Issue 4, 2017

Selective N-terminal functionalization of native peptides and proteins


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

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Article information

Article type
Edge Article
25 Oct 2016
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
Creative Commons BY license

Chem. Sci., 2017,8, 2717-2722

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

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