Site-Selective Peptide and Protein Functionalization with Cyclopropenium Cations.

Area of Science:

• Organic Chemistry
• Biochemistry
• Chemical Biology

Background:

• Carbocations are key reactive intermediates in organic synthesis, particularly in natural product biosynthesis.
• The application of carbocation chemistry for peptide and protein modification in aqueous environments is largely unexplored.
• Selective modification of peptides and proteins is crucial for developing bioconjugates with tailored functions.

Purpose of the Study:

• To discover and develop a new method for modifying peptides and proteins using aromatic cyclopropenium cations.
• To achieve selective bioconjugation at cysteine residues in aqueous media.
• To explore the utility of the resulting bioconjugates.

Main Methods:

• Development of a novel bioconjugation reaction utilizing aromatic cyclopropenium cations.
• Application of the reaction to peptides and proteins under aqueous conditions.
• Characterization of the site selectivity and efficiency of the bioconjugation.
• Evaluation of the bioconjugates in a thiol-ene radical trapping process.

Main Results:

• A new chemical modification of peptides and proteins with aromatic cyclopropenium cations was established.
• The bioconjugation demonstrated high selectivity for cysteine residues, particularly internal cysteines.
• The reaction is fast, operationally simple, and effective at low concentrations in aqueous media.
• The resulting cyclopropenylated peptides and proteins were utilized in a thiol-ene reaction to form cyclopropane-linked conjugates.

Conclusions:

• A novel and efficient method for site-selective bioconjugation of peptides and proteins at cysteine residues has been developed.
• This cyclopropenylation strategy offers a complementary approach to existing terminal cysteine modification techniques.
• The generated bioconjugates show promise as radical traps, enabling further applications in bioconjugation chemistry.