Dual-Bioorthogonal Catalysis by a Palladium Peptide Complex.

Area of Science:

• Bioorthogonal Chemistry
• Catalysis
• Medicinal Chemistry

Background:

• Artificial metalloenzymes (ArMs) offer new bioorthogonal reactions for biomedical applications.
• Combination therapy is a key strategy in cancer treatment, but dual catalysis by ArMs remains unexplored.
• Metal deactivation and toxicity are significant challenges in developing ArMs for in vivo applications.

Purpose of the Study:

• To develop a dual-catalytic artificial metalloenzyme for simultaneous synthesis of anticancer drugs.
• To investigate the role of a peptide scaffold in metal protection, toxicity reduction, and catalytic enhancement.
• To demonstrate the feasibility of ArM-mediated combination therapy in human cancer cells.

Main Methods:

• Design and synthesis of a heptapeptidic ArM with a methyl salicylate palladium complex.
• Evaluation of the ArM's catalytic activity for depropargylation and Suzuki-Miyaura cross-coupling reactions.
• Assessment of metal toxicity and deactivation in cellular environments.
• Demonstration of simultaneous drug synthesis and combination therapy in non-small-cell lung cancer (NSCLC) A549 cells.

Main Results:

• The novel peptide ligand protected the palladium complex from deactivation and reduced metal toxicity.
• The peptide scaffold enhanced catalytic efficiency, indicating involvement in the reaction mechanism.
• The methyl salicylate palladium LLEYLKR peptide (2-Pd) successfully synthesized paclitaxel and linifanib simultaneously.
• Achieved combination therapy by dual drug synthesis directly within NSCLC A549 cells.

Conclusions:

• Artificial metalloenzymes can be engineered for dual catalysis, enabling simultaneous synthesis of multiple drugs.
• Peptide scaffolds are effective in mitigating metal toxicity and deactivation while improving catalytic performance.
• This work establishes a new platform for ArM-mediated combination therapy, with potential for in situ drug activation in cancer treatment.