Publications

What is a Publication?
92 Publications visible to you, out of a total of 92
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4-Methyl-7-beta-D-ribofuranosyl-7H-pyrrolo[2,3-d]pyrimidine (CL5564), an analogue of tubercidin in which the amine has been replaced by a methyl group, demonstrates activity against Trypanosoma cruzi and Leishmania infantum.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

Discovery of 1,3,4-Oxadiazole Derivatives as Broad-Spectrum Antiparasitic Agents

Abstract

Not specified

Authors: Alexandra Ioana Corfu, Nuno Santarem, Sara Luelmo, Gaia Mazza, Alessandro Greco, Alessandra Altomare, Giulio Ferrario, Giulia Nasta, Oliver Keminer, Giancarlo Aldini, Lucia Tamborini, Nicoletta Basilico, Silvia Parapini, Sheraz Gul, Anabela Cordeiro-da-Silva, Paola Conti, Chiara Borsari

Date Published: 8th 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

Synthesis and Anti-Chagas Activity Profile of a Redox-Active Lead 3-Benzylmenadione Revealed by High-Content Imaging

Abstract

Not specified

Authors: Nathan Trometer, Jérémy Pecourneau, Liwen Feng, José A. Navarro-Huerta, Danielle Lazarin-Bidóia, Sueli de Oliveira Silva Lautenschlager, Louis Maes, Amanda Fortes Francisco, John M. Kelly, Brigitte Meunier, Monica Cal, Pascal Mäser, Marcel Kaiser, Elisabeth Davioud-Charvet

Date Published: 12th Apr 2024

Publication Type: Journal Article

Chemoselective Synthesis and Anti-Kinetoplastidal Properties of 2,6-Diaryl-4H-tetrahydro-thiopyran-4-one S-Oxides: Their Interplay in a Cascade of Redox Reactions from Diarylideneacetones

Abstract (Expand)

2,6-Diaryl-4H-tetrahydro-thiopyran-4-ones and corresponding sulfoxide and sulfone derivatives were designed to lower the major toxicity of their parent anti-kinetoplatidal diarylideneacetones through … a prodrug effect. Novel diastereoselective methodologies were developed and generalized from diarylideneacetones and 2,6-diaryl-4H-tetrahydro-thiopyran-4-ones to allow the introduction of a wide substitution profile and to prepare the related S-oxides. The in vitro biological activity and selectivity of diarylideneacetones, 2,6-diaryl-4H-tetrahydro-thiopyran-4-ones, and their S-sulfoxide and sulfone metabolites were evaluated against Trypanosoma brucei brucei, Trypanosoma cruzi, and various Leishmania species in comparison with their cytotoxicity against human fibroblasts hMRC-5. The data revealed that the sulfides, sulfoxides, and sulfones, in which the Michael acceptor sites are temporarily masked, are less toxic against mammal cells while the anti-trypanosomal potency was maintained against T. b. brucei, T. cruzi, L. infantum, and L. donovani, thus confirming the validity of the prodrug strategy. The mechanism of action is proposed to be due to the involvement of diarylideneacetones in cascades of redox reactions involving the trypanothione system. After Michael addition of the dithiol to the double bonds, resulting in an elongated polymer, the latter—upon S-oxidation, followed by syn-eliminations—fragments, under continuous release of reactive oxygen species and sulfenic/sulfonic species, causing the death of the trypanosomal parasites in the micromolar or submicromolar range with high selectivity indexes.

Authors: Thibault Gendron, Don Antoine Lanfranchi, Nicole I. Wenzel, Hripsimée Kessedjian, Beate Jannack, Louis Maes, Sandrine Cojean, Thomas J. J. Müller, Philippe M. Loiseau, Elisabeth Davioud-Charvet

Date Published: 4th Apr 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

Chelation of Mitochondrial Iron as an Antiparasitic Strategy

Abstract

Not specified

Authors: Dominik Arbon, Jan Mach, Aneta Čadková, Anna Sipkova, Jan Stursa, Kristýna Klanicová, Marta Machado, Markus Ganter, Viktoriya Levytska, Daniel Sojka, Jaroslav Truksa, Lukáš Werner, Robert Sutak

Date Published: 30th Jan 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

The discovery of aryl-2-nitroethyl triamino pyrimidines as anti-Trypanosoma brucei agents

Abstract

Not specified

Authors: Pasquale Linciano, Cecilia Pozzi, Giusy Tassone, Giacomo Landi, Stefano Mangani, Matteo Santucci, Rosaria Luciani, Stefania Ferrari, Nuno Santarem, Lorenzo Tagliazucchi, Anabela Cordeiro-da-Silva, Michele Tonelli, Donatella Tondi, Laura Bertarini, Sheraz Gul, Gesa Witt, Carolina B. Moraes, Luca Costantino, Maria Paola Costi

Date Published: 2024

Publication Type: Journal Article

Design, synthesis and modelling of photoreactive chemical probes for investigating target engagement of plasmepsin IX and X in <i>Plasmodium falciparum</i>

Abstract (Expand)

We report the synthesis and biological profiling of photoreactive chemical probes based on an established plasmepsin X inhibitor scaffold. Maintained antimalarial and recombinant enzyme activity support … their use in future chemical proteomic studies.

Authors: Monika Lisauskaitė, Gemma L. Nixon, Christopher M. Woodley, Neil G. Berry, Andy Coninckx, L. Charlie Qie, Suet C. Leung, Donatella Taramelli, Nicoletta Basilico, Silvia Parapini, Stephen A. Ward, Oscar Vadas, Dominique Soldati-Favre, W. David Hong, Paul M. O'Neill

Date Published: 2024

Publication Type: Journal Article

Solid Lipid Nanoparticles Enhancing the Leishmanicidal Activity of Delamanid

Abstract (Expand)

Leishmaniasis, a zoonotic parasitic disease transmitted by infected sandflies, impacts nearly 1 million people yearly and is endemic in many countries across Asia, Africa, the Americas, and the … Mediterranean; despite this, it remains a neglected disease with limited effective treatments, particularly in impoverished communities with limited access to healthcare. This study aims to repurpose approved drugs for an affordable leishmaniasis treatment. After the screening of potential drug candidates by reviewing databases and utilizing molecular docking analysis, delamanid was chosen to be incorporated into solid lipid nanoparticles (SLNPs). Both in cellulo and in vivo tests confirmed the successful payload release within macrophages and through the epidermis following topical application on murine skin. The evaluation of macrophages infected with L. infantum amastigotes showed that the encapsulated delamanid exhibited greater leishmanicidal activity compared with the free drug. The process of encapsulating delamanid in SLNPs, as demonstrated in this study, places a strong emphasis on employing minimal technology, ensuring energy efficiency, cost-effectiveness, and reproducibility. It enables consistent, low-cost production of nanomedicines, even on a small scale, offering a promising step toward more accessible and effective leishmaniasis treatments.

Authors: Javier Santamaría-Aguirre, Daniela Jacho, Miguel A. Méndez, Ana Poveda, Javier Carrión, Mónica L. Fanarraga

Date Published: 27th Dec 2023

Publication Type: Journal Article

FLAgellum Member 8 modulates extravascular distribution of African trypanosomes

Abstract (Expand)

In the mammalian host, the biology of tissue-dwelling Trypanosoma brucei parasites is not completely understood, especially the mechanisms involved in their extravascular colonization. The trypanosome …ravascular colonization. The trypanosome flagellum is an essential organelle in multiple aspects of the parasites’ development. The flagellar protein termed FLAgellar Member 8 (FLAM8) acts as a docking platform for a pool of cyclic AMP response protein 3 (CARP3) that is involved in signaling. FLAM8 exhibits a stage-specific distribution suggesting specific functions in the mammalian and vector stages of the parasite. Analyses of knockdown and knockout trypanosomes in their mammalian forms demonstrated that FLAM8 is not essential in vitro for survival, growth, motility and stumpy differentiation. Functional investigations in experimental infections showed that FLAM8 -deprived trypanosomes can establish and maintain an infection in the blood circulation and differentiate into insect transmissible forms. However, quantitative bioluminescence imaging and gene expression analysis revealed that FLAM8 -null parasites exhibit a significantly impaired dissemination in the extravascular compartment, that is restored by the addition of a single rescue copy of FLAM8 . In vitro trans-endothelial migration assays revealed significant defects in trypanosomes lacking FLAM8 . FLAM8 is the first flagellar component shown to modulate T . brucei distribution in the host tissues, possibly through sensing functions, contributing to the maintenance of extravascular parasite populations in mammalian anatomical niches, especially in the skin.

Authors: Estefanía Calvo-Alvarez, Jean Marc Tsagmo Ngoune, Parul Sharma, Anneli Cooper, Aïssata Camara, Christelle Travaillé, Aline Crouzols, Annette MacLeod, Brice Rotureau

Date Published: 21st Dec 2023

Publication Type: Journal Article

High-Throughput Phenotypic Screening and Machine Learning Methods Enabled the Selection of Broad-Spectrum Low-Toxicity Antitrypanosomatidic Agents

Abstract

Not specified

Authors: Pasquale Linciano, Antonio Quotadamo, Rosaria Luciani, Matteo Santucci, Kimberley M. Zorn, Daniel H. Foil, Thomas R. Lane, Anabela Cordeiro da Silva, Nuno Santarem, Carolina B Moraes, Lucio Freitas-Junior, Ulrike Wittig, Wolfgang Mueller, Michele Tonelli, Stefania Ferrari, Alberto Venturelli, Sheraz Gul, Maria Kuzikov, Bernhard Ellinger, Jeanette Reinshagen, Sean Ekins, Maria Paola Costi

Date Published: 3rd Nov 2023

Publication Type: Journal Article

Drug repurposing: a nexus of innovation, science, and potential

Abstract

Not specified

Authors: Maria Cristina De Rosa, Rituraj Purohit, Alfonso T. García-Sosa

Date Published: 19th Oct 2023

Publication Type: Journal Article

Synthesis and Biophysical and Biological Studies of <i>N</i>-Phenylbenzamide Derivatives Targeting Kinetoplastid Parasites

Abstract

Not specified

Authors: J. Jonathan Nué-Martinez, David Cisneros, María del Valle Moreno-Blázquez, Cristina Fonseca-Berzal, José Ignacio Manzano, Damien Kraeutler, Marzuq A. Ungogo, Maha A. Aloraini, Hamza A. A. Elati, Alexandra Ibáñez-Escribano, Laura Lagartera, Tomás Herraiz, Francisco Gamarro, Harry P. de Koning, Alicia Gómez-Barrio, Christophe Dardonville

Date Published: 20th Sep 2023

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

Call for Papers: One Health and Vector-Borne Parasitic Diseases

Abstract

Not specified

Authors: Maria P. Costi, Anabela Cordeiro-da-Silva

Date Published: 23rd Jul 2023

Publication Type: Journal Article

BRCT Domains: Structure, Functions, and Implications in Disease—New Therapeutic Targets for Innovative Drug Discovery against Infections

Abstract (Expand)

The search for new therapeutic targets and their implications in drug development remains an emerging scientific topic. BRCT-bearing proteins are found in Archaea, Bacteria, Eukarya, and viruses. They … are traditionally involved in DNA repair, recombination, and cell cycle control. To carry out these functions, BRCT domains are able to interact with DNA and proteins. Moreover, such domains are also implicated in several pathogenic processes and malignancies including breast, ovarian, and lung cancer. Although these domains exhibit moderately conserved folding, their sequences show very low conservation. Interestingly, sequence variations among species are considered positive traits in the search for suitable therapeutic targets, since non-specific drug interactions might be reduced. These main characteristics of BRCT, as well as its critical implications in key biological processes in the cell, have prompted the study of these domains as therapeutic targets. This review explores the possible roles of BRCT domains as therapeutic targets for drug discovery. We describe their common structural features and relevant interactions and pathways, as well as their implications in pathologic processes. Drugs commonly used to target these domains are also presented. Finally, based on their structures, we describe new drug design possibilities using modern and innovative techniques.

Authors: José Peña-Guerrero, Celia Fernández-Rubio, Alfonso T. García-Sosa, Paul A. Nguewa

Date Published: 27th Jun 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

Supramolecular assemblies from antimony(V) complexes for the treatment of leishmaniasis

Abstract

Not specified

Authors: Cynthia Demicheli, Virgínia M. R. Vallejos, Juliane S. Lanza, Guilherme S. Ramos, Bruno R. Do Prado, Sébastien Pomel, Philippe M. Loiseau, Frédéric Frézard

Date Published: 6th Jun 2023

Publication Type: Journal Article

Favorable Preclinical Pharmacological Profile of a Novel Antimalarial Pyrrolizidinylmethyl Derivative of 4-amino-7-chloroquinoline with Potent In Vitro and In Vivo Activities

Abstract (Expand)

