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34 Publications visible to you, out of a total of 34
A strategic discovery roadmap towards high-quality leads and drug development candidates for kinetoplastid diseases. Part 3: from lead towards a drug development candidate

Abstract (Expand)

Abstract Neglected tropical diseases such as leishmaniasis, Chagas disease, sleeping sickness and animal trypanosomiasis remain a significant global health challenge. This part of the roadmap outlines …e roadmap outlines a streamlined path for progressing from lead identification to a drug development candidate, tailored to the specific needs of kinetoplastid infections. Besides the medicinal upscaling of synthesis, this review highlights key experiments in pharmacology in non-rodent species, toxicology, pharmacokinetics and pharmaceutics. These include but are not limited to early evaluation of safety using refined in vitro and in vivo methods to enhance predictive value, bioavailability and distribution to target tissues, and formulation strategies leveraging various delivery systems to optimize efficacy and safety. Environmental toxicity is also addressed proactively, for which in silico tools are presented. Collectively, this roadmap provides a practical, scalable approach to deliver high-quality drug candidates capable of addressing the urgent needs for kinetoplastid diseases (Figure 1).

Authors: Sarah Hendrickx, Kayhan Ilbeigi, Eli S J Thoré, Michael G Bertram, Estefanía Calvo-Alvarez, Sener Cintesun, Ana Isabel Olías-Molero, María Jesús Corral, Marta Mateo-Barrientos, Jérôme Estaquier, Sébastien Pomel, José María Alunda, Sheraz Gul, Katrien Van Bocxlaer, Frédéric Frézard, Joana Tavares, Anabela Cordeiro Da Silva, Maria Paola Costi, Louis Maes, Guy Caljon

Date Published: 5th May 2026

Publication Type: Journal Article

The EamA metabolite transporter does not affect antileishmanial drug susceptibility.

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Leishmaniasis is a major neglected tropical disease, exists in 98 countries and constitutes a global public health threat. As chemotherapy is confronted with drug resistance and treatment failure, … understanding the underlying mechanisms and continued drug discovery efforts are needed in the fight against leishmaniasis. A previous cosmid-based overexpression study suggested a role for EamA (LINF_020008400), annotated as a putative drug-metabolite transporter, in resistance to novel antileishmanial oxaboroles. To assess fitness cost and drug susceptibility, gene deficient Leishmania infantum lines were generated using CRISPR-Cas9 gene editing and overexpression from the ssu locus was achieved using the pLEXSY system. While in vitro parasite growth and survival were unchanged compared to control lines, the intracellular burden of the null mutant was lower. In vitro exposure to current antileishmanial drugs and several novel leads revealed an unchanged drug sensitivity profile in extracellular and intramacrophage assays. Similarly, the overexpression lines showed a significantly lower infection rate, but their drug susceptibility profiles showed no significant differences from the control. Collectively, these data suggest that -under the tested conditions- LINF_020008400 is not essential for parasite fitness, host cell infectivity and survival following exposure to antiparasitic drugs.

Authors: R. Ahmad, G. Gastoldi, S. T. Wong, A. Baeza Garcia, G. Caljon

Date Published: 19th Apr 2026

Publication Type: Journal Article

A strategic discovery roadmap towards high-quality leads and drug development candidates for kinetoplastid diseases. Part 1: setting the stage

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Abstract Given the impact of kinetoplastid diseases, the limited therapeutic options and risk of treatment failure, continued research efforts to discover novel drug entities are required. The ambition …ired. The ambition to deliver drug development candidates has mainly been taken on board by academia and public private partnerships, but remains highly challenging because of the lack of adequate funding and standardized laboratory procedures. Establishing a systematic roadmap of experiments and decision criteria to attain high-quality leads and drug candidates with lower risk profiles remains the logical path to deliver more compelling proof-of-concepts for impactful diseases, such as African trypanosomiasis, Chagas disease and visceral and cutaneous leishmaniasis. In a three-part series, a structured roadmap from ‘hit finding’ to ‘drug development candidate’ is presented with a focus on the minimal essential data package, laboratory experimental models and endpoints. Part 1 introduces the concept of a pragmatic framework with reference to specific preclinical R&D stages: (i) hit finding, (ii) hit profiling, (iii) lead definition and (iv) drug development candidate to support a more focused early development path that remains accessible to engaged stakeholders. The experiment-oriented roadmap is presented in the next parts addressing the discovery and characterization of confirmed hits (Part 2) and the lead discovery phase towards identification of a drug development candidate (Part 3). Although specifically focusing on kinetoplastid diseases, the principles also apply to small-molecule preclinical R&D against other microbial diseases, evidently with specific adaptation of the primary pharmacology models.

Authors: Sarah Hendrickx, Kayhan Ilbeigi, Eli S J Thoré, Michael G Bertram, Estefanía Calvo-Alvarez, Sener Cintesun, Ana Isabel Olías-Molero, María Jesús Corral, Marta Mateo-Barrientos, Jérôme Estaquier, Sébastien Pomel, José María Alunda, Sheraz Gul, Katrien Van Bocxlaer, Frédéric Frézard, Joana Tavares, Anabela Cordeiro Da Silva, Maria Paola Costi, Louis Maes, Guy Caljon

Date Published: 3rd Apr 2026

Publication Type: Journal Article

Multifaceted biological and computational assessment of aromatic and N-heteroaromatic non-substituted thiosemicarbazones.

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Thiosemicarbazones (TSCs) constitute a pharmacologically versatile class of compounds with documented antimicrobial, antiviral, and anticancer properties. Despite their therapeutic potential, their … biological mechanisms and pharmacokinetic behaviour remain insufficiently characterized. In this study, we investigated the biological activity of the library consisting of 28 aromatic and heteroaromatic compounds against twelve cancer cell and two normal cell lines, and four parasites. Six N-heteroaromatic thiosemicarbazones based on pyridine (13, 14, and 18), quinoline (24 and 26), and indole (27) moieties show promising anticancer and/or antiparasitic activity. Density functional theory (DFT) calculations indicated that the biological activity of 13, 14, 18, 24, and 26 arises from their ability to chelate d-metals, whereas 27 operates via a distinct mechanism. The passive gastrointestinal absorption and Human serum albumin (HSA) binding ability of these six compounds were evaluated by the Parallel artificial membrane permeability (PAMPA) technique and high-performance affinity chromatography, respectively. Compound 26 emerged as the most potent and selective anticancer agent and was further examined through cell cycle profiling, caspase-3/7 activation, DNA double-strand break quantification, 3D spheroid assays, and an in ovo chorioallantoic membrane (CAM) model, supported by HSA docking and molecular dynamics simulations. Collectively, our results indicate that 26 is a selective anticancer agent that exerts cytotoxic effects preferentially in cancer cells, by inducing apoptosis and DNA double-strand breaks.

Authors: N. Macijewska, P. Ristic, A. Kallingal, M. Gulea, M. Donnard, N. Girard, A. Matheeussen, N. Van Pelt, G. Caljon, V. Dobricic, J. Boskovic, M. Popovic-Nikolic, K. Nikolic, M. Zloh, V. Blagojevic, T. Todorovic, N. Filipovic

Date Published: 25th Mar 2026

Publication Type: Journal Article

A strategic discovery roadmap towards high-quality leads and drug development candidates for kinetoplastid diseases. Part 2: from molecule to confirmed hit

Abstract (Expand)

Abstract Given the medical importance and challenges related to kinetoplastid diseases, a strategic roadmap is needed for the identification of high-quality leads and drug development candidates. Within …candidates. Within the aim to deliver more compelling proof-of-concept read-outs, this part proposes a systematic flow-chart of laboratory experiments and decision criteria, focusing on African trypanosomiasis, Chagas disease and visceral and cutaneous leishmaniasis. Next to precision experimental design and reporting, an overview is provided of various complementary laboratory models reproducing kinetoplastid infection and disease. Technical aspects of conventional in vitro and in vivo approaches and, more recently, in silico methods are presented with reference to specific preclinical R&D stages from ‘hit finding’ to ‘profiling of a confirmed hit’, covering the expertise areas of medicinal chemistry, primary pharmacology, (eco)toxicology, pharmacokinetics and pharmaceutics (Figure 1).

Authors: Sarah Hendrickx, Kayhan Ilbeigi, Eli S J Thoré, Michael G Bertram, Estefanía Calvo-Alvarez, Sener Cintesun, Ana Isabel Olías-Molero, María Jesús Corral, Marta Mateo-Barrientos, Jérôme Estaquier, Sébastien Pomel, José María Alunda, Sheraz Gul, Katrien Van Bocxlaer, Frédéric Frézard, Joana Tavares, Anabela Cordeiro Da Silva, Maria Paola Costi, Louis Maes, Guy Caljon

Date Published: 4th Mar 2026

Publication Type: Journal Article

Cytotoxicity and Antimicrobial Activity of GaMF1 Analogs.

