Issue 47, 2023

Use of pyridazinediones for tuneable and reversible covalent cysteine modification applied to peptides, proteins and hydrogels

Abstract

Reversible cysteine modification has been found to be a useful tool for a plethora of applications such as selective enzymatic inhibition, activity-based protein profiling and/or cargo release from a protein or a material. However, only a limited number of reagents display reliable dynamic/reversible thiol modification and, in most cases, many of these reagents suffer from issues of stability, a lack of modularity and/or poor rate tunability. In this work, we demonstrate the potential of pyridazinediones as novel reversible and tuneable covalent cysteine modifiers. We show that the electrophilicity of pyridazinediones correlates to the rates of the Michael addition and retro-Michael deconjugation reactions, demonstrating that pyridazinediones provide an enticing platform for readily tuneable and reversible thiol addition/release. We explore the regioselectivity of the novel reaction and unveil the reason for the fundamental increased reactivity of aryl bearing pyridazinediones by using DFT calculations and corroborating findings with SCXRD. We also applied this fundamental discovery to making more rapid disulfide rebridging agents in related work. We finally provide the groundwork for potential applications in various areas with exemplification using readily functionalised “clickable” pyridazinediones on clinically relevant cysteine and disulfide conjugated proteins, as well as on a hydrogel material.

Graphical abstract: Use of pyridazinediones for tuneable and reversible covalent cysteine modification applied to peptides, proteins and hydrogels

Supplementary files

Article information

Article type
Edge Article
Submitted
21 Sept. 2023
Accepted
27 Okt. 2023
First published
01 Nov. 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 license

Chem. Sci., 2023,14, 13743-13754

Use of pyridazinediones for tuneable and reversible covalent cysteine modification applied to peptides, proteins and hydrogels

L. N. C. Rochet, C. Bahou, J. P. Wojciechowski, I. Koutsopetras, P. Britton, R. J. Spears, I. A. Thanasi, B. Shao, L. Zhong, D. Bučar, A. E. Aliev, M. J. Porter, M. M. Stevens, J. R. Baker and V. Chudasama, Chem. Sci., 2023, 14, 13743 DOI: 10.1039/D3SC04976K

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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