The 4-aminoquinoline drugs, such as chloroquine (CQ), amodiaquine or piperaquine, are still commonly used for malaria treatment, either alone (CQ) or in combination with artemisinin derivatives. We … previously described the excellent in vitro activity of a novel pyrrolizidinylmethyl derivative of 4-amino-7-chloroquinoline, named MG3, against P. falciparum drug-resistant parasites. Here, we report the optimized and safer synthesis of MG3, now suitable for a scale-up, and its additional in vitro and in vivo characterization. MG3 is active against a panel of P. vivax and P. falciparum field isolates, either alone or in combination with artemisinin derivatives. In vivo MG3 is orally active in the P. berghei, P. chabaudi, and P. yoelii models of rodent malaria with efficacy comparable, or better, than that of CQ and of other quinolines under development. The in vivo and in vitro ADME-Tox studies indicate that MG3 possesses a very good pre-clinical developability profile associated with an excellent oral bioavailability, and low toxicity in non-formal preclinical studies on rats, dogs, and non-human primates (NHP). In conclusion, the pharmacological profile of MG3 is in line with those obtained with CQ or the other quinolines in use and seems to possess all the requirements for a developmental candidate.

Authors: Nicoletta Basilico, Silvia Parapini, Sarah D’Alessandro, Paola Misiano, Sergio Romeo, Giulio Dondio, Vanessa Yardley, Livia Vivas, Shereen Nasser, Laurent Rénia, Bruce M. Russell, Rossarin Suwanarusk, François Nosten, Anna Sparatore, Donatella Taramelli

Date Published: 14th May 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

Label-Free Mass Spectrometry Proteomics Reveals Different Pathways Modulated in THP-1 Cells Infected with Therapeutic Failure and Drug Resistance <i>Leishmania infantum</i> Clinical Isolates

Abstract

Not specified

Authors: Lorenzo Tagliazucchi, Ana Perea-Martinez, Greta Fiorini, José Ignacio Manzano, Filippo Genovese, Raquel García-Hernández, Diego Pinetti, Francisco Gamarro, Maria Paola Costi

Date Published: 10th Feb 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

Comparison of Bioluminescent Substrates in Natural Infection Models of Neglected Parasitic Diseases

Abstract (Expand)

The application of in vivo bioluminescent imaging in infectious disease research has significantly increased over the past years. The detection of transgenic parasites expressing wildtype firefly … luciferase is however hampered by a relatively low and heterogeneous tissue penetrating capacity of emitted light. Solutions are sought by using codon-optimized red-shifted luciferases that yield higher expression levels and produce relatively more red or near-infrared light, or by using modified bioluminescent substrates with enhanced cell permeability and improved luminogenic or pharmacokinetic properties. In this study, the in vitro and in vivo efficacy of two modified bioluminescent substrates, CycLuc1 and AkaLumine-HCl, were compared with that of D-luciferin as a gold standard. Comparisons were made in experimental and insect-transmitted animal models of leishmaniasis (caused by intracellular Leishmania species) and African trypanosomiasis (caused by extracellular Trypanosoma species), using parasite strains expressing the red-shifted firefly luciferase PpyRE9. Although the luminogenic properties of AkaLumine-HCl and D-luciferin for in vitro parasite detection were comparable at equal substrate concentrations, AkaLumine-HCl proved to be unsuitable for in vivo infection follow-up due to high background signals in the liver. CycLuc1 presented a higher in vitro luminescence compared to the other substrates and proved to be highly efficacious in vivo, even at a 20-fold lower dose than D-luciferin. This efficacy was consistent across infections with the herein included intracellular and extracellular parasitic organisms. It can be concluded that CycLuc1 is an excellent and broadly applicable alternative for D-luciferin, requiring significantly lower doses for in vivo bioluminescent imaging in rodent models of leishmaniasis and African trypanosomiasis.

Authors: Sarah Hendrickx, Dimitri Bulté, Dorien Mabille, Roxanne Mols, Mathieu Claes, Kayhan Ilbeigi, Rokaya Ahmad, Laura Dirkx, Sara I. Van Acker, Guy Caljon

Date Published: 16th Dec 2022

Publication Type: Journal Article

Comparison of Bioluminescent Substrates in Natural Infection Models of Neglected Parasitic Diseases.