Abstract (Expand)

Recent studies have identified the mycobacterial adenosine triphosphate synthase inhibitor GaMF1 and its structural analogs as compounds with noteworthy antituberculosis activity. Despite these promising … results, a significant limitation remains their cytotoxicity against human cells, which, in its current state, overshadows the therapeutic potential. Therefore, addressing this off-target toxicity is essential for the further development of these compounds as viable drug candidates. In this study, we systematically explored structural modifications of the original GaMF1 scaffold with the primary aim of reducing its inherent cytotoxicity. Individual regions of the parent structure were progressively replaced, enabling the identification of substituents that effectively attenuate cytotoxic effects. Importantly, these structural refinements also led to the emergence of pronounced antiparasitic activity, particularly against trypanosomal species such as Trypanosoma cruzi, Trypanosoma brucei brucei, and Trypanosoma brucei rhodesiense. These findings suggest that the biological potential of this compound class extends beyond what has previously been described. Furthermore, we evaluated the cytotoxicity of selected derivatives against a panel of tumor cell lines, where some compounds showed encouraging antiproliferative effects.

Authors: J. Chasak, P. Vyvlecka, I. Nemec, A. Matheeussen, N. Van Pelt, P. Cos, G. Caljon, V. Krystof, L. Brulikova

Date Published: 25th Feb 2026

Publication Type: Journal Article

Thiazolidinones and related analogues as efficient antitrypanosomal agents.

Abstract (Expand)

We designed and synthesised a series of thiazolidinediones and related analogues and evaluated their antiparasitic activity. A structure-activity relationship (SAR) study focused on modifications of … specific parts of the molecule revealed derivatives that displayed significant activity against Trypanosoma brucei species. Notably, the analogue 6i exhibited exceptional activity, with an EC(50) value of 30 nM and a selectivity index of >2000, against the protozoan Trypanosoma brucei rhodesiense, which causes human African trypanosomiasis. Additionally, compounds 6a, 6k, 7e, and 18 demonstrated antitrypanosomal activities in the less than 5 muM range. Our most active analogue 6i represents a promising candidate for further preclinical development.

Authors: M. Kolarik, K. Ilbeigi, G. Caljon, L. Brulikova

Date Published: 1st Dec 2025

Publication Type: Journal Article

Sustainable Antiparasitic Agents from an Agro-Industrial Waste: Mitochondria-Targeting Cashew Nutshell Liquid-Derived Phosphonium and Ammonium Salts

Abstract

Not specified

Authors: Bianca Martinengo, Cecilia Baldassarri, Kayhan Ilbeigi, Hamed E. Alkhalaf, Aditya Sarode, Ehab Kotb Elmahallawy, Ba Reum Kwon, Amos Sarpong Agyei, Aigerim Abdimanova, Ludmila Ferreira de Almeida Fiuza, Raquel Azevedo, Ketlym da Conceição, Marcos Meuser Batista, Ellyêssa Nascimento Borges, Kleber Santiago Freitas e Silva, Éder Jéferson Souza Cardoso, Natália Cipriano Monteiro, Lais Flavia Nunes Lemes, Luiz Antonio Soares Romeiro, Antonio Alonso, Maria de Nazaré Correia Soeiro, Guy Caljon, Bryan W. Brooks, Harry P. De Koning, Maria Laura Bolognesi

Date Published: 8th Sep 2025

Publication Type: Journal Article

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

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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

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

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

Abstract

Not specified

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

Hydrazinated geraniol derivatives as potential broad-spectrum antiprotozoal agents.

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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

Effect of Leishmania infantum infection on B cell lymphopoiesis and memory in the bone marrow and spleen.

Abstract (Expand)

Visceral leishmaniasis (VL) is characterized by an uncontrolled infection of internal organs such as the spleen, liver and bone marrow (BM) and can be lethal when left untreated. No effective vaccination … is currently available for humans. The importance of B cells in infection and VL protective immunity has been controversial, with both detrimental and protective effects described. VL infection was found in this study to increase not only all analyzed B cell subsets in the spleen but also the B cell progenitors in the BM. The enhanced B lymphopoiesis aligns with the clinical manifestation of polyclonal hypergammaglobulinemia and the occurrence of autoantibodies. In line with earlier reports, flow cytometric and microscopic examination identified parasite attachment to B cells of the BM and spleen without internalization, and transformation of promastigotes into amastigote morphotypes. The interaction appears independent of IgM expression and is associated with an increased detection of activated lysosomes. Furthermore, the extracellularly attached amastigotes could be efficiently transferred to infect macrophages. The observed interaction underscores the potentially crucial role of B cells during VL infection. Additionally, using immunization against a fluorescent heterologous antigen, it was shown that the infection does not impair immune memory, which is reassuring for vaccination campaigns in VL endemic areas.

