On-Membrane Supramolecular Assemblies Serving as Bioorthogonal Gating for Melphalan

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Drug Delivery

Background:

• Covalent drugs offer advantages in pharmacodynamics and targeting challenging proteins.
• Achieving selectivity, reactivity, and potency balance is crucial for covalent drug safety and efficacy.

Purpose of the Study:

• To develop a cell-selective bioorthogonal prodrug system to enhance covalent inhibitor selectivity.
• To maintain reactivity and potency while minimizing off-target effects.

Main Methods:

• Utilized enzyme-instructed supramolecular assemblies (EISA) on cancer cell membranes.
• Employed a bioorthogonal prodrug (TCO-Mel) activated by tetrazine (Tz) localized by EISA.
• Investigated disruption of LAT1-mediated transport and Melphalan influx.

Main Results:

• The prodrug design reduced TCO-Mel permeability and cytotoxicity in normal cells.
• Cell-selective EISA enabled targeted Melphalan release and influx into cancer cells.
• Demonstrated potent tumor suppression and good biocompatibility in vivo.

Conclusions:

• The bioorthogonal prodrug strategy successfully enhances selectivity for covalent drugs.
• Regulating the cellular influx of active pharmaceutical ingredients (APIs) is a viable approach for covalent drug design.
• This method offers a promising platform for developing safer and more effective covalent therapies.