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Article: Cyclic Dichalcogenides Extend the Reach of Bioreductive Prodrugs to Harness Thiol/Disulfide Oxidoreductases: Applications to

Felber, Jan G / Kitowski, Annabel / Zeisel, Lukas / Maier, Martin S / Heise, Constanze / Thorn-Seshold, Julia / Thorn-Seshold, Oliver

ACS central science

2023 Volume 9, Issue 4, Page(s) 763–776

Abstract: Small-molecule prodrug approaches that can activate cancer therapeutics selectively in tumors are urgently needed. Here, we developed the first antitumor prodrugs designed for activation by thiol-manifold oxidoreductases, targeting the thioredoxin (Trx) ... ...

Abstract	Small-molecule prodrug approaches that can activate cancer therapeutics selectively in tumors are urgently needed. Here, we developed the first antitumor prodrugs designed for activation by thiol-manifold oxidoreductases, targeting the thioredoxin (Trx) system. The Trx system is a critical cellular redox axis that is tightly linked to dysregulated redox/metabolic states in cancer, yet it cannot be addressed by current bioreductive prodrugs, which mainly cluster around oxidized nitrogen species. We instead harnessed Trx/TrxR-specific artificial dichalcogenides to gate the bioactivity of 10 "off-to-on" reduction-activated duocarmycin prodrugs. The prodrugs were tested for cell-free and cellular reductase-dependent activity in 177 cell lines, establishing broad trends for redox-based cellular bioactivity of the dichalcogenides. They were well tolerated
Language	English
Publishing date	2023-03-28
Publishing country	United States
Document type	Journal Article
ISSN	2374-7943
ISSN	2374-7943
DOI	10.1021/acscentsci.2c01465
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Article ; Online: Photoswitchable Epothilone-Based Microtubule Stabilisers Allow GFP-Imaging-Compatible, Optical Control over the Microtubule Cytoskeleton.

Gao, Li / Meiring, Joyce C M / Heise, Constanze / Rai, Ankit / Müller-Deku, Adrian / Akhmanova, Anna / Thorn-Seshold, Julia / Thorn-Seshold, Oliver

Angewandte Chemie (International ed. in English)

2022 Volume 61, Issue 10, Page(s) e202114614

Abstract: Optical methods to modulate microtubule dynamics show promise for reaching the micron- and millisecond-scale resolution needed to decrypt the roles of the cytoskeleton in biology. However, optical microtubule stabilisers are under-developed. We introduce ...

Abstract	Optical methods to modulate microtubule dynamics show promise for reaching the micron- and millisecond-scale resolution needed to decrypt the roles of the cytoskeleton in biology. However, optical microtubule stabilisers are under-developed. We introduce "STEpos" as GFP-orthogonal, light-responsive epothilone-based microtubule stabilisers. They use a novel styrylthiazole photoswitch in a design to modulate hydrogen-bonding and steric effects that control epothilone potency. STEpos photocontrol microtubule dynamics and cell division with micron- and second-scale spatiotemporal precision. They substantially improve potency, solubility, and ease-of-use compared to previous optical microtubule stabilisers, and the structure-photoswitching-activity relationship insights in this work will guide future optimisations. The STEpo reagents can contribute greatly to high-precision research in cytoskeleton biophysics, cargo transport, cell motility, cell division, development, and neuroscience.
MeSH term(s)	Cytoskeleton/chemistry ; Epothilones/chemistry ; Green Fluorescent Proteins/chemistry ; Microtubules/chemistry ; Models, Molecular ; Molecular Structure ; Photochemical Processes ; Styrenes/chemistry ; Thiazoles/chemistry
Chemical Substances	Epothilones ; Styrenes ; Thiazoles ; Green Fluorescent Proteins (147336-22-9)
Language	English
Publishing date	2022-01-20
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2011836-3
ISSN	1521-3773 ; 1433-7851
ISSN (online)	1521-3773
ISSN	1433-7851
DOI	10.1002/anie.202114614
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Article ; Online: Fluorogenic Chemical Probes for Wash-free Imaging of Cell Membrane Damage in Ferroptosis, Necrosis, and Axon Injury.

Mauker, Philipp / Beckmann, Daniela / Kitowski, Annabel / Heise, Constanze / Wientjens, Chantal / Davidson, Andrew J / Wanderoy, Simone / Fabre, Gabin / Harbauer, Angelika B / Wood, Will / Wilhelm, Christoph / Thorn-Seshold, Julia / Misgeld, Thomas / Kerschensteiner, Martin / Thorn-Seshold, Oliver

Journal of the American Chemical Society

2024

Abstract: Selectively labeling cells with damaged membranes is needed not only for identifying dead cells in culture, but also for imaging membrane barrier dysfunction in ... ...

Abstract	Selectively labeling cells with damaged membranes is needed not only for identifying dead cells in culture, but also for imaging membrane barrier dysfunction in pathologies
Language	English
Publishing date	2024-04-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/jacs.3c07662
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Article ; Online: Endolysosomal TRPML1 channel regulates cancer cell migration by altering intracellular trafficking of E-cadherin and β

Frey, Nadine / Ouologuem, Lina / Blenninger, Julia / Siow, Wei-Xiong / Thorn-Seshold, Julia / Stöckl, Jan / Abrahamian, Carla / Fröhlich, Thomas / Vollmar, Angelika M / Grimm, Christian / Bartel, Karin

The Journal of biological chemistry

2023 Volume 300, Issue 1, Page(s) 105581

Abstract: Metastasis still accounts for 90% of all cancer-related death cases. An increase of cellular mobility and invasive traits of cancer cells mark two crucial prerequisites of metastasis. Recent studies highlight the involvement of the endolysosomal cation ... ...

Abstract	Metastasis still accounts for 90% of all cancer-related death cases. An increase of cellular mobility and invasive traits of cancer cells mark two crucial prerequisites of metastasis. Recent studies highlight the involvement of the endolysosomal cation channel TRPML1 in cell migration. Our results identified a widely antimigratory effect upon loss of TRPML1 function in a panel of cell lines in vitro and reduced dissemination in vivo. As mode-of-action, we established TRPML1 as a crucial regulator of cytosolic calcium levels, actin polymerization, and intracellular trafficking of two promigratory proteins: E-cadherin and β
MeSH term(s)	Cadherins/metabolism ; Cell Line, Tumor ; Cell Movement ; Integrin beta1/metabolism ; Neoplasms/metabolism ; NF-kappa B ; Humans ; Lysosomes ; Transient Receptor Potential Channels/genetics ; Transient Receptor Potential Channels/metabolism ; Animals ; Mice ; Calcium/metabolism ; Protein Transport
Chemical Substances	Cadherins ; Integrin beta1 ; NF-kappa B ; MCOLN1 protein, human ; CDH1 protein, human ; Transient Receptor Potential Channels ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2023-12-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2023.105581
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Article ; Online: Pyrrole Hemithioindigo Antimitotics with Near-Quantitative Bidirectional Photoswitching that Photocontrol Cellular Microtubule Dynamics with Single-Cell Precision*.

Sailer, Alexander / Meiring, Joyce C M / Heise, Constanze / Pettersson, Linda N / Akhmanova, Anna / Thorn-Seshold, Julia / Thorn-Seshold, Oliver

Angewandte Chemie (International ed. in English)

2021 Volume 60, Issue 44, Page(s) 23695–23704

Abstract: We report the first cellular application of the emerging near-quantitative photoswitch pyrrole hemithioindigo, by rationally designing photopharmaceutical PHTub inhibitors of the cytoskeletal protein tubulin. PHTubs allow simultaneous visible-light ... ...

Abstract	We report the first cellular application of the emerging near-quantitative photoswitch pyrrole hemithioindigo, by rationally designing photopharmaceutical PHTub inhibitors of the cytoskeletal protein tubulin. PHTubs allow simultaneous visible-light imaging and photoswitching in live cells, delivering cell-precise photomodulation of microtubule dynamics, and photocontrol over cell cycle progression and cell death. This is the first acute use of a hemithioindigo photopharmaceutical for high-spatiotemporal-resolution biological control in live cells. It additionally demonstrates the utility of near-quantitative photoswitches, by enabling a dark-active design to overcome residual background activity during cellular photopatterning. This work opens up new horizons for high-precision microtubule research using PHTubs and shows the cellular applicability of pyrrole hemithioindigo as a valuable scaffold for photocontrol of a range of other biological targets.
MeSH term(s)	Antimitotic Agents/chemistry ; Antimitotic Agents/metabolism ; Cell Cycle ; Cell Death ; Cell Line, Tumor ; HeLa Cells ; Humans ; Indigo Carmine/analogs & derivatives ; Indigo Carmine/chemistry ; Indigo Carmine/metabolism ; Microtubules/chemistry ; Microtubules/metabolism ; Molecular Structure ; Photochemical Processes ; Pyrroles/chemistry ; Pyrroles/metabolism ; Single-Cell Analysis
Chemical Substances	Antimitotic Agents ; Pyrroles ; hemithioindigo ; Indigo Carmine (D3741U8K7L)
Language	English
Publishing date	2021-10-01
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2011836-3
ISSN	1521-3773 ; 1433-7851
ISSN (online)	1521-3773
ISSN	1433-7851
DOI	10.1002/anie.202104794
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Article ; Online: Prior flavivirus immunity skews the yellow fever vaccine response to cross-reactive antibodies with potential to enhance dengue virus infection.

Nature communications

2024 Volume 15, Issue 1, Page(s) 1696

Abstract: The yellow fever 17D vaccine (YF17D) is highly effective but is frequently administered to individuals with pre-existing cross-reactive immunity, potentially impacting their immune responses. Here, we investigate the impact of pre-existing flavivirus ... ...

Abstract	The yellow fever 17D vaccine (YF17D) is highly effective but is frequently administered to individuals with pre-existing cross-reactive immunity, potentially impacting their immune responses. Here, we investigate the impact of pre-existing flavivirus immunity induced by the tick-borne encephalitis virus (TBEV) vaccine on the response to YF17D vaccination in 250 individuals up to 28 days post-vaccination (pv) and 22 individuals sampled one-year pv. Our findings indicate that previous TBEV vaccination does not affect the early IgM-driven neutralizing response to YF17D. However, pre-vaccination sera enhance YF17D virus infection in vitro via antibody-dependent enhancement (ADE). Following YF17D vaccination, TBEV-pre-vaccinated individuals develop high amounts of cross-reactive IgG antibodies with poor neutralizing capacity. In contrast, TBEV-unvaccinated individuals elicit a non-cross-reacting neutralizing response. Using YF17D envelope protein mutants displaying different epitopes, we identify quaternary dimeric epitopes as the primary target of neutralizing antibodies. Additionally, TBEV-pre-vaccination skews the IgG response towards the pan-flavivirus fusion loop epitope (FLE), capable of mediating ADE of dengue and Zika virus infections in vitro. Together, we propose that YF17D vaccination conceals the FLE in individuals without prior flavivirus exposure but favors a cross-reactive IgG response in TBEV-pre-vaccinated recipients directed to the FLE with potential to enhance dengue virus infection.
MeSH term(s)	Humans ; Yellow Fever Vaccine ; Antibodies, Viral ; Antibodies, Neutralizing ; Encephalitis Viruses, Tick-Borne ; Zika Virus ; Zika Virus Infection/prevention & control ; Epitopes ; Immunoglobulin G ; Dengue/prevention & control
Chemical Substances	Yellow Fever Vaccine ; Antibodies, Viral ; Antibodies, Neutralizing ; Epitopes ; Immunoglobulin G
Language	English
Publishing date	2024-02-24
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-45806-x
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Article ; Online: FluoRNT: A robust, efficient assay for the detection of neutralising antibodies against yellow fever virus 17D.

Scheck, Magdalena K / Lehmann, Lisa / Zaucha, Magdalena / Schwarzlmueller, Paul / Huber, Kristina / Pritsch, Michael / Barba-Spaeth, Giovanna / Thorn-Seshold, Oliver / Krug, Anne B / Endres, Stefan / Rothenfusser, Simon / Thorn-Seshold, Julia

PloS one

2022 Volume 17, Issue 2, Page(s) e0262149

Abstract: There is an urgent need for better diagnostic and analytical methods for vaccine research and infection control in virology. This has been highlighted by recently emerging viral epidemics and pandemics (Zika, SARS-CoV-2), and recurring viral outbreaks ... ...

Abstract	There is an urgent need for better diagnostic and analytical methods for vaccine research and infection control in virology. This has been highlighted by recently emerging viral epidemics and pandemics (Zika, SARS-CoV-2), and recurring viral outbreaks like the yellow fever outbreaks in Angola and the Democratic Republic of Congo (2016) and in Brazil (2016-2018). Current assays to determine neutralising activity against viral infections in sera are costly in time and equipment and suffer from high variability. Therefore, both basic infection research and diagnostic population screenings would benefit from improved methods to determine virus-neutralising activity in patient samples. Here we describe a robust, objective, and scalable Fluorescence Reduction Neutralisation Test (FluoRNT) for yellow fever virus, relying on flow cytometric detection of cells infected with a fluorescent Venus reporter containing variant of the yellow fever vaccine strain 17D (YF-17D-Venus). It accurately measures neutralising antibody titres in human serum samples within as little as 24 h. Samples from 32 vaccinees immunised with YF-17D were tested for neutralising activity by both a conventional focus reduction neutralisation test (FRNT) and FluoRNT. Both types of tests proved to be equally reliable for the detection of neutralising activity, however, FluoRNT is significantly more precise and reproducible with a greater dynamic range than conventional FRNT. The FluoRNT assay protocol is substantially faster, easier to control, and cheaper in per-assay costs. FluoRNT additionally reduces handling time minimising exposure of personnel to patient samples. FluoRNT thus brings a range of desirable features that can accelerate and standardise the measurement of neutralising anti-yellow fever virus antibodies. It could be used in applications ranging from vaccine testing to large cohort studies in systems virology and vaccinology. We also anticipate the potential to translate the methodology and analysis of FluoRNT to other flaviviruses such as West Nile, Dengue and Zika or to RNA viruses more generally.
MeSH term(s)	Animals ; Antibodies, Neutralizing/blood ; Antibodies, Neutralizing/immunology ; Antibodies, Viral/blood ; Antibodies, Viral/immunology ; Chlorocebus aethiops ; Fluorescence ; Humans ; Neutralization Tests/economics ; Neutralization Tests/methods ; Vero Cells ; Yellow Fever/blood ; Yellow Fever/immunology ; Yellow Fever/virology ; Yellow fever virus/immunology
Chemical Substances	Antibodies, Neutralizing ; Antibodies, Viral
Language	English
Publishing date	2022-02-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0262149
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Article: Selective cellular probes for mammalian thioredoxin reductase TrxR1: rational design of RX1, a modular 1,2-thiaselenane redox probe.

Zeisel, Lukas / Felber, Jan G / Scholzen, Karoline C / Poczka, Lena / Cheff, Dorian / Maier, Martin S / Cheng, Qing / Shen, Min / Hall, Matthew D / Arnér, Elias S J / Thorn-Seshold, Julia / Thorn-Seshold, Oliver

Chem

2022 Volume 8, Issue 5, Page(s) 1493–1517

Abstract: Quantifying the activity of key cellular redox players is crucial for understanding physiological homeostasis, and for targeting their perturbed states in pathologies including cancer and inflammatory diseases. However, cellularly-selective probes for ... ...

Abstract	Quantifying the activity of key cellular redox players is crucial for understanding physiological homeostasis, and for targeting their perturbed states in pathologies including cancer and inflammatory diseases. However, cellularly-selective probes for oxidoreductase turnover are sorely lacking. We rationally developed the first probes that selectively target the mammalian selenoprotein thioredoxin reductase (TrxR), using a cyclic selenenylsulfide oriented to harness TrxR's unique selenolthiol chemistry while resisting the cellular monothiol background. Lead probe
Language	English
Publishing date	2022-04-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	2869032-1
ISSN	2451-9294 ; 2451-9294 ; 2451-9308
ISSN (online)	2451-9294
ISSN	2451-9294 ; 2451-9308
DOI	10.1016/j.chempr.2022.03.010
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Article ; Online: Cyclic 5-membered disulfides are not selective substrates of thioredoxin reductase, but are opened nonspecifically.

Felber, Jan G / Poczka, Lena / Scholzen, Karoline C / Zeisel, Lukas / Maier, Martin S / Busker, Sander / Theisen, Ulrike / Brandstädter, Christina / Becker, Katja / Arnér, Elias S J / Thorn-Seshold, Julia / Thorn-Seshold, Oliver

Nature communications

2022 Volume 13, Issue 1, Page(s) 1754

Abstract: The cyclic five-membered disulfide 1,2-dithiolane has been widely used in chemical biology and in redox probes. Contradictory reports have described it either as nonspecifically reduced in cells, or else as a highly specific substrate for thioredoxin ... ...

Abstract	The cyclic five-membered disulfide 1,2-dithiolane has been widely used in chemical biology and in redox probes. Contradictory reports have described it either as nonspecifically reduced in cells, or else as a highly specific substrate for thioredoxin reductase (TrxR). Here we show that 1,2-dithiolane probes, such as "TRFS" probes, are nonspecifically reduced by thiol reductants and redox-active proteins, and their cellular performance is barely affected by TrxR inhibition or knockout. Therefore, results of cellular imaging or inhibitor screening using 1,2-dithiolanes should not be interpreted as reflecting TrxR activity, and previous studies may need re-evaluation. To understand 1,2-dithiolanes' complex behaviour, probe localisation, environment-dependent fluorescence, reduction-independent ring-opening polymerisation, and thiol-dependent cellular uptake must all be considered; particular caution is needed when co-applying thiophilic inhibitors. We present a general approach controlling against assay misinterpretation with reducible probes, to ensure future TrxR-targeted designs are robustly evaluated for selectivity, and to better orient future research.
MeSH term(s)	Disulfides/metabolism ; Fluorescence ; Oxidation-Reduction ; Thioredoxin-Disulfide Reductase/metabolism
Chemical Substances	Disulfides ; Thioredoxin-Disulfide Reductase (EC 1.8.1.9)
Language	English
Publishing date	2022-04-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-29136-4
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Article ; Online: Self-reporting styrylthiazolium photopharmaceuticals: mitochondrial localisation as well as SAR drive biological activity.

Gao, Li / Kraus, Yvonne / Stegner, Andrea / Wein, Thomas / Heise, Constanze / von Brunn, Leonie / Fajardo-Ruiz, Elena / Thorn-Seshold, Julia / Thorn-Seshold, Oliver

Organic & biomolecular chemistry

2022 Volume 20, Issue 39, Page(s) 7787–7794

Abstract: Novel photoswitches offering features complementary to the well-established azobenzenes are increasingly driving high-precision research in cellular photopharmacology. Styrylthiazolium (StyTz) and styrylbenzothiazolium (StyBtz) are cellularly ... ...

Abstract	Novel photoswitches offering features complementary to the well-established azobenzenes are increasingly driving high-precision research in cellular photopharmacology. Styrylthiazolium (StyTz) and styrylbenzothiazolium (StyBtz) are cellularly untested
MeSH term(s)	Azo Compounds/pharmacology ; Cell Death ; Coloring Agents ; Mitochondria/metabolism
Chemical Substances	Azo Compounds ; Coloring Agents ; azobenzene (F0U1H6UG5C)
Language	English
Publishing date	2022-10-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2097583-1
ISSN	1477-0539 ; 1477-0520
ISSN (online)	1477-0539
ISSN	1477-0520
DOI	10.1039/d2ob00347c
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