Organelle-specific prodrug activation

29 December 2020
Organelle-specific prodrug activation
Overview of the workflow leading to the development of mitochondria-specific bioorthogonal release reaction. Mitochondriotropic tetrazines are selected from a pool of tetrazines based on the right combination of lipophilicity and positive delocalized charge. After addition to cells, the optimized tetrazine reagents react with TCO-caged compounds, enabling their reactivation in a mitochondria-specific manner.

Many drug targets are located in particular cellular compartments known as organelles. Traditional medicinal chemistry approaches focus on bioavailability and tissue targeting, but rarely address drug delivery to specific cellular organelles. A joint team of researchers led by Milan Vrábel has demonstrated that the delivery and release of biologically active molecules from inactive precursors can be achieved in an organelle-specific manner.

To achieve inherent localization of bioorthogonal activation reagents in mitochondria of live cells, the team prepared a series of tetrazine reagents and optimized their structure to include the right combination of lipophilicity and positive delocalized charge.

These mitochondriotropic reagents were then used in experiments with a fluorogenic substrate to study all factors that influence the efficient release of the compound inside the organelle. Using an FDA approved niclosamide as a model compound, they finally demonstrated enhanced toxicity of the drug by its delivery and specific release in mitochondria of human cancer cells.

Beyond organelle-specific prodrug activation, the work can open new avenues for the study and manipulation of biological processes at the subcellular level. The developed methodology is currently being used in the Vrabel group to activate other functional molecules in the organelle and to study, for example, the role of specific metabolites in human disease.

An artistic rendering of a prodrug and its activator penetrating the membrane into a cell, meeting in the mitochondria, reacting with each other, and releasing an active molecule. (Graphic design: Tomáš Belloň / IOCB Prague)

The original article

Rastislav Dzijak, Juraj Galeta, Arcadio Vázquez, Jaroslav Kozák, Marika Matoušová, Helena Fulka, Martin Dračínský, Milan Vrábel, “Structurally Redesigned Bioorthogonal Reagents for Mitochondria-Specific Prodrug Activation” JACS Au 2020, 
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