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Synthesis and Bioconjugation of Thiol-Reactive Reagents for the Creation of Site-Selectively Modified Immunoconjugates
Published on: March 6, 2019
Modular Assembly of Bioconjugates Enabled by a Pyridine-Based Chemoselective Sequential Conjugation Platform.
Xiaobo Dang1, Chenyang Zhang1, Jinlong Shang1
1Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
Angewandte Chemie (International Ed. in English)
|July 8, 2026
Summary
This study introduces a new pyridine-based platform for site-selective bioconjugation, enabling stable, sequential coupling of amines and Cys residues. This method enhances therapeutic development by creating robust linkages for antibody-drug conjugates (ADCs).
Area of Science:
- Chemical Biology
- Medicinal Chemistry
- Organic Synthesis
Background:
- Site-selective cysteine (Cys) bioconjugation is crucial for developing chemical biology tools and therapeutics.
- Existing methods for amine and Cys conjugation often result in unstable linkages, stereochemical issues, or limited versatility.
- There is a need for robust and modular conjugation strategies for applications like antibody-drug conjugates (ADCs).
Purpose of the Study:
- To develop a novel, programmable platform for chemoselective, sequential conjugation of alkylamines and Cys residues.
- To create stable, non-chiral aryl-Cys linkages with high functional group tolerance and chemoselectivity.
- To demonstrate the platform's utility in late-stage peptide modification, protein functionalization, and ADC construction.
Main Methods:
- A pyridine-based scaffold was designed, incorporating a thianthrenium leaving group and a fluorine handle for sequential conjugation.
- The platform was utilized for orthogonal coupling of alkylamines followed by Cys residues.
- The method was applied to peptide diversification, protein modification, and the synthesis of a HER2-targeting ADC analog.
Main Results:
- The developed platform enables sequential and orthogonal conjugation of alkylamines and Cys to form stable aryl-Cys linkages.
- The conjugation process exhibits high chemoselectivity and broad functional group compatibility.
- A HER2-targeting ADC analog (MRG002) was synthesized, demonstrating enhanced cytotoxicity and improved payload retention in serum.
Conclusions:
- The pyridine-based conjugation platform offers a versatile and efficient approach for site-selective bioconjugation.
- This strategy facilitates the development of advanced therapeutics, including ADCs with improved properties.
- The platform enables modular assembly and late-stage functionalization for diverse bioconjugation applications.
