Issue 3, 2018

De novo design of constrained and sequence-independent peptide scaffolds with topologically-formidable disulfide connectivities

Abstract

Disulfide-rich peptides are interesting scaffolds for drug design and discovery. However, peptide scaffolds constrained by disulfide bonds, either naturally occurring or computationally designed, have been suffering from the elusive (oxidative) folding behavior complying with Anfinsen's dogma, which strongly restricts their applicability in bioactive peptide design and discovery; because when primary peptide sequences are extensively manipulated, their disulfide connectivities might become scrambled. Here we present the design of cysteine/penicillamine (C/Pen)-mixed peptide frameworks that are capable of folding into specific regioisomers without dependence on primary amino acid sequences. Even certain folds that are considered to be topologically formidable can be generated in high yields. Currently, almost all disulfide-rich peptide scaffolds are vitally correlated to primary amino acid sequences, but ours are exceptional. These scaffolds should be of particular interest for further designing constrained peptides with new structures and functions, and more importantly, the ultimately designed peptides would not suffer from general oxidative folding problems.

Graphical abstract: De novo design of constrained and sequence-independent peptide scaffolds with topologically-formidable disulfide connectivities

Supplementary files

Article information

Article type
Edge Article
Submitted
09 sep 2017
Accepted
17 nov 2017
First published
20 nov 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., 2018,9, 569-575

De novo design of constrained and sequence-independent peptide scaffolds with topologically-formidable disulfide connectivities

Y. Zheng, X. Meng, Y. Wu, Y. Zhao and C. Wu, Chem. Sci., 2018, 9, 569 DOI: 10.1039/C7SC03956E

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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