Authors: L. Dirkx, M. Loyens, S. I. Van Acker, D. Bulte, M. Claes, M. Radwanska, S. Magez, G. Caljon

Date Published: 31st Aug 2024

Publication Type: Journal Article

A breath of fresh air: impact of insect-borne protozoan parasites on the respiratory system.

Abstract (Expand)

The protozoan parasites Plasmodium, Leishmania, and Trypanosoma are transmitted by hematophagous insects and cause severe diseases in humans. These infections pose a global threat, particularly in … low-resource settings, and are increasingly extending beyond the current endemic regions. Tropism of parasites is crucial for their development, and recent studies have revealed colonization of noncanonical tissues, aiding their survival and immune evasion. Despite receiving limited attention, cumulative evidence discloses the respiratory system as a significant interface for host-pathogen interactions, influencing the course of (co)infection and disease onset. Due to its pathophysiological and clinical implications, we emphasize that further research is needed to better understand the involvement of the respiratory system and its potential to improve prevention, diagnosis, treatment, and interruption of the chain of transmission.

Authors: S. Araujo, D. Mabille, A. B. Garcia, G. Caljon

Date Published: 9th Aug 2024

Publication Type: Journal Article

N-Pyrazolyl- and N-Triazolylamines and -Ureas as Antileishmanial and Antitrypanosomal Drugs.

Abstract (Expand)

Three types of modifications of antileishmanial pyrazole lead compounds 7 and 8 were conducted to expand understanding of the relationships between structural features and antileishmanial/antitrypanosomal … activity: (1) the pyrazole core was retained or replaced by a 1,2,4-triazole ring; (2) various aryl moieties including 2-fluorophenyl, pyridin-3-yl and pyrazin-2-yl rings were attached at 3-position of the core azole; (3) either arylmethylamino or ureido substituents were introduced at 5-position of the azole core. The synthesis followed established routes starting with esters 9 or 15 and anhydride 21. The synthesized 3-arylpyrazoles and 3-aryl-1,2,4-triazoles had only very low antileishmanial activity. The 2-fluorophenyl-substituted pyrazole 18c revealed the highest antileishmanial activity of this series of compounds, but its IC(50) value (20 muM) still indicates low activity. However, low micromolar antitrypanosomal activity was detected for the pyridin-3-yl-substituted pyrazoles 12b (IC(50)=4.7 muM) and 14a (IC(50)=2.1 muM). Their IC(50) values are comparable with the IC(50) values of the reference compounds benznidazole and nifurtimox. Whereas only low unspecific cytotoxicity at the primary peritoneal mouse macrophages (PMM) was detected, considerable cytotoxicity at MRC-5 human fibroblast cells was found for both pyrazoles 12b an 14a. The activity of pyrazole 12b against T. cruzi is 4-fold higher than its unspecific MRC-5 cytotoxicity.

Authors: T. Winge, L. Imberg, B. Perry, A. Matheeussen, G. Caljon, D. Kalinin, B. Wunsch

Date Published: 1st Aug 2024

Publication Type: Journal Article

Spliced-Leader RNA as a Dynamic Marker for Monitoring Viable Leishmania Parasites During and After Treatment.

Abstract (Expand)

Accurate detection of viable Leishmania parasites is critical for evaluating visceral leishmaniasis (VL) treatment response at an early timepoint. We compared the decay of kinetoplast DNA (kDNA) and … spliced-leader RNA (SL-RNA) in vitro, in vivo, and in a VL patient cohort. An optimized combination of blood preservation and nucleic acid extraction improved efficiency for both targets. SL-RNA degraded more rapidly during treatment than kDNA, and correlated better with microscopic examination. SL-RNA quantitative polymerase chain reaction emerges as a superior method for dynamic monitoring of viable Leishmania parasites. It enables individualized treatment monitoring for improved prognoses and has potential as an early surrogate endpoint in clinical trials.

Authors: R. Hendrickx, R. Melkamu, D. Tadesse, T. Teferi, P. B. Feijens, M. Vleminckx, S. van Henten, F. Alves, T. Shibru, J. van Griensven, G. Caljon, M. Pareyn

Date Published: 25th Jul 2024

Publication Type: Journal Article

Metronidazole Interaction with Cu(2+) and Zn(2+): Speciation Study in Aqueous Solution and Biological Activity Evaluation.