Abstract (Expand)

The application of in vivo bioluminescent imaging in infectious disease research has significantly increased over the past years. The detection of transgenic parasites expressing wildtype firefly … luciferase is however hampered by a relatively low and heterogeneous tissue penetrating capacity of emitted light. Solutions are sought by using codon-optimized red-shifted luciferases that yield higher expression levels and produce relatively more red or near-infrared light, or by using modified bioluminescent substrates with enhanced cell permeability and improved luminogenic or pharmacokinetic properties. In this study, the in vitro and in vivo efficacy of two modified bioluminescent substrates, CycLuc1 and AkaLumine-HCl, were compared with that of D-luciferin as a gold standard. Comparisons were made in experimental and insect-transmitted animal models of leishmaniasis (caused by intracellular Leishmania species) and African trypanosomiasis (caused by extracellular Trypanosoma species), using parasite strains expressing the red-shifted firefly luciferase PpyRE9. Although the luminogenic properties of AkaLumine-HCl and D-luciferin for in vitro parasite detection were comparable at equal substrate concentrations, AkaLumine-HCl proved to be unsuitable for in vivo infection follow-up due to high background signals in the liver. CycLuc1 presented a higher in vitro luminescence compared to the other substrates and proved to be highly efficacious in vivo, even at a 20-fold lower dose than D-luciferin. This efficacy was consistent across infections with the herein included intracellular and extracellular parasitic organisms. It can be concluded that CycLuc1 is an excellent and broadly applicable alternative for D-luciferin, requiring significantly lower doses for in vivo bioluminescent imaging in rodent models of leishmaniasis and African trypanosomiasis.

Authors: S. Hendrickx, D. Bulte, D. Mabille, R. Mols, M. Claes, K. Ilbeigi, R. Ahmad, L. Dirkx, S. I. Van Acker, G. Caljon

Date Published: 16th Dec 2022

Publication Type: Journal Article

Impact of pulmonary African trypanosomes on the immunology and function of the lung

Abstract (Expand)

AbstractApproximately 20% of sleeping sickness patients exhibit respiratory complications, however, with a largely unknown role of the parasite. Here we show that tsetse fly-transmitted Trypanosoma … brucei parasites rapidly and permanently colonize the lungs and occupy the extravascular spaces surrounding the blood vessels of the alveoli and bronchi. They are present as nests of multiplying parasites exhibiting close interactions with collagen and active secretion of extracellular vesicles. The local immune response shows a substantial increase of monocytes, macrophages, dendritic cells and γδ and activated αβ T cells and a later influx of neutrophils. Interestingly, parasite presence results in a significant reduction of B cells, eosinophils and natural killer cells. T. brucei infected mice show no infection-associated pulmonary dysfunction, mirroring the limited pulmonary clinical complications during sleeping sickness. However, the substantial reduction of the various immune cells may render individuals more susceptible to opportunistic infections, as evident by a co-infection experiment with respiratory syncytial virus. Collectively, these observations provide insights into a largely overlooked target organ, and may trigger new diagnostic and supportive therapeutic approaches for sleeping sickness.

Authors: Dorien Mabille, Laura Dirkx, Sofie Thys, Marjorie Vermeersch, Daniel Montenye, Matthias Govaerts, Sarah Hendrickx, Peter Takac, Johan Van Weyenbergh, Isabel Pintelon, Peter Delputte, Louis Maes, David Pérez-Morga, Jean-Pierre Timmermans, Guy Caljon

Date Published: 18th Nov 2022

Publication Type: Journal Article

Impact of pulmonary African trypanosomes on the immunology and function of the lung.

Abstract (Expand)

Approximately 20% of sleeping sickness patients exhibit respiratory complications, however, with a largely unknown role of the parasite. Here we show that tsetse fly-transmitted Trypanosoma brucei … parasites rapidly and permanently colonize the lungs and occupy the extravascular spaces surrounding the blood vessels of the alveoli and bronchi. They are present as nests of multiplying parasites exhibiting close interactions with collagen and active secretion of extracellular vesicles. The local immune response shows a substantial increase of monocytes, macrophages, dendritic cells and gammadelta and activated alphabeta T cells and a later influx of neutrophils. Interestingly, parasite presence results in a significant reduction of B cells, eosinophils and natural killer cells. T. brucei infected mice show no infection-associated pulmonary dysfunction, mirroring the limited pulmonary clinical complications during sleeping sickness. However, the substantial reduction of the various immune cells may render individuals more susceptible to opportunistic infections, as evident by a co-infection experiment with respiratory syncytial virus. Collectively, these observations provide insights into a largely overlooked target organ, and may trigger new diagnostic and supportive therapeutic approaches for sleeping sickness.

Authors: D. Mabille, L. Dirkx, S. Thys, M. Vermeersch, D. Montenye, M. Govaerts, S. Hendrickx, P. Takac, J. Van Weyenbergh, I. Pintelon, P. Delputte, L. Maes, D. Perez-Morga, J. P. Timmermans, G. Caