Structurally Redesigned Bioorthogonal Reagents for Mitochondria-Specific Prodrug Activation

0538814 - ÚOCHB 2022 RIV US eng J - Journal Article
Dzijak, Rastislav - Galeta, Juraj - Vázquez, Arcadio - Kozák, Jaroslav - Matoušová, Marika - Fulka, Helena - Dračínský, Martin - Vrábel, Milan
Structurally Redesigned Bioorthogonal Reagents for Mitochondria-Specific Prodrug Activation.
JACS Au. Roč. 1, č. 1 (2021), s. 23-30. E-ISSN 2691-3704
R&D Projects: GA ČR(CZ) GA19-13811S
EU Projects: European Commission(XE) 677465 - SWEETOOLS
Institutional support: RVO:61388963 ; RVO:68378041
Keywords : bioorthogonal reactions * click-to-release * mitochondria * prodrug activation * tetrazines
OECD category: Organic chemistry; Medicinal chemistry (UEM-P)
Method of publishing: Open access
https://doi.org/10.1021/jacsau.0c00053

The development of abiotic chemical reactions that can be performed in anorganelle-specific manner can provide new opportunities in drug delivery and cell and chemicalbiology. However, due to the complexity of the cellular environment, this remains a significantchallenge. Here, we introduce structurally redesigned bioorthogonal tetrazine reagents thatspontaneously accumulate in mitochondria of live mammalian cells. The attributes leading totheir efficient accumulation in the organelle were optimized to include the right combinationof lipophilicity and positive delocalized charge. The best performing mitochondriotropictetrazines enable subcellular chemical release of TCO-caged compounds as we show usingfluorogenic substrates and mitochondrial uncoupler niclosamide. Our work demonstrates thata shrewd redesign of common bioorthogonal reagents can lead to their transformation intoorganelle-specific probes, opening the possibility to activate prodrugs and m anipulatebiological processes at the subcellular level by using purely chemical tools.
Permanent Link: http://hdl.handle.net/11104/0316967