Site-selective peptide functionalisation mediated via vinyl-triazine linchpins

Area of Science:

• Organic Chemistry
• Bioconjugation Chemistry
• Medicinal Chemistry

Background:

• Site-selective bioconjugation is crucial for developing targeted therapeutics and diagnostics.
• Existing bioconjugation methods often lack selectivity or require harsh reaction conditions.
• The development of novel linkers with orthogonal reactivity is highly desirable.

Purpose of the Study:

• To introduce novel 3-vinyl-1,2,4-triazines derivatives as versatile dual-reactive linkers.
• To demonstrate the selective reactivity of these linkers towards cysteine and strained alkynes.
• To enable efficient and site-specific bioconjugation of peptides.

Main Methods:

• Synthesis of 3-vinyl-1,2,4-triazines derivatives.
• Evaluation of reactivity towards cysteine via conjugate addition.
• Assessment of reactivity with strained alkynes (e.g., bicyclononyne) via inverse electron-demand Diels-Alder (IEDDA) reactions.
• Application in site-selective bioconjugation of biologically relevant peptides.

Main Results:

• 3-vinyl-1,2,4-triazines derivatives exhibit dual reactivity, selectively reacting with cysteine and strained alkynes.
• Conjugate addition with cysteine and IEDDA reactions with bicyclononyne (BCN) proceed with high efficiency and selectivity.
• The developed linker system allows for site-selective bioconjugation of peptides.
• Subsequent rapid and selective reactions with BCN reagents are demonstrated.

Conclusions:

• 3-vinyl-1,2,4-triazines derivatives are effective dual-reactive linkers for bioconjugation.
• This approach offers a versatile platform for orthogonal functionalization of biomolecules.
• The method facilitates precise modification of peptides for various applications in chemical biology and drug development.