Nickel-Catalyzed Antibody Bioconjugation.

Area of Science:

• Biochemistry
• Organic Chemistry
• Chemical Biology

Background:

• Developing biocompatible methods for protein modification is essential for creating advanced chemical probes and biologic therapies.
• Antibody-drug conjugates (ADCs) represent a promising class of next-generation therapeutics requiring efficient bioconjugation strategies.

Purpose of the Study:

• To develop a novel, aqueous, nickel-catalyzed cross-coupling method for the site-specific arylation of cysteine residues on peptides and proteins.
• To demonstrate the utility of this platform for the preparation of antibody-drug conjugates (ADCs).

Main Methods:

• Bottom-up construction of an aqueous nickel-catalyzed cross-coupling reaction.
• Chemospecific arylation of cysteine residues in peptides and proteins.
• Incorporation of diverse arene linkages, small molecules, probes, and cytotoxic payloads.
• Preparation and evaluation of novel ADCs.

Main Results:

• Successful demonstration of aqueous nickel-catalyzed arylation of cysteine residues on peptides and proteins.
• Versatile incorporation of various arene linkages and functional payloads, including cytotoxic agents.
• Construction of novel ADCs with demonstrated target-mediated in vitro cytotoxic activity.

Conclusions:

• The developed bioconjugation platform offers a new, biocompatible method for protein modification.
• This approach facilitates the preparation of diverse ADCs with potential therapeutic applications.
• The method is valuable for drug discovery, enabling the creation of novel ADCs with potent cytotoxic activity.