NSPs: chromogenic linkers for fast, selective, and irreversible cysteine modification
Yong Hua1,2, Zhi Zou1,2, Alessandro Prescimone1,2
1Department of Chemistry, University of Basel St. Johannsring 19 CH-4056 Basel Switzerland valentin.koehler@unibas.ch.
Chemical Science
|July 19, 2024
Summary
A new "Click & Lock" reaction enables stable cysteine conjugation by forming an S-C bond. This method offers a versatile and efficient alternative for labeling peptides and proteins.
Area of Science:
- Bioconjugation Chemistry
- Organic Synthesis
- Chemical Biology
Background:
- Cysteine conjugation is crucial for bioconjugation, drug delivery, and diagnostics.
- Existing methods often face limitations in stability, reaction rate, or selectivity.
Purpose of the Study:
- To develop a novel, efficient, and stable method for cysteine conjugation.
- To demonstrate the versatility of the new method in peptide and protein modification.
Main Methods:
- Utilized water-soluble N-alkyl(o-nitrostyryl)pyridinium ions (NSPs) for reaction with sulfhydryl groups.
- Developed the "Click & Lock" reaction sequence involving cyclization and aromatization.
- Employed UV-vis spectroscopy for monitoring labeling yield via spectral shifts.
Main Results:
- Achieved stable S-C sp2-bond formation with cysteine residues.
- Demonstrated successful peptide stapling and protein derivatization, including modified trastuzumab.
- Observed high stability in human plasma and fast reaction kinetics (kapp up to 4.4 M-1 s-1).
Conclusions:
- The "Click & Lock" reaction is a highly selective and efficient method for cysteine conjugation.
- Its favorable properties make it a promising alternative to current bioconjugation techniques.
- The method facilitates advanced applications in chemical biology and therapeutic development.
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