Abstract (Expand)

Metronidazole (2-methyl-5-nitro-1H-imidazole-1-ethanol, MNZ) is a well-known and widely used drug for its excellent activity against various anaerobic bacteria and protozoa. The purpose of this study … is to elucidate the ability of MNZ to form metal complexes with Cu(2+) and Zn(2+) and to demonstrate that complexation increases its bioactivity profile against different pathogenic microorganisms. The interaction of MNZ with Cu(2+) and Zn(2+) was investigated in NaCl aqueous solution under different conditions of temperature (15, 25, and 37 degrees C) and ionic strength (0.15, 0.5, and 1 mol L(-1)) by potentiometric and spectrophotometric titrations. The obtained speciation models include two species for the Cu(2+)-containing system, namely, CuL and CuL(2), and three species for the Zn(2+)-containing system, namely, ZnLH, ZnL, and ZnLOH. The formation constants of the species were calculated and their dependence on temperature and ionic strength evaluated. Comparison of the sequestering ability of MNZ under physiological conditions revealed a capacity toward Cu(2+) higher than that toward Zn(2+). A simulation under the same conditions also showed a significant percentage of the Cu(2+)-MNZ species. The biological assessments highlighted that the complexation of MNZ with Cu(2+) has a relevant impact on the potency of the drug against two Trypanosoma spp. (i.e., T. b. brucei and T. b. rhodesiense) and one gram-(-) bacterial species (i.e., Escherichia coli). It is noteworthy that the increased potency upon complexation with Cu(2+) did not result in cytotoxicity against MRC-5 human fetal lung fibroblasts and primary peritoneal mouse macrophages.

Authors: F. Carnamucio, C. Foti, N. Micale, N. Van Pelt, A. Matheeussen, G. Caljon, O. Giuffre

Date Published: 2nd Jul 2024

Publication Type: Journal Article

In Vivo Bioluminescence Imaging Reveals Differences in Leishmania infantum Parasite Killing Kinetics by Antileishmanial Reference Drugs.

Abstract (Expand)

The bioluminescent Leishmania infantum BALB/c mouse model was used to evaluate the parasiticidal drug action kinetics of the reference drugs miltefosine, paromomycin, sodium stibogluconate, and liposomal … amphotericin B. Infected mice were treated for 5 days starting from 7 days post-infection, and parasite burdens were monitored over time via bioluminescence imaging (BLI). Using nonlinear regression analyses of the BLI signal, the parasite elimination half-life (t(1/2)) in the liver, bone marrow, and whole body was determined and compared for the different treatment regimens. Significant differences in parasiticidal kinetics were recorded. A single intravenous dose of 0.5 mg/kg liposomal amphotericin B was the fastest acting with a t(1/2) of less than 1 day. Intraperitoneal injection of paromomycin at 320 mg/kg for 5 days proved to be the slowest with a t(1/2) of about 5 days in the liver and 16 days in the bone marrow. To conclude, evaluation of the cidal kinetics of the different antileishmanial reference drugs revealed striking differences in their parasite elimination half-lives. This BLI approach also enables an in-depth pharmacodynamic comparison between novel drug leads and may constitute an essential tool for the design of potential drug combinations.

Authors: S. Hendrickx, P. B. Feijens, F. Escudie, E. Chatelain, L. Maes, G. Caljon

Date Published: 14th Jun 2024

Publication Type: Journal Article

Novel quinoline derivatives with broad-spectrum antiprotozoal activities.

Abstract (Expand)

Several quinoline derivatives incorporating arylnitro and aminochalcone moieties were synthesized and evaluated in vitro against a broad panel of trypanosomatid protozoan parasites responsible for … sleeping sickness (Trypanosoma brucei rhodesiense), nagana (Trypanosoma brucei brucei), Chagas disease (Trypanosoma cruzi), and leishmaniasis (Leishmania infantum). Several of the compounds demonstrated significant antiprotozoal activity. Specifically, compounds 2c, 2d, and 4i displayed submicromolar activity against T. b. rhodesiense with half-maximal effective concentration (EC(50)) values of 0.68, 0.8, and 0.19 microM, respectively, and with a high selectivity relative to human lung fibroblasts and mouse primary macrophages ( approximately 100-fold). Compounds 2d and 4i also showed considerable activity against T. b. brucei with EC(50) values of 1.4 and 0.4 microM, respectively.

Authors: C. B. Hartman, P. S. Dube, L. J. Legoabe, N. Van Pelt, A. Matheeussen, G. Caljon, R. M. Beteck

Date Published: 3rd Jun 2024

Publication Type: Journal Article

N(6)-methyltubercidin gives sterile cure in a cutaneous Leishmania amazonensis mouse model.

