Gold-Catalyzed Carbonyl Release and its Adaptation for Prodrug Therapy Using Multivalent Lectin-Directed Artificial...

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Nanotechnology

Background:

• Developing artificial metalloenzymes (ArMs) for prodrug therapies requires effective cancer targeting and bioorthogonal activation.
• Existing ArM strategies face challenges in specificity and controlled drug release.

Purpose of the Study:

• To design and validate an artificial metalloenzyme (ArM) prodrug strategy for cancer therapy.
• To investigate cancer cell targeting and bioorthogonal prodrug activation mechanisms.

Main Methods:

• Engineered a Halotag-PduU-ACG lectin fusion protein (HtPA) with a gold catalyst for multivalent lectin-directed ArMs.
• Developed a propargylbenzoxime (PBO) prodrug for gold-catalyzed hydroamination and N-O bond cleavage.
• Utilized HtPA-based ArMs in cell assays to activate PBO prodrugs.

Main Results:

• Demonstrated selective binding of HtPA to sialic acid-rich cancer cells via multivalent lectin interactions.
• Achieved mild and physiological conditions for PBO prodrug activation, releasing carbonyl groups.
• Showcased the potential for carbonyl release to synthesize indole-containing molecules.

Conclusions:

• The developed HtPA-based ArMs offer a promising platform for targeted cancer prodrug therapy.
• This approach provides a new strategy for bioorthogonal activation of prodrugs within cancer cells.
• Further research can explore the therapeutic efficacy of this ArM prodrug system.