Browse
Submit Data
Databases
API
Help

Dataset Information

29 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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 |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Tetrazine-mediated bioorthogonal prodrug-prodrug activation.

Project description:The selective and biocompatible activation of prodrugs within complex biological systems remains a key challenge in medical chemistry and chemical biology. Herein we report, for the first time, a dual prodrug activation strategy that fully satisfies the principle of bioorthogonality by the symbiotic formation of two active drugs. This dual and traceless prodrug activation strategy takes advantage of the INVDA chemistry of tetrazines (here a prodrug), generating a pyridazine-based miR21 inhibitor and the anti-cancer drug camptothecin and offers a new concept in prodrug activation.

| S-EPMC6148199 | biostudies-literature

Bioorthogonal prodrug activation driven by a strain-promoted 1,3-dipolar cycloaddition.

Project description:Due to the formation of hydrolysis-susceptible adducts, the 1,3-dipolar cycloaddition between an azide and strained trans-cyclooctene (TCO) has been disregarded in the field of bioorthogonal chemistry. We report a method which uses the instability of the adducts to our advantage in a prodrug activation strategy. The reaction of trans-cyclooctenol (TCO-OH) with a model prodrug resulted in a rapid 1,3-dipolar cycloaddition with second-order rates of 0.017 M-1 s-1 and 0.027 M-1 s-1 for the equatorial and axial isomers, respectively, resulting in release of the active compound. 1H NMR studies showed that activation proceeded via a triazoline and imine, both of which are rapidly hydrolyzed to release the model drug. Cytotoxicity of a doxorubicin prodrug was restored in vitro upon activation with TCO-OH, while with cis-cyclooctenol (CCO-OH) no activation was observed. The data also demonstrates the potential of this reaction in organic synthesis as a mild orthogonal protecting group strategy for amino and hydroxyl groups.

| S-EPMC5811098 | biostudies-literature

Synergistic enzymatic and bioorthogonal reactions for selective prodrug activation in living systems.

Project description:Adverse drug reactions (ADRs) restrict the maximum doses applicable in chemotherapy, which leads to failure in cancer treatment. Various approaches, including nano-drug and prodrug strategies aimed at reducing ADRs, have been developed, but these strategies have their own pitfalls. A renovated strategy for ADR reduction is urgently needed. Here, we employ an enzymatic supramolecular self-assembly process to accumulate a bioorthogonal decaging reaction trigger inside targeted cancer cells, enabling spatiotemporally controlled, synergistic prodrug activation. The bioorthogonally activated prodrug exhibits significantly enhanced potency against cancer cells compared with normal cells. This prodrug activation strategy further demonstrates high tumour inhibition efficacy with satisfactory biocompatibility, pharmacokinetics, and safety in vivo. We envision that integration of enzymatic and bioorthogonal reactions will serve as a general small-molecule-based strategy for alleviation of ADRs in chemotherapy.

| S-EPMC6261997 | biostudies-literature

Modular Nanoparticulate Prodrug Design Enables Efficient Treatment of Solid Tumors Using Bioorthogonal Activation.

Project description:Prodrug strategies that facilitate localized and controlled activity of small-molecule therapeutics can reduce systemic exposure and improve pharmacokinetics, yet limitations in activation chemistry have made it difficult to assign tunable multifunctionality to prodrugs. Here, we present the design and application of a modular small-molecule caging strategy that couples bioorthogonal cleavage with a self-immolative linker and an aliphatic anchor. This strategy leverages recently discovered in vivo catalysis by a nanoencapsulated palladium compound (Pd-NP), which mediates alloxylcarbamate cleavage and triggers release of the activated drug. The aliphatic anchor enables >90% nanoencapsulation efficiency of the prodrug, while also allowing >104-fold increased cytotoxicity upon prodrug activation. We apply the strategy to a prodrug formulation of monomethyl auristatin E (MMAE), demonstrating its ability to target microtubules and kill cancer cells only after selective activation by Pd-NP. Computational pharmacokinetic modeling provides a mechanistic basis for the observation that the nanotherapeutic prodrug strategy can lead to more selective activation in the tumor, yet in a manner that is more sensitive to variable enhanced permeability and retention (EPR) effects. Combination treatment with the nanoencapsulated MMAE prodrug and Pd-NP safely blocks tumor growth, especially when combined with a local radiation therapy regimen that is known to improve EPR effects, and represents a conceptual step forward in prodrug design.

| S-EPMC6307086 | biostudies-literature

Coordinating bioorthogonal reactions with two tumor-microenvironment-responsive nanovehicles for spatiotemporally controlled prodrug activation.

Project description:Precise activation of prodrugs in tumor tissues is critical to ensuring specific antitumor efficacy, meanwhile reducing the serious adverse effects. Here, a spatiotemporally controlled prodrug activation strategy was provided by integrating the inverse electron demand Diels-Alder (IEDDA) reaction with two tumor-microenvironment-responsive nanovehicles. The prodrug (Dox-TCO) and [4-(6-methyl-1,2,4,5-tetrazin-3-yl)phenyl]methanamine (Tz) were separately camouflaged into low pH and matrix metalloproteinase 2 (MMP-2) sensitive micellar nanoparticles. After systemic administration, only in the tumor tissues could both the nanovehicles dissociate via responding to two special tumor microenvironments, with Dox-TCO and Tz released and then immediately triggering the prodrug activation through the IEDDA reaction. The hierarchically regulated and locally confined Dox liberation led to dramatically decreased side-effects that were much lower than those of the clinical Doxorubicin Hydrochloride Liposomal Injection (Doxil), while the antitumor therapeutic effect was potent.

| S-EPMC8150104 | biostudies-literature

Riboflavin as a bioorthogonal photocatalyst for the activation of a Pt<sup>IV</sup> prodrug.

Project description:Encouraging developments demonstrate that few transition metal and organometallic catalysts can operate in a bioorthogonal fashion and promote non-natural chemistry in living systems by minimizing undesired side reactions with cellular components. These catalytic processes have potential for applications in medicinal chemistry and chemical biology. However, the stringent conditions of the cell environment severely limit the number of accessible metal catalysts and exogenous reactions. Herein, we report an unorthodox approach and a new type of bioorthogonal catalytic reaction, in which a metal complex is an unconventional substrate and an exogenous biological molecule acts as a catalyst. In this reaction, riboflavin photocatalytically converts a PtIV prodrug into cisplatin within the biological environment. Due to the catalytic activity of riboflavin, cisplatin-like apoptosis is induced in cancer cells under extremely low doses of light, potentially preventing systemic off-target reactions. Photocatalytic and bioorthogonal turnover of PtIV into PtII species is an attractive strategy to amplify the antineoplastic action of metal-based chemotherapeutics with spatio-temporal control.

| S-EPMC5471451 | biostudies-literature

Bioorthogonal 4<i>H</i>-pyrazole "click" reagents.

Project description:4H-Pyrazoles are emerging as useful click reagents. Fluorinating the saturated center enables 4H-pyrazoles to react rapidly as Diels-Alder dienes without a catalyst but compromises the stability of these dienes under physiological conditions. To identify more stable 4H-pyrazoles for bioorthogonal chemistry applications, we investigated the Diels-Alder reactivity and biological stability of three 4-oxo-substituted 4H-pyrazoles. We found that these dienes undergo rapid Diels-Alder reactions with endo-bicyclo[6.1.0]non-4-yne (BCN) while being much more stable to biological nucleophiles than their fluorinated counterparts. We attribute the rapid Diels-Alder reactivity of the optimal oxygen-substituted pyrazole to a combination of antiaromaticity, predistortion, and spirocyclization. Their reactivity and stability suggest that 4-oxo-4H-pyrazoles can be useful bioorthogonal reagents.

| S-EPMC10088812 | biostudies-literature

A Bioorthogonal Reaction of N-Oxide and Boron Reagents.

Project description:The development of bioorthogonal reactions has classically focused on bond-forming ligation reactions. In this report, we seek to expand the functional repertoire of such transformations by introducing a new bond-cleaving reaction between N-oxide and boron reagents. The reaction features a large dynamic range of reactivity, showcasing second-order rate constants as high as 2.3×10(3) M(-1) s(-1) using diboron reaction partners. Diboron reagents display minimal cell toxicity at millimolar concentrations, penetrate cell membranes, and effectively reduce N-oxides inside mammalian cells. This new bioorthogonal process based on miniscule components is thus well-suited for activating molecules within cells under chemical control. Furthermore, we demonstrate that the metabolic diversity of nature enables the use of naturally occurring functional groups that display inherent biocompatibility alongside abiotic components for organism-specific applications.

| S-EPMC4715665 | biostudies-literature

Multifunctional Clickable Reagents for Rapid Bioorthogonal Astatination and Radio-Crosslinking.

Project description:In the past decade, several developments have expanded the chemical toolbox for astatination and the preparation of 211At-labeled radiopharmaceuticals. However, there is still a need for advanced methods for the synthesis of astatinated (bio)molecules to address challenges such as limited in vivo stability. Herein, we report the development of multifunctional 211At-labeled reagents that can be prepared by applying a modular and versatile click approach for rapid assembly. The introduction of tetrazines as bioorthogonal tags enables rapid radiolabeling and radio-crosslinking, which is demonstrated by steric shielding of 211At to significantly increase label stability in human blood plasma.

| S-EPMC6813637 | biostudies-literature

Enrichment-triggered prodrug activation demonstrated through mitochondria-targeted delivery of doxorubicin and carbon monoxide.

Project description:Controlled activation is a critical component in prodrug development. Here we report a concentration-sensitive platform approach for bioorthogonal prodrug activation by taking advantage of reaction kinetics. Using two 'click and release' systems, we demonstrate enrichment and prodrug activation specifically in mitochondria to demonstrate the principle of the approach. In both cases, the payload (doxorubicin or carbon monoxide) was released inside the mitochondrial matrix following the enrichment-initiated click reaction. Furthermore, mitochondria-targeted delivery yielded substantial augmentation of functional biological and therapeutic effects in vitro and in vivo when compared to controls, which did not result in enrichment. This method is thus a platform for targeted drug delivery that is amenable to conjugation with a variety of molecules and is not limited to cell-surface delivery. Taken together, these two 'click and release' pairs clearly demonstrate the concept of enrichment-triggered drug release and the critical feasibility of treating clinically relevant diseases such as acute liver injury and cancer.

| S-EPMC6235738 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data