Abstract (Expand)

Leishmania is a trypanosomatid parasite that causes skin lesions in its cutaneous form. Current therapies rely on old and expensive drugs, against which the parasites have acquired considerable resistance. … Trypanosomatids are unable to synthesize purines relying on salvaging from the host, and nucleoside analogues have emerged as attractive antiparasitic drug candidates. 4-Methyl-7-beta-D-ribofuranosyl-7H-pyrrolo[2,3-d]pyrimidine (CL5564), an analogue of tubercidin in which the amine has been replaced by a methyl group, demonstrates activity against Trypanosoma cruzi and Leishmania infantum. Herein, we investigated its in vitro and in vivo activity against L. amazonensis. CL5564 was 6.5-fold (P = 0.0002) more potent than milteforan (ML) against intracellular forms in peritoneal mouse macrophages, and highly selective, while combination with ML gave an additive effect. These results stimulated us to study the activity of CL5564 in mouse model of cutaneous Leishmania infection. BALB/c female and male mice infected by L. amazonensis treated with CL5564 (10 mg kg(-1), intralesional route for five days) presented a >93% reduction of paw lesion size likely ML given orally at 40 mg kg(-1), while the combination (10 + 40 mg kg(-1) of CL5564 and ML, respectively) caused >96% reduction. The qPCR confirmed the suppression of parasite load, but only the combination approach reached 66% of parasitological cure. These results support additional studies with nucleoside derivatives.

Authors: C. Present, R. D. Girao, C. Lin, G. Caljon, S. Van Calenbergh, O. Moreira, L. A. S. Ruivo, M. M. Batista, R. Azevedo, D. D. G. J. Batista, M. N. C. Soeiro

Date Published: 17th May 2024

Publication Type: Journal Article

Long-term hematopoietic stem cells trigger quiescence in Leishmania parasites.

Abstract (Expand)

Addressing the challenges of quiescence and post-treatment relapse is of utmost importance in the microbiology field. This study shows that Leishmania infantum and L. donovani parasites rapidly enter … into quiescence after an estimated 2-3 divisions in both human and mouse bone marrow stem cells. Interestingly, this behavior is not observed in macrophages, which are the primary host cells of the Leishmania parasite. Transcriptional comparison of the quiescent and non-quiescent metabolic states confirmed the overall decrease of gene expression as a hallmark of quiescence. Quiescent amastigotes display a reduced size and signs of a rapid evolutionary adaptation response with genetic alterations. Our study provides further evidence that this quiescent state significantly enhances resistance to treatment. Moreover, transitioning through quiescence is highly compatible with sand fly transmission and increases the potential of parasites to infect cells. Collectively, this work identified stem cells in the bone marrow as a niche where Leishmania quiescence occurs, with important implications for antiparasitic treatment and acquisition of virulence traits.

Authors: L. Dirkx, S. I. Van Acker, Y. Nicolaes, J. L. R. Cunha, R. Ahmad, R. Hendrickx, B. Caljon, H. Imamura, D. G. Ebo, D. C. Jeffares, Y. G. Sterckx, L. Maes, S. Hendrickx, G. Caljon

Date Published: 6th May 2024

Publication Type: Journal Article

Assessing Environmental Risks during the Drug Development Process for Parasitic Vector-Borne Diseases: A Critical Reflection

Abstract

Not specified

Authors: Kayhan Ilbeigi, Carlos Barata, João Barbosa, Michael G. Bertram, Guy Caljon, Maria Paola Costi, Alexandra Kroll, Luigi Margiotta-Casaluci, Eli S.J. Thoré, Mirco Bundschuh

Date Published: 27th Mar 2024

Publication Type: Journal Article

Q586B2 is a crucial virulence factor during the early stages of Trypanosoma brucei infection that is conserved amongst trypanosomatids

Abstract (Expand)

AbstractHuman African trypanosomiasis or sleeping sickness, caused by the protozoan parasite Trypanosoma brucei, is characterized by the manipulation of the host’s immune response to ensure parasite … invasion and persistence. Uncovering key molecules that support parasite establishment is a prerequisite to interfere with this process. We identified Q586B2 as a T. brucei protein that induces IL-10 in myeloid cells, which promotes parasite infection invasiveness. Q586B2 is expressed during all T. brucei life stages and is conserved in all Trypanosomatidae. Deleting the Q586B2-encoding Tb927.6.4140 gene in T. brucei results in a decreased peak parasitemia and prolonged survival, without affecting parasite fitness in vitro, yet promoting short stumpy differentiation in vivo. Accordingly, neutralization of Q586B2 with newly generated nanobodies could hamper myeloid-derived IL-10 production and reduce parasitemia. In addition, immunization with Q586B2 delays mortality upon a challenge with various trypanosomes, including Trypanosoma cruzi. Collectively, we uncovered a conserved protein playing an important regulatory role in Trypanosomatid infection establishment.

Authors: Benoit Stijlemans, Patrick De Baetselier, Inge Van Molle, Laurence Lecordier, Erika Hendrickx, Ema Romão, Cécile Vincke, Wendy Baetens, Steve Schoonooghe, Gholamreza Hassanzadeh-Ghassabeh, Hannelie Korf, Marie Wallays, Joar E. Pinto Torres, David Perez-Morga, Lea Brys, Oscar Campetella, María S. Leguizamón, Mathieu Claes, Sarah Hendrickx, Dorien Mabille, Guy Caljon, Han Remaut, Kim Roelants, Stefan Magez, Jo A. Van Ginderachter, Carl De Trez

Date Published: 27th Feb 2024

Publication Type: Journal Article

Design and synthesis of imidazo[1,2-a]pyridine-chalcone conjugates as antikinetoplastid agents.

Abstract (Expand)

A library of imidazo[1,2-a]pyridine-appended chalcones were synthesized and characterized using (1) H NMR, (13) C NMR and HRMS. The synthesized analogues were screened for their antikinetoplastid … activity against Trypanosoma cruzi, Trypanosoma brucei brucei, Trypanosoma brucei rhodesiense and Leishmania infantum. The analogues were also tested for their cytotoxicity activity against human lung fibroblasts and primary mouse macrophages. Among all screened derivatives, 7f was found to be the most active against T. cruzi and T. b. brucei exhibiting IC(50) values of 8.5 and 1.35 muM, respectively. Against T. b. rhodesiense, 7e was found to be the most active with an IC(50) value of 1.13 muM. All synthesized active analogues were found to be non-cytotoxic against MRC-5 and PMM with selectivity indices of up to more than 50.

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

Date Published: 18th Jan 2024

Publication Type: Journal Article

2-Aroyl quinazolinone: Synthesis and in vitro anti-parasitic activity.

Abstract (Expand)

Trypanosomes and Leishmania are parasitic protozoans that affect millions of people globally. Herein we report the synthesis of 2-aroyl quinazolinones and their antiprotozoal efficacy against Trypanosoma … brucei, Trypanosoma brucei rhodesiense, Trypanosoma cruzi, and Leishmania infantum. These compounds were counter-screened against a human cell line for cytotoxicity. Thirteen of the twenty target compounds in this study inhibited the growth of these parasites, with compounds KJ1, and KJ10 exhibiting IC(50) values of 4.7 muM (T. b. brucei) and 1.1 muM (T. b. rhodesiense), respectively.

Authors: K. J. Setshedi, R. M. Beteck, O. J. Jesumoroti, K. Ilbeigi, D. Mabille, G. Caljon, F. Van der Kooy, L. J. Legoabe

Date Published: 13th Sep 2023

Publication Type: Journal Article

Discovery of 5-Phenylpyrazolopyrimidinone Analogs as Potent Antitrypanosomal Agents with In Vivo Efficacy.

Abstract (Expand)

Human African Trypanosomiasis (HAT), caused by Trypanosoma brucei, is one of the neglected tropical diseases with a continuing need for new medication. We here describe the discovery of … 5-phenylpyrazolopyrimidinone analogs as a novel series of phenotypic antitrypanosomal agents. The most potent compound, 30 (NPD-2975), has an in vitro IC(50) of 70 nM against T. b. brucei with no apparent toxicity against human MRC-5 lung fibroblasts. Showing good physicochemical properties, low toxicity potential, acceptable metabolic stability, and other pharmacokinetic features, 30 was further evaluated in an acute mouse model of T. b. brucei infection. After oral dosing at 50 mg/kg twice per day for five consecutive days, all infected mice were cured. Given its good drug-like properties and high in vivo antitrypanosomal potential, the 5-phenylpyrazolopyrimidinone analog 30 represents a promising lead for future drug development to treat HAT.

Authors: Y. Zheng, M. van den Kerkhof, T. van der Meer, S. Gul, M. Kuzikov, B. Ellinger, I. J. P. de Esch, M. Siderius, A. Matheeussen, L. Maes, G. J. Sterk, G. Caljon, R. Leurs

Date Published: 10th Aug 2023

Publication Type: Journal Article

Structural Optimization of BIPPO Analogs as Potent Antimalarials.

Abstract (Expand)

Malaria continues to pose a significant health threat, causing thousands of deaths each year. The limited availability of vaccines and medications, combined with the emergence of drug resistance, further … complicates the fight against this disease. In this study, we aimed to enhance the antimalarial potency of the previously reported hit compound BIPPO (pIC(50) 5.9). Through systematic modification of pyrazolopyrimidinone analogs, we discovered the promising analog 30 (NPD-3547), which exhibited approximately one log unit higher in vitro potency (pIC(50) 6.8) against Plasmodium falciparum. Furthermore, we identified several other BIPPO analogs (23, 28, 29 and 47a) with potent antimalarial activity (pIC(50) > 6.0) and favorable metabolic stability in mouse liver microsomes. These compounds can serve as new tools for further optimization towards the development of potential candidates for antimalarial studies.

Authors: Y. Zheng, A. Matheeussen, L. Maes, G. Caljon, G. J. Sterk, R. Leurs

Date Published: 23rd Jun 2023

Publication Type: Journal Article

To Target or Not to Target Schistosoma mansoni Cyclic Nucleotide Phosphodiesterase 4A?

Abstract (Expand)

Schistosomiasis is a neglected tropical disease with high morbidity. Recently, the Schistosoma mansoni phosphodiesterase SmPDE4A was suggested as a putative new drug target. To support SmPDE4A targeted … drug discovery, we cloned, isolated, and biochemically characterized the full-length and catalytic domains of SmPDE4A. The enzymatically active catalytic domain was crystallized in the apo-form (PDB code: 6FG5) and in the cAMP- and AMP-bound states (PDB code: 6EZU). The SmPDE4A catalytic domain resembles human PDE4 more than parasite PDEs because it lacks the parasite PDE-specific P-pocket. Purified SmPDE4A proteins (full-length and catalytic domain) were used to profile an in-house library of PDE inhibitors (PDE4NPD toolbox). This screening identified tetrahydrophthalazinones and benzamides as potential hits. The PDE inhibitor NPD-0001 was the most active tetrahydrophthalazinone, whereas the approved human PDE4 inhibitors roflumilast and piclamilast were the most potent benzamides. As a follow-up, 83 benzamide analogs were prepared, but the inhibitory potency of the initial hits was not improved. Finally, NPD-0001 and roflumilast were evaluated in an in vitro anti-S. mansoni assay. Unfortunately, both SmPDE4A inhibitors were not effective in worm killing and only weakly affected the egg-laying at high micromolar concentrations. Consequently, the results with these SmPDE4A inhibitors strongly suggest that SmPDE4A is not a suitable target for anti-schistosomiasis therapy.

Authors: Y. Zheng, S. Schroeder, G. K. Kanev, S. S. Botros, S. William, A. A. Sabra, L. Maes, G. Caljon, C. Gil, A. Martinez, I. G. Salado, K. Augustyns, E. Edink, M. Sijm, E. de Heuvel, I. J. P. de Esch, T. van der Meer, M. Siderius, G. J. Sterk, D. Brown, R. Leurs

Date Published: 6th Apr 2023

Publication Type: Journal Article

Cloning and Characterization of Trypanosoma congolense and T. vivax Nucleoside Transporters Reveal the Potential of P1-Type Carriers for the Discovery of Broad-Spectrum Nucleoside-Based Therapeutics against Animal African Trypanosomiasis.

Abstract (Expand)

African Animal Trypanosomiasis (AAT), caused predominantly by Trypanosoma brucei brucei, T. vivax and T. congolense, is a fatal livestock disease throughout Sub-Saharan Africa. Treatment options are … very limited and threatened by resistance. Tubercidin (7-deazaadenosine) analogs have shown activity against individual parasites but viable chemotherapy must be active against all three species. Divergence in sensitivity to nucleoside antimetabolites could be caused by differences in nucleoside transporters. Having previously characterized the T. brucei nucleoside carriers, we here report the functional expression and characterization of the main adenosine transporters of T. vivax (TvxNT3) and T. congolense (TcoAT1/NT10), in a Leishmania mexicana cell line ('SUPKO') lacking adenosine uptake. Both carriers were similar to the T. brucei P1-type transporters and bind adenosine mostly through interactions with N3, N7 and 3'-OH. Expression of TvxNT3 and TcoAT1 sensitized SUPKO cells to various 7-substituted tubercidins and other nucleoside analogs although tubercidin itself is a poor substrate for P1-type transporters. Individual nucleoside EC(50)s were similar for T. b. brucei, T. congolense, T. evansi and T. equiperdum but correlated less well with T. vivax. However, multiple nucleosides including 7-halogentubercidines displayed pEC50>7 for all species and, based on transporter and anti-parasite SAR analyses, we conclude that nucleoside chemotherapy for AAT is viable.

Authors: M. A. Ungogo, M. M. Aldfer, M. J. Natto, H. Zhuang, R. Chisholm, K. Walsh, M. McGee, K. Ilbeigi, J. I. Asseri, R. J. S. Burchmore, G. Caljon, S. Van Calenbergh, H. P. De Koning

Date Published: 5th Feb 2023

Publication Type: Journal Article

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