Dataset Information

Structurally Redesigned Bioorthogonal Reagents for Mitochondria-Specific Prodrug Activation.

ABSTRACT: The development of abiotic chemical reactions that can be performed in an organelle-specific manner can provide new opportunities in drug delivery and cell and chemical biology. However, due to the complexity of the cellular environment, this remains a significant challenge. Here, we introduce structurally redesigned bioorthogonal tetrazine reagents that spontaneously accumulate in mitochondria of live mammalian cells. The attributes leading to their efficient accumulation in the organelle were optimized to include the right combination of lipophilicity and positive delocalized charge. The best performing mitochondriotropic tetrazines enable subcellular chemical release of TCO-caged compounds as we show using fluorogenic substrates and mitochondrial uncoupler niclosamide. Our work demonstrates that a shrewd redesign of common bioorthogonal reagents can lead to their transformation into organelle-specific probes, opening the possibility to activate prodrugs and manipulate biological processes at the subcellular level by using purely chemical tools.

SUBMITTER: Dzijak R

PROVIDER: S-EPMC7851953 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Structurally Redesigned Bioorthogonal Reagents for Mitochondria-Specific Prodrug Activation.

Dzijak Rastislav R Galeta Juraj J Vázquez Arcadio A Kozák Jaroslav J Matoušová Marika M Fulka Helena H Dračínský Martin M Vrabel Milan M

JACS Au 20201215 1

The development of abiotic chemical reactions that can be performed in an organelle-specific manner can provide new opportunities in drug delivery and cell and chemical biology. However, due to the complexity of the cellular environment, this remains a significant challenge. Here, we introduce structurally redesigned bioorthogonal tetrazine reagents that spontaneously accumulate in mitochondria of live mammalian cells. The attributes leading to their efficient accumulation in the organelle were ...[more]

PMID: 33554213

Similar Datasets

Project description:Non-toxic prodrugs have proved of great value in medicinal chemistry programmes for cancer, due to their ability to selectively deliver toxic components at tumour sites once they are activated by a localised mechanism. Since activation of the prodrug to afford the toxic drug is a prerequisite for success of the approach, much interest has focused on the localised chemical and enzymatic mechanisms for activating the prodrugs. Bioorthogonal chemistry has positively impacted this area by providing biocompatible reactions that enable on-demand prodrug activation and active drug release. However, to be effective, it is essential that one of the components of the bioorthogonal reaction is localised at the tumour, in order to initiate the on-demand and on-target activation of the prodrug. Polymers such as poly(ethylene glycol) (PEG) are known to target solid tumours by passive targeting via the enhanced permeability and retention (EPR) effect. In this paper, the feasibility of derivatising long PEG chains to afford bioorthogonal activators (PEG-azide and PEG-tetrazine) for prodrug activation via the Staudinger ligation and the tetrazine ligation reactions, respectively, is evaluated. The molecular weight of the PEG in the activator and the type of linkage in the prodrug moiety were shown to significantly affect the rate of prodrug activation and hence the rate of drug release. In vitro cytotoxicity studies on breast cancer cells (MCF-7 and MDA-MB-231) showed ∼68-76% restoration of the parent drug's cytotoxicity for the Staudinger ligation-based prodrug activation strategy, and 100% restoration of the parent drug's cytotoxicity for the tetrazine ligation-based prodrug activation strategy. Restoration of doxorubicin's ability to intercalate with DNA upon activation of the prodrug by the PEG-activators was also demonstrated via fluorescence spectroscopy. Moreover, conjugation of the tetrazine bioorthogonal activator to a 10 kDa PEG polymer improved its serum stability in comparison with other reported tetrazine activators that completely lose their stability in serum over the same period of time. The feasibility of the combined passive targeting/bioorthogonal prodrug activation approach has therefore been demonstrated using a range of prodrugs, activation mechanisms, and in vitro assays.

Dataset Information

Structurally Redesigned Bioorthogonal Reagents for Mitochondria-Specific Prodrug Activation.

Publications

Structurally Redesigned Bioorthogonal Reagents for Mitochondria-Specific Prodrug Activation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets