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744 Publications visible to you, out of a total of 744
Drug Repurposing for Kala-Azar

Abstract (Expand)

Objective: Visceral leishmaniasis (VL), a Neglected Tropical Disease caused by Leishmania donovani, remains insufficiently addressed by current therapies due to high toxicity, poor efficacy, and … immunosuppressive complications. This study aimed to identify and characterize repurposed drugs that simultaneously target parasite-encoded and host-associated mechanisms essential for VL pathogenesis. Methods: Two complementary in silico drug repurposing strategies were employed. The first method utilized electron–ion interaction potential (EIIP) screening followed by molecular docking and molecular dynamics (MD) simulations targeting two L. donovani proteins: Rab5a and pteridine reductase 1 (PTR1). The second approach employed network-based drug repurposing using the Drugst.One platform, prioritizing candidates via STAT3-associated gene networks. Predicted drug–target complexes were validated by 100 ns MD simulations, and pharmacokinetic parameters were assessed via ADMET profiling using QikProp v7.0 and SwissADME web server. Results: Entecavir and valganciclovir showed strong binding to Rab5a and PTR1, respectively, with Glide Scores of −9.36 and −9.10 kcal/mol, and corresponding MM-GBSA ΔG_bind values of −14.00 and −13.25 kcal/mol, confirming their stable interactions and repurposing potential. Network-based analysis identified nifuroxazide as the top candidate targeting the host JAK2/TYK2–STAT3 axis, with high stability confirmed in MD simulations. Nifuroxazide also displayed the most favorable ADMET profile, including oral bioavailability, membrane permeability, and absence of PAINS alerts. Conclusions: This study highlights the potential of guanine analogs such as entecavir and valganciclovir, and the nitrofuran derivative nifuroxazide, as promising multi-target drug repurposing candidates for VL. Their mechanisms support a dual strategy targeting both parasite biology and host immunoregulation, warranting further preclinical investigation.

Authors: Biljana Arsić, Budimir S. Ilić, Andreas Maier, Michael Hartung, Jovana Janjić, Jelena Milićević, Jan Baumbach

Date Published: 6th Aug 2025

Publication Type: Journal Article

Human Dialyzable Leukocyte Extract Enhances Albendazole Efficacy and Promotes Th1/Th2-Biased Lymphocyte and Antibody Responses in Peritoneal Cavity of Murine Model of Mesocestoides vogae Infection

Abstract (Expand)

Human leukocyte extract (HLE), a non-immunogenic dialyzable leukocyte preparation (<10 kDa), may serve as a safe adjuvant in immunotherapy. We investigated the effects of albendazole (ABZ), HLE, and … their combination in Mesocestoides vogae infected mice, focusing on lymphoid cells in the peritoneal cavity, the site of larval proliferation and parasite-induced immunosuppression. Peritoneal lymphoid cells were analysed by flow cytometry and qPCR. Cells proliferative responses to ConA, LPS, and parasite excretory/secretory (E/S) antigens, cytokine production (ELISA), IgM and IgG isotypes in exudates and parasite antigen recognition (Western blot) were assessed. Efficacy was measured by larval burden and 14-3-3 gene expression in larvae. HLE combined with ABZ enhanced larval clearance and suppressed 14-3-3 gene expression in larvae. HLE and combination therapy increased CD3+ T cell frequencies, especially CD3+high, reduced regulatory CD3+/IL-10 Tregs and expression of Foxp3+. All treatments diminished CD19+/IL-10+ Bregs, correlating with lower CD9 and Atf3 mRNA levels compared to infected mice. Transcription factors T-bet expression was strongly upregulated, while GATA3 was moderately elevated. IFN-γ production and T/B cell proliferation were restored after HLE and combination therapy, partially, even in the presence of E/S antigens. IgM and total IgG levels against parasite antigens declined, while Th1-associated IgG2a increased in ABZ+HLE and HLE-treated groups. Albendazole failed to reverse the immunosuppressive Treg-type immunity but was more effective in reducing Breg populations and their functions. HLE enhanced ABZ efficacy by restoring Th1 responsiveness, reducing Treg/Breg activity, and modulating antibody profiles. It represents a promising immunomodulatory adjuvant in the treatment of the infections associated with Th2/Treg-driven immunosuppression.

Authors: Gabriela Hrčková, Dagmar Mudroňová, Katarína Reiterová, Serena Cavallero, Ilaria Bellini

Date Published: 21st Jul 2025

Publication Type: Journal Article

Diverse Metabolic Control of Phosphoglucomutases by Bisphosphorylated Sugars in Heterotrophic Bacteria

Abstract (Expand)

Introduction: Phosphoglucomutases (PGM) are crucial for bacterial fitness, environmental survival, pathogenicity, and cell envelope stability, making them potential new targets for combating bacterial … infection and transmission. PGM functionality relies on initial phosphorylation by the activator glucose-1,6-bisphosphate (glucose-1,6-BP). While the origin of glucose-1,6-BP in vertebrates is well investigated, a bacterial glucose-1,6-BP synthase was only recently identified in the cyanobacterium Synechocystis. In this photoautotroph, a secondary PGM (SynPGM2) efficiently catalyzes glucose-1,6-BP synthesis from fructose-1,6-bisphosphate (fructose-1,6-BP) and glucose-1-phosphate or glucose-6-phosphate . A homologous PGM from the heterotrophic Bacteroides salyersiae, belonging to the same conserved domain subfamily (cd05800) as SynPGM2, exhibited similar activity, suggesting that bacterial glucose-1,6-BP synthesis is a feature of this specific subfamily. Methods: To investigate the specificity and regulation of various PGM enzymes from different heterotrophic bacteria, recombinant enzymes were purified and analyzed using enzymatic assays and HPLC-MS. Results: We demonstrate that glucose-1,6-BP synthesis extends beyond the cd5800 subfamily to the cd05801, cd05799, and cd03089 subfamilies. PGMs from Escherichia coli (cd05801 and cd03089), Enterococcus faecium (cd05799), Yersinia enterocolitica (cd05801), and Candidatus Gastranaerophilales (cd05800) catalyze the same fructose-1,6-BP-dependent synthesis reaction of glucose-1,6-BP as SynPGM2. Notably, fructose-1,6-BP, a known inhibitor of some PGM, does not inhibit these bacterial PGMs. Moreover, E. faecium PGM, belonging to the same subfamily as the mammalian glucose 1,6 BP synthase, efficiently catalyzes the mammalian-type 1,3-bisphosphoglycerate-dependent glucose 1,6-BP synthesis reaction. Conclusion: All investigated heterotrophic bacteria appear to use their primary PGM for both PGM activity and activator synthesis, suggesting a more versatile and less specialized role for PGMs in heterotrophic bacteria.

Authors: Janette T. Alford, Marina Borisova-Mayer, Christoph Mayer, Karl Forchhammer

Date Published: 16th Jul 2025

Publication Type: Journal Article

Uncovering the Unusual Inhibition Mechanism of a Trypanosome Alternative Oxidase Inhibitor Displaying Broad-Spectrum Activity against African Animal Trypanosomes

Abstract

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Authors: Godwin U. Ebiloma, Emmanuel O. Balogun, Natsumi Arai, Momoka Otani, Cecilia Baldassarri, Amani Alhejely, Eduardo Cueto-Díaz, Harry P. De Koning, Christophe Dardonville, Tomoo Shiba

Date Published: 4th Jun 2025

Publication Type: Journal Article

Design, Synthesis and Antiplasmodial Activities of a Library of Fluorine-Based 3-Benzylmenadiones

Abstract (Expand)

Plasmodione is a potent early antiplasmodial compound. A metabolic study on mice treated with plasmodione revealed that 6-hydroxy–plasmodione was the main metabolite eliminated in the urine of treated … mice. To block the metabolic pathway in the host, the introduction of fluorine at C-6 of the 3-benzylmenadione core was applied and showed potent antiplasmodial activity similar to that of the plasmodione analogue in vitro. In this work, a library of 38 6-fluoro-3-benzylmenadione analogues (a series) was constructed by incorporating structurally diverse groups in place of the 4-(trifluoromethyl) substituent present in the antiplasmodial plasmodione, via three synthetic routes. All new compounds were tested against the P. falciparum NF54 strain and for cytotoxicity with the rat L6 line. With a fluorine atom at C-6, A-a-21 was revealed to be the only compound from the a series, superior to the 6-H- analogue from the b series, with an IC50 value of 70 nM versus 200 nM. Then, five other fluorine-based 3-benzylmenadiones, in which the fluorine was introduced in various positions of the 3-benzylmenadione core, were synthetized to assist our understanding of the impact of fluorine on antiplasmodial potencies in vitro; in particular, the aim here was to compare the effects of human serum and P. berghei species in these drug screens. This was also conducted in vivo with the P. berghei-infected mouse model. In the P. berghei species assay, PD and the 4′-fluoro-3′-trifluoromethyl-benzylmenadione A-b-9 exhibited a similar antiplasmodial behavior toward P. falciparum versus P. berghei. In the human serum versus Albumax assays, only the 6-fluoro–plasmodione showed a lower shift factor between Albumax assays and human serum conditions, suggesting a lower protein binding for the 6-F-PD compared to plasmodione or A-b-9. In vivo, 6-fluoro–plasmodione proved to be the most potent 3-benzylmenadione, reducing parasitemia by 50% after oral administration at 50 mg/kg.

Authors: Matthieu Roignant, Jimmy Richard, Maxime Donzel, Matthias Rottmann, Pascal Mäser, Elisabeth Davioud-Charvet

Date Published: 3rd Jun 2025

Publication Type: Journal Article

Antileishmanial activity of Ptilostemon chamaepeuce subsp. cyprius

Abstract

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Authors: Chad Schou, Justus Mukavi, Jandirk Sendker, Androulla Miliotou, Vasiliki Christodoulou, Yiannis Sarigiannis, Aleksandar Jovanovic, Thomas J. Schmidt, Panagiotis Karanis

Date Published: 1st May 2025

Publication Type: Journal Article

Synthesis of Tricyclic and Tetracyclic Lactone Derivatives of Thieno[2,3-b]pyrazine or Thieno[2,3-b]quinoline: Preliminary Antitumor and Antiparasitic Activity Evaluation

Abstract (Expand)

Tricyclic and tetracyclic lactone derivatives of thieno[2,3-b]pyrazine or thieno[2,3-b]quinoline, and 2H-pyrones were prepared using different methodologies. Pd/Cu-catalyzed Sonogashira coupling using … Et3N as a base, of methyl 7-bromothieno[2,3-b]pyrazine-6-carboxylate and (het)arylalkynes to yield the Sonogashira ester products, gave also the corresponding tricyclic lactones as minor products. However, the major products did not cyclize with TFA. Tricyclic lactones were then obtained by a tandem one-pot Sonogashira coupling and 6-endo-dig lactonization of 7-bromothieno[2,3-b]pyrazine-6-carboxylic acid with (het)arylalkynes, in good yields. Halogenated tricyclic lactones were synthesized by halocyclization using CuX and NXS. Tetracyclic lactones were synthesized through a Rh(III)-catalyzed formal [4+2] cycloaddition, between thieno[2,3-b]quinoline-2-carboxylic acid and internal alkynes, triggered by C-H activation, with the carboxylic group acting as a directing group. Using the SRB assay, the antitumor activity of both Sonogashira products and lactones was evaluated across five human cancer cell lines (CaCo-2, MCF-7, AGS, HeLa, NCI-H460). The best-performing compound was a Sonogashira product showing a GI50 < 10 µM in all tumor cell lines and low toxicity in PLP2 cells. Additionally, antiparasitic testing against Trypanosoma brucei and Leishmania infantum revealed some compounds with IC50 < 11 µM, though some level of cytotoxicity was observed in THP-1—derived macrophages.

Authors: Maria F. Martins, Francisco Ribeiro, Ana Borges, Ricardo C. Calhelha, Nuno Santarém, Anabela Cordeiro-da-Silva, Maria-João R. P. Queiroz

Date Published: 30th Apr 2025

Publication Type: Journal Article

3'-deoxytubercidin: A potent therapeutic candidate for the treatment of Surra and Dourine.

Abstract (Expand)

Surra and Dourine are widespread diseases caused by two protozoan parasites Trypanosoma brucei evansi and Trypanosoma brucei equiperdum, respectively. A wide range of animals including camels, horses, … cattle and buffaloes are susceptible to infection. These diseases pose a significant socio-economic burden, primarily due to the limited therapeutic options and the complications associated with toxicity and drug resistance, making disease management particularly challenging. This study evaluated the potential of 3'-deoxytubercidin, a previously identified antitrypanosomal nucleoside, as a therapeutic candidate for Surra and Dourine using mouse models. Mice infected with either T. b. evansi or T. b. equiperdum were treated with 3'-deoxytubercidin at a dosage of 6.25 mg kg(-1) administrated intraperitoneally once daily for five consecutive days. The treatment resulted in full cure, as confirmed by both microscopic examination and quantitative PCR, without any observed toxicity. Given the importance of considering the One Health concept in developing new antiparasitic drugs for veterinary use, the environmental impact of 3'-deoxytubercidin was assessed through the ecotoxicity tests on aquatic organisms, conducted in accordance with OECD guidelines. The compound showed some toxicity to Daphnia (EC(50) = 0.54 mg L(-1) in acute Daphnia test) but had no significant adverse effects on green alga at concentrations tested (up to 50 mg L(-1)). This study confirms the suitability of 3'-deoxytubercidin as an effective and safe therapeutic candidate for further development in the treatment of Surra and Dourine, highlighting its potential for improving disease management in affected regions.

Authors: K. Ilbeigi, D. Mabille, R. Roy, M. Bundschuh, E. Van de Velde, F. Hulpia, S. Van Calenbergh, G. Caljon

Date Published: 12th Apr 2025

Publication Type: Journal Article

Pyrazolyl amide-chalcones conjugates: Synthesis and antikinetoplastid activity.

Abstract (Expand)

A series of novel pyrazolyl amide-chalcones conjugates was synthesized in five steps and evaluated against a range of medically important kinetoplastid parasites including Trypanosoma cruzi, Trypanosoma … brucei brucei, Trypanosoma brucei rhodesiense and Leishmania infantum. In addition, the series was also tested for in vitro cytotoxicity activity against human lung fibroblasts and primary mouse macrophages. Among all synthetised compounds, 9b was found to be the most active against T. b. brucei with an IC(50) value of 0.51 +/- 0.06 muM. Against T. b. rhodesiense, 9n was found to be the most potent with an IC(50) value of 0.46 +/- 0.07 muM. While against L. infantum, 9a was found to be most active with an IC(50) value of 7.16 +/- 1.88 muM. Based on the results and SAR, further modifications will be carried out to increase potency.

Authors: D. S. Agarwal, R. M. Beteck, D. Mabille, G. Caljon, L. J. Legoabe

Date Published: 9th Apr 2025

Publication Type: Journal Article

Bridging the gap between research and decision making: A European survey to enhance cooperation in wastewater-based epidemiology (WBE) for illicit drugs

Abstract

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Authors: Jose Antonio Baz-Lomba, AlexanderL.N. van Nuijs, Anna Lenart-Boroń, Anna Péterfi, Anne de l’Eprevier, Arndís Sue Ching Löve, Barbara Kasprzyk-Hordern, Christoph Ort, Elisabetta Simeoni, Ester Heath, Evelina Pridotkiene, Foon Yin Lai, Frederic Béen, Herbert Oberacher, Igor Bodík, Iva Valenčić, Jaroslav Slobodnik, Joakim Strandberg, Kevin Sheeran, Laura Alexandra Smit-Rigter, Leon P. Barron, Lubertus Bijlsma, Magda Psichoudaki, Maria Savvidou, Marit Edland-Gryt, Martin Busch, Mateja Jandl, Michael G. Bertram, Miren López de Alda, Nadine Berndt, Nebile Daglioglu, Nikolaos Thomaidis, Loïc Fabien, Pavla Chomynova, Reinhard Oertel, Sara Castiglioni, Selda Mercan, Serap Annette Akgür, Serge Schneider, Teemu Gunnar, Thomas L. ter Laak, Thomas Thiebault, João Pedro Matias

Date Published: 1st Apr 2025

Publication Type: Journal Article

Allosteric inhibition of trypanosomatid pyruvate kinases by a camelid single-domain antibody.

Abstract (Expand)

African trypanosomes are the causative agents of neglected tropical diseases affecting both humans and livestock. Disease control is highly challenging due to an increasing number of drug treatment … failures. African trypanosomes are extracellular, blood-borne parasites that mainly rely on glycolysis for their energy metabolism within the mammalian host. Trypanosomal glycolytic enzymes are therefore of interest for the development of trypanocidal drugs. Here, we report the serendipitous discovery of a camelid single-domain antibody (sdAb aka Nanobody) that selectively inhibits the enzymatic activity of trypanosomatid (but not host) pyruvate kinases through an allosteric mechanism. By combining enzyme kinetics, biophysics, structural biology, and transgenic parasite survival assays, we provide a proof-of-principle that the sdAb-mediated enzyme inhibition negatively impacts parasite fitness and growth.

Authors: J. E. Pinto Torres, M. Claes, R. Hendrickx, M. Yuan, N. Smiejkowska, P. Van Wielendaele, A. Hacisuleyman, H. De Winter, S. Muyldermans, P. A. M. Michels, M. D. Walkinshaw, W. Versees, G. Caljon, S. Magez, Y. G. Sterckx

Date Published: 31st Mar 2025

Publication Type: Journal Article

Reactions of Plasmodium falciparum Type II NADH: Ubiquinone Oxidoreductase with Nonphysiological Quinoidal and Nitroaromatic Oxidants

Abstract (Expand)

In order to detail the antiplasmodial effects of quinones (Q) and nitroaromatic compounds (ArNO2), we investigated their reduction mechanism by Plasmodium falciparum flavoenzyme type II NADH:ubiquinone … oxidoreductase (PfNDH2). The reactivity of Q and ArNO2 (n = 29) follows a common trend and exhibits a parabolic dependence on their single-electron reduction potential (E71), albeit with significantly scattered data. The reactivity of quinones with similar E71 values increases with their lipophilicity. Quinones are reduced by PfNDH2 in a two-electron way, but ArNO2 are reduced in a single-electron way. The inhibition studies using NAD+ and ADP-ribose showed that quinones oxidize the complexes of reduced enzyme with NADH and NAD+. This suggests that, as in the case of other NDH2s, quinones and the nicotinamide ring of NAD(H) bind at separate sites. A scheme of PfNDH2 catalysis is proposed, consistent with both the observed ‘ping-pong’ mechanism and the presence of two substrate binding sites. Molecular docking showed that Q and ArNO2 bind in a similar manner and that lipophilic quinones have a higher affinity for the binding site. One may expect that PfNDH2 can be partially responsible for the previously observed enhanced antiplasmodial activity of aziridinylbenzoquinones caused by their two-electron reduction, as well as for the redox cycling and oxidative stress-type action of ArNO2.

Authors: Lina Misevičienė, Marie-Pierre Golinelli-Cohen, Visvaldas Kairys, Audronė Marozienė, Mindaugas Lesanavičius, Narimantas Čėnas

Date Published: 11th Mar 2025

Publication Type: Journal Article

The race with microbial factories: Metabolic and protein engineering for production small molecules in plants

Abstract

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Authors: Iryna Gerasymenko, • Sheludko YV, Heribert Warzecha

Date Published: 5th Mar 2025

Publication Type: Conference Proceeding

Nanostructured Lipid Carrier for Intracellular Delivery of a Bis(pyridine-2-carboxamidine) DNA Minor Groove Binder Active against <i>Leishmania</i>

Abstract

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Authors: J. Jonathan Nué-Martinez, Marta Leo-Barriga, Fernando Herranz, Zisis Koutsogiannis, Paul W. Denny, Godwin U. Ebiloma, Christophe Dardonville, Ana González-Paredes

Date Published: 19th Feb 2025

Publication Type: Journal Article

Flavonolignans silybin, silychristin and 2,3-dehydrosilybin showed differential cytoprotective, antioxidant and anti-apoptotic effects on splenocytes from Balb/c mice

Abstract

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Authors: Zuzana Jurčacková, Gabriela Hrčková, Dagmar Mudroňová, Anna Alexovič Matiašová, David Biedermann

Date Published: 15th Feb 2025

Publication Type: Journal Article

BioHackEU24 report: Creating user benefit from ARC-ISA RO-Crate machine-actionability &amp; Increasing FAIRness of digital agrosystem resources by extending Bioschemas

Abstract (Expand)

<p>As part of the BioHackathon Europe 2024, we here report on the progress that both project 19 and project 24 have made during the event. For the purpose of this report we will present the … abstract of both projects and then dive deeper on what work was done during the BioHackathon.</p>

Authors: Sebastian Beier, Daniel Arend, Daniel Bauer, Marco Brandizi, Dominik Brilhaus, Eli Chadwick, Vera Clemens, Michael Robin Crusoe, Manuel Feser, Jonas Grieb, Xiaoming Hu, Abigail Miller, Timo Mühlhaus, Stuart Owen, Maja Rey, Gabriel Schneider, Julian Schneider, Kevin Schneider, Heinrich Lukas Weil, Florian Wetzels

Date Published: 2nd Feb 2025

Publication Type: Report

Synthesis of 1,2,3‐Triazole‐Methyl‐Menadione Derivatives: Evaluation of Electrochemical and Antiparasitic Properties against two Blood‐Dwelling Parasites

Abstract (Expand)

AbstractThis study explores the synthesis and evaluation of novel 1,2,3‐triazole‐methyl‐1,4‐naphthoquinone hybrids, focusing on their electrochemical properties and antiparasitic efficacies against two … human blood‐dwelling parasites Plasmodium falciparum and Schistosoma mansoni. Using copper‐catalyzed azide‐alkyne cycloaddition (CuAAC), a well‐established tool in click chemistry, two synthetic routes were assessed to develop α‐ and β‐[triazole‐methyl]‐menadione derivatives. By optimizing the CuAAC reaction conditions, yields were significantly improved, reaching up to 94 % for key intermediates and resulting in the formation of a library of approximately 30 compounds. Biological evaluation of the compounds in antiparasitic drug assays demonstrated notable antischistosomal potencies, while no significant activity was observed for the same series against P. falciparum parasites. Electrochemical and ‘benzylic’ oxidation studies confirmed that the active ‘benzoyl’ metabolite responsible for the antiplasmodial activity of plasmodione cannot be generated. These findings highlight the potential of triazole‐linked menadione hybrids as promising early candidates for antischistosomal drug development, and provides insights into structure‐activity relationships crucial for future therapeutic strategies.

Authors: Baptiste Dupouy, Tanja Karpstein, Cécile Häberli, Monica Cal, Matthias Rottmann, Pascal Mäser, Jennifer Keiser, Mourad Elhabiri, Elisabeth Davioud‐Charvet

Date Published: 8th Jan 2025

Publication Type: Journal Article

Flexible Metadata Structuring for Research Data Management Through the FAIRDOM-SEEK Platform - Implementing Tailored and Complex Metadata Schemes in SEEK

Abstract (Expand)

Modern research projects increasingly require hybrid metadata approaches that balance adherence to domain-overarching, as well as domain-specific community standards with flexibility for project- or … resource-specific metadata. The FAIRDOM-SEEK platform [1] is a widely used research data management system designed to support diverse domains, from systems biology to health research data, by integrating standardized metadata models (e.g., the ISA framework [2]) with customizable extensions. To address this need, we introduce the Extended Metadata feature in SEEK, which allows researchers to extend core metadata schemas with user-defined fields, hierarchies, and semantic annotations while ensuring interoperability with domain-specific standards. We demonstrate this capability through two use cases: 1. NFDI4Health Local Data Hubs (LDH) [3],[4]: In the context of the German National Research Data Infrastructure for Personal Health Data (NFDI4Health [5]), we have developed Local Data Hubs (LDH) based on the SEEK platform. These hubs support federated data structuring and sharing for sensitive health data from clinical trials, epidemiological studies, and public health research and allow to connect local platforms to the central metadata repository of NFDI4Health, the German Health Study Hub. Given the complexity of the NFDI4Health metadata schema (MDS) [6], the SEEK-based LDH software utilizes the Extended Metadata feature to fully represent the schema, allowing for flexible project-defined metadata extensions. 2. FAIR Data Station (FAIR-DS) [7]: Based on the ISA-framework, with the addition of Observation units from MIAPPE [8], the FAIR-DS is a web application that enables users to create and manage metadata according to FAIR principles. Using packages and terms configured through the UI, it generates Excel spreadsheets which are then populated to gather the metadata. FAIR-DS is then used to validate the metadata and generates RDF datasets representing the content. SEEK has been updated to allow Extended Metadata and Sample Types to be configured automatically via these RDF datasets, and also the content can be imported, and updated, in a single action. The Extended Metadata feature allows users to define additional metadata attributes to be tailored to specific data types, ensuring compliance with standards. When creating a resource, users can select an Extended Metadata type from a dropdown menu, dynamically triggering the rendering of associated metadata input forms within the web interface. This enables seamless integration of resource-specific metadata (e.g., clinical trial study metadata) alongside core descriptive fields. Currently, only instance administrators can create, manage (enable/disable), and delete additional attributes for specific resource types (e.g., ISA items such as Investigation, Study, Assay, as well as Projects and Models) based on specific schemas (e.g., the NFDI4Health MDS). Attribute types range from simple (e.g., string, text, date, integer, Boolean) to complex (e.g., controlled vocabularies linked to ontologies, nested hierarchical structures), with validation rules for mandatory or optional fields. Regular expressions are introduced to ensure correct input formatting. Metadata schemas can be created through backend seed files, JSON uploads, or FAIR-DS RDF imports. These schemas are programmatically accessible via the SEEK REST API, enabling automated metadata creation and retrieval. This ensures interoperability with external tools while adhering to FAIR data principles.

Authors: Xiaoming Hu, Stuart Owen, Frank Meineke, Finn Bacall, Carole Goble, Wolfgang Müller, Martin Golebiewski

Date Published: 2025

Publication Type: Conference Paper

New <i>Trypanosoma brucei</i> acting derivatives incorporating 1-(4-phenyl)adamantane and 1-(4-phenoxyphenyl)adamantane

Abstract (Expand)

New 1-(4-phenyl)adamantane and 1-(4-phenoxyphenyl)adamantane derivatives, functionalised with imidazolines, linear amidines, aminoguanylhydrazone and thiosemicarbazone moieties present activity against … T. brucei .

Authors: Konstantina Stavropoulou, Angeliki Kaimaki, Maria Nikolaou, Ana K. Brown, Andrew Tsotinis, Martin C. Taylor, John M. Kelly, Ioannis P. Papanastasiou

Date Published: 2025

Publication Type: Journal Article

Development of environmentally biodegradable drugs: what are the key challenges?

Abstract

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Authors: Michael G. Bertram, Bob B.M. Wong, Klaus Kümmerer, Manuela Jörg

Date Published: 24th Dec 2024

Publication Type: Journal Article

Click Coupling of Flavylium Dyes with Plasmodione Analogues: Towards New Redox‐Sensitive Pro‐Fluorophores

Abstract (Expand)

Abstract The development of redox‐sensitive molecular fluorescent probes for the detection of redox changes in Plasmodium falciparum ‐parasitized red blood cells remains of interest due to the limitations … ‐parasitized red blood cells remains of interest due to the limitations of current genetically encoded biosensors. This study describes the design, screening and synthesis of new pro‐fluorophores based on flavylium azido dyes coupled by CuAAC click chemistry to alkynyl analogues of plasmodione oxide, the key metabolite of the potent redox‐active antimalarial plasmodione. The photophysical and electrochemical properties of these probes were evaluated, focusing on their fluorogenic responses. The influence of both the redox status of the quinone and the length of the PEG chain separating the fluorophore from the electrophore on the photophysical properties was investigated. The fluorescence quenching by photoinduced electron transfer is reversible and of high amplitude for probes in oxidized quinone forms and fluorescence is reinstated for reduced hydroquinone forms. Our results demonstrate that shortening the PEG chain has the effect of enhancing the fluorogenic response, likely due to non‐covalent interactions between the two chromophores. All these systems were evaluated for their antiparasitic activities and fluorescence imaging suggests the efficacy of the fluorescent flavylium dyes in P. falciparum ‐parasitized red blood cells, paving the way for future parasite imaging studies to monitor cellular redox processes.

Authors: Baptiste Dupouy, Leandro Cotos, Annika Binder, Lucie Slavikova, Matthias Rottmann, Pascal Mäser, Denis Jacquemin, Markus Ganter, Elisabeth Davioud‐Charvet, Mourad Elhabiri

Date Published: 16th Dec 2024

Publication Type: Journal Article

Discovery and Development of an Advanced Lead for the Treatment of African Trypanosomiasis

Abstract

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Authors: Kayhan Ilbeigi, Dorien Mabille, An Matheeussen, Rik Hendrickx, Mathieu Claes, Nick Van Reet, Roel Anthonissen, Fabian Hulpia, Cai Lin, Louis Maes, Clement Regnault, Phillip Whitfield, Rajdeep Roy, Marzuq A. Ungogo, Yann G.-J. Sterckx, Hans De Winter, Birgit Mertens, Mirco Bundschuh, Harry P. De Koning, Serge Van Calenbergh, Guy Caljon

Date Published: 12th Dec 2024

Publication Type: Journal Article

Biological properties and in silico studies of thiazolopyrimidine derivatives active against visceral and cutaneous Leishmania spp. amastigote forms

Abstract

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Authors: Gulsah Bayraktar, Pascal Marchand, Euzébio Guimarães Barbosa, Marilia Cecilia da Silva, Karen Cacilda Weber, Sandrine Cojean, Merve Saylam, Huseyin Istanbullu

Date Published: 1st Dec 2024

Publication Type: Journal Article

Regioselective Synthesis of Potential Non-Quinonoid Prodrugs of Plasmodione: Antiparasitic Properties Against Two Hemoglobin-Feeding Parasites and Drug Metabolism Studies

Abstract (Expand)

Ψ-1,4-naphthoquinones (Ψ-NQ) are non-quinoid compounds in which aromaticity—found in 1,4-naphthoquinones—is broken by the introduction of an angular methyl at C-4a or -8a. This series was designed to … act as prodrugs of 1,4-naphthoquinones in an oxidative environment. Furthermore, from a medicinal chemistry point of view, the loss of planarity of the scaffold might lead to an improved solubility and circumvent the bad reputation of quinones in the pharmaceutical industry. In this work, we illustrated the concept by the synthesis of Ψ -plasmodione regioisomers as prodrugs of the antimalarial plasmodione. The presence of a chiral center introduces a new degree of freedom to be controlled by enantioselectivity and regioselectivity of the cycloaddition in the Diels–Alder reaction. The first strategy that was followed was based on the use of a chiral enantiopure sulfoxide to govern the stereoselective formation of (+)Ψ-NQ or (−)Ψ-NQ, depending on the chirality of the sulfoxide (R or S). New sulfinylquinones were synthesized but were found to be ineffective in undergoing cycloaddition with different dienes under a wide range of conditions (thermal, Lewis acid). The second strategy was based on the use of boronic acid-substituted benzoquinones as auxiliaries to control the regioselectivity. Using this methodology to prepare the (±)Ψ-NQ racemates, promising results (very fast cycloaddition time: ~2 h) were obtained with boronic acid-based quinones 25 and 27 in the presence of 1-methoxy-1,3-butadiene, to generate the 4a- and the 8a-Ψ-plasmodione regioisomers 1 and 2 (synthesized in six steps with a total yield of 10.5% and 4.1%, respectively. As the expected prodrug effect can only be revealed if the molecule undergoes an oxidation of the angular methyl, e.g., in blood-feeding parasites that digest hemoglobin from the host, the antimalarial and the antischistosomal properties of both (±)Ψ-NQ regioisomers were determined in drug assays with Plasmodium falciparum and Schistosoma mansoni. Metabolic studies under quasi-physiological conditions and LC-MS analyses were undertaken to reveal the generation of plasmodione from both the 4a- and the 8a-Ψ-plasmodione regioisomers.

Authors: Elena Cesar-Rodo, Baptiste Dupouy, Cécile Häberli, Jean-Marc Strub, David L. Williams, Pascal Mäser, Matthias Rottmann, Jennifer Keiser, Don Antoine Lanfranchi, Elisabeth Davioud-Charvet

Date Published: 7th Nov 2024

Publication Type: Journal Article

Environmental impacts of drugs against parasitic vector-borne diseases and the need to integrate sustainability into their development and use

Abstract (Expand)

<ns3:p> Background The current scientific discourse on environmental impacts of veterinary medicines mostly focuses on ectoparasiticides. Meanwhile, the environmental impacts of widely prescribed …of widely prescribed drugs for the treatment of human and animal parasitic vector-borne diseases (PVBD) remain largely unexplored. There is thus a need for evidence-based information to support guidelines and protocols for sustainable One Health PVBD drug development and use, while promoting greener research practices. Here, we reflect on the potential environmental impacts of PVBD drugs in current use, and the environmental impact of our research practices for developing new antiparasitics. Methods We conducted a survey of the membership of the “One Health drugs against parasitic vector borne diseases in Europe and beyond” Cooperation in Science and Technology (COST) Action 21111 (OneHealth <ns3:italic>drugs</ns3:italic> ) to assess the current appreciation of sustainable drug design concepts and the extent to which One Health and sustainability principles are integrated into PVBD drug discovery and development. The survey also explored which human, technical, and funding resources are currently used in Europe and neighbouring countries in PVBD drugs research. Results The survey was conducted and analysed by OneHealth <ns3:italic>drugs</ns3:italic> and garnered 89 respondents, representing a response rate of 66% from 32 countries, predominantly European. 87% of participating collaborators worked in Academia; research groups were small (60% with 1–4 researchers) and mostly consist of few researchers, mostly at early career stages (63% <35 years old). Collaborations were mostly between academics, and 60% collaborated with non-European researchers, while funding was mostly from national governments. Motivation for greener research practices was high but there was as yet low implementation of green strategies or the incorporation of ecotoxicological test in drug development workflows, due to cost and unfamiliarity. Conclusions We highlight the need for early-ecotoxicological testing of new drug candidates and suggest best practices as we move towards standardized protocols in developing safe and efficacious PVBD drugs. </ns3:p>

Authors: Clara M. Lima, Elisa Uliassi, Eli S.J. Thoré, Michael G. Bertram, Luis Cardoso, Anabela Cordeiro da Silva, Maria Paola Costi, Harry P. de Koning

Date Published: 4th Nov 2024

Publication Type: Journal Article

Choosing the right partner: Maximizing the efficiency of foreign P450s in plant cells

Abstract

Not specified

Authors: • Sheludko YV, Gerasymenko I

Date Published: 7th Oct 2024

Publication Type: Conference Paper

Hydrazinated geraniol derivatives as potential broad-spectrum antiprotozoal agents.

Abstract (Expand)

Geraniol, a primary component of several essential oils, has been associated with broad-spectrum antiprotozoal activities, although moderate to weak. This study primarily concentrated on the synthesis … of hydrazinated geraniol derivatives as potential antiprotozoal agents. The synthesised compounds were tested in vitro against different parasitic protozoans of clinical relevance, including Trypanosoma brucei brucei, Trypanosoma brucei rhodesiense, Trypanosoma cruzi and Leishmania infantum. Compounds 6, 8, 13, 14 and 15 demonstrated low micromolar activity against the different parasites. Compounds 8, 13, 14 and 15 had the highest efficacy against Trypanosoma brucei rhodesiense, as indicated by their respective IC(50) values of 0.74, 0.56, 1.26 and 1.00 microM. Compounds 6, 14 and 15 displayed the best activity against Trypanosoma brucei brucei, with IC(50) values of 1.49, 1.48 and 1.85 microM, respectively. The activity of compounds 6, 14 and 15 also extended to intracellular Trypanosoma cruzi, with IC(50) values of 5.14, 6.30 and 4.90 microM, respectively. Compound 6, with an IC(50) value of 11.73 microM, and compound 14, with an IC(50) value of 8.14 microM, demonstrated some modest antileishmanial activity.

Authors: J. Jooste, L. J. Legoabe, K. Ilbeigi, G. Caljon, R. M. Beteck

Date Published: 4th Oct 2024

Publication Type: Journal Article

In situ Product Recovery of Microbially Synthesized Ethyl Acetate from the Exhaust Gas of a Bioreactor by Membrane Technology

Abstract (Expand)

Ethyl acetate is at present exclusively produced from fossil resources. Microbial synthesis of this ester from sugar‐rich waste as an alternative is an aerobic process. Ethyl acetate is highly volatile … and therefore stripped with the exhaust gas from the bioreactor which enables in situ product recovery. Previous research on microbial formation of ethyl acetate has focused on the kinetics of ester synthesis and in part on the ester stripping, while the separation of the ester from the exhaust gas has hardly been investigated. A mixed matrix membrane was developed consisting of Silikalite‐1 embedded in polydimethylsiloxane which was installed in a radial–symmetrical membrane module. Evaluation of the separation of ethyl acetate was based on the analysis of the composition of the feed and retentate gas by mass spectrometry. The separation efficiency of the membrane was first tested with varied flows of artificial exhaust gas, containing defined amounts of ethyl acetate. A model for describing the separation process was parametrized by the measured data and used to design a real separation experiment. Ethyl acetate produced from delactosed whey permeate by Kluyveromyces marxianus DSM 5422 in a stirred bioreactor gassed with 0.5 vvm air was successfully separated from the exhaust gas by membranes; 93.6% of the stripped ester was separated. Liquid ethyl acetate was recovered by cooling the permeate gas to ‒78°C, whereby 99.75% of the condensed organic compounds were ethyl acetate. This study demonstrates for the first time that microbially produced and stripped ethyl acetate can be effectively separated from the exhaust gas of bioreactors by membrane technology to obtain the ester in high yield and purity.

Authors: Andreas Hoffmann, Alexander Franz, Christian Löser, Thomas Hoyer, Marcus Weyd, Thomas Walther

Date Published: 30th Sep 2024

Publication Type: Journal Article

3-Benzylmenadiones and their Heteroaromatic Analogues Target the Apicoplast of Apicomplexa Parasites: Synthesis and Bioimaging Studies

Abstract

Not specified

Authors: Baptiste Dupouy, Maxime Donzel, Matthieu Roignant, Sarah Charital, Rodrigue Keumoe, Yoshiki Yamaryo-Botté, Alexander Feckler, Mirco Bundschuh, Yann Bordat, Matthias Rottmann, Pascal Mäser, Cyrille Y. Botté, Stéphanie A. Blandin, Sébastien Besteiro, Elisabeth Davioud-Charvet

Date Published: 27th Sep 2024

Publication Type: Journal Article

Abundant clock proteins point to missing molecular regulation in the plant circadian clock

Abstract (Expand)

Understanding the biochemistry behind whole-organism traits such as flowering time is a longstanding challenge, where mathematical models are critical. Very few models of plant gene circuits use the … absolute units required for comparison to biochemical data. We refactor two detailed models of the plant circadian clock from relative to absolute units. Using absolute RNA quantification, a simple model predicted abundant clock protein levels in Arabidopsis thaliana , up to 100,000 proteins per cell. NanoLUC reporter protein fusions validated the predicted levels of clock proteins in vivo . Recalibrating the detailed models to these protein levels estimated their DNA-binding dissociation constants (Kd). We estimate the same Kd from multiple results in vitro , extending the method to any promoter sequence. The detailed models simulated the Kd range estimated from LUX DNA-binding in vitro but departed from the data for CCA1 binding, pointing to further circadian mechanisms. Our analytical and experimental methods should transfer to understand other plant gene regulatory networks, potentially including the natural sequence variation that contributes to evolutionary adaptation.

Authors: Uriel Urquiza-García, Nacho Molina, Karen J. Halliday, Andrew J. Millar

Date Published: 3rd Sep 2024

Publication Type: Journal Article

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