired. In this work, we report the design and synthesis of a novel class of artificial disulfide-rich peptide scaffolds with precisely defined disulfide patterns and a minimized number of isomers. In theory, natural peptides with three disulfide bonds have 15 possible isomers. By rationally engineering the thiol-framework of a peptide containing six cysteines with penicillamines and a dithiol amino acid, we demonstrated, for the first time, that the total number of isomers formed after oxidative folding can be decreased to a minimum of two (i.e., from 15 to 2). As fewer isomeric folds are involved in the oxidative folding, the pathway of the folding becomes more concise and the yield of the artificial scaffolds is substantially increased compared to that of its six-cysteine-containing analogue, which makes the artificial disulfide-rich scaffolds (with only 2 predefined isomeric folds) extremely promising for being exploited as structurally complex templates for the design of peptide therapeutics and ligands.

Graphical abstract: Artificial disulfide-rich peptide scaffolds with precisely defined disulfide patterns and a minimized number of isomers

Supplementary files

Article information

Article type
Edge Article
Submitted
30 Dec. 2016
Accepted
15 Febr. 2017
First published
17 Febr. 2017
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2017,8, 2547-2552

Artificial disulfide-rich peptide scaffolds with precisely defined disulfide patterns and a minimized number of isomers

Y. Zheng, Z. Li, J. Ren, W. Liu, Y. Wu, Y. Zhao and C. Wu, Chem. Sci., 2017, 8, 2547 DOI: 10.1039/C6SC05710A

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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