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Issue 4, 2017

Selective N-terminal functionalization of native peptides and proteins

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Abstract

We report an efficient, highly selective modification on the N-terminal amines of peptides and proteins using aldehyde derivatives via reductive alkylation. After modification of a library of unprotected peptides XYSKEASAL (X varies over 20 natural amino acids) by benzaldehyde at room temperature, pH 6.1 resulted in excellent N-terminal selectivity (α-amino/ε-amino: >99 : 1) and high reaction conversion for 19 out of the 20 peptides. Under similar conditions, highly selective N-terminal modifications were achieved with a variety of aldehydes. Furthermore, N-termini of native peptides and proteins could be selectively modified under the same conditions to introduce bioorthogonal functional groups. Using human insulin as an example, we further demonstrated that preserving the positive charge in the N-terminus using reductive alkylation instead of acylation leads to a 5-fold increase in bioactivity. In summary, our reported method provides a universal strategy for site-selective N-terminal functionalization in native peptides and proteins.

Graphical abstract: Selective N-terminal functionalization of native peptides and proteins

Supplementary files

Article information


Submitted
25 Oct 2016
Accepted
06 Jan 2017
First published
09 Jan 2017

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2017,8, 2717-2722
Article type
Edge Article

Selective N-terminal functionalization of native peptides and proteins

D. Chen, M. M. Disotuar, X. Xiong, Y. Wang and D. H. Chou, Chem. Sci., 2017, 8, 2717 DOI: 10.1039/C6SC04744K

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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