Issue 35, 2023

Light-initiated 1,3-dipolar cycloaddition between dehydroalanines and tetrazoles: application to late-stage peptide and protein modifications

Abstract

As an easily introduced noncoded amino acid with unique electrophilicity distinct from the 20 natural amino acids, dehydroalanine (Dha) is not only a precise protein post-translational modification (PTM) insertion tool, but also a promising multifunctional labelling site for peptides and proteins. However, achieving a balance between the reaction rate and mild reaction conditions has been a major challenge in developing novel Dha-modified strategies. Rapid, efficient, and mild Dha modification strategies are highly desired. Additionally, catalyst-free photocontrollable reactions for Dha-containing peptide and protein modification have yet to be developed. Here, we report a photoinitiated 1,3-dipolar cycloaddition reaction between Dha and 2,5-diaryl tetrazoles. Under low-power UV lamp irradiation, this reaction is completed within minutes without catalysis, resulting in a fluorescent pyrazoline-modified peptide or protein with excellent chemoselectivity for Dha residues. Notably, this reaction exhibits complete site-specificity in the modification of thiostrepton, a natural antimicrobial peptide containing multiple Dha residues (Dha3, Dha16, and Dha17), within 20 minutes in high yields. This is currently the fastest reaction for modifying the Dha residue in thiostrepton with clear site-specificity towards Dha16. This photoinitiated reaction also provides a chemoselective strategy for precise functionalization of proteins. Additionally, the rapidity and efficiency of the reaction minimize UV light damage to the biological reaction system. Combined with fluorogenic properties, this photo-controllable methodology can be applied to live cell imaging, further broadening the application scope of the Dha modification methodology.

Graphical abstract: Light-initiated 1,3-dipolar cycloaddition between dehydroalanines and tetrazoles: application to late-stage peptide and protein modifications

Supplementary files

Article information

Article type
Edge Article
Submitted
02 Jun 2023
Accepted
18 Aug 2023
First published
22 Aug 2023
This article is Open Access

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

Chem. Sci., 2023,14, 9418-9426

Light-initiated 1,3-dipolar cycloaddition between dehydroalanines and tetrazoles: application to late-stage peptide and protein modifications

M. Zhang, P. He and Y. Li, Chem. Sci., 2023, 14, 9418 DOI: 10.1039/D3SC02818F

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