Water-soluble, stable and azide-reactive strained dialkynes for biocompatible double strain-promoted click chemistry.


Type
Article
Change log
Authors
Sharma, Krishna 
Strizhak, Alexander V 
Fowler, Elaine 
Xu, Wenshu 
Abstract

The Sondheimer dialkyne is extensively used in double strain-promoted azide-alkyne cycloadditions. This reagent suffers with poor water-solubility and rapidly decomposes in aqueous solutions. This intrinsically limits its application in biological systems, and no effective solutions are currently available. Herein, we report the development of novel highly water-soluble, stable, and azide-reactive strained dialkyne reagents. To demonstrate their extensive utility, we applied our novel dialkynes to a double strain-promoted macrocyclisation strategy to generate functionalised p53-based stapled peptides for inhibiting the oncogenic p53-MDM2 interaction. These functionalised stapled peptides bind MDM2 with low nanomolar affinity and show p53 activation in a cellular environment. Overall, our highly soluble, stable and azide-reactive dialkynes offer significant advantages over the currently used Sondheimer dialkyne, and could be utilised for numerous biological applications.

Description
Keywords
Alkynes, Animals, Azides, Cell Line, Click Chemistry, Cycloaddition Reaction, Escherichia coli, Humans, Mice, Peptides, Protein Binding, Proto-Oncogene Proteins c-mdm2, Solubility, Triazoles, Tumor Suppressor Protein p53, Water
Journal Title
Org Biomol Chem
Conference Name
Journal ISSN
1477-0520
1477-0539
Volume Title
17
Publisher
Royal Society of Chemistry (RSC)
Rights
All rights reserved
Sponsorship
Engineering and Physical Sciences Research Council (EP/P020291/1)
Engineering and Physical Sciences Research Council (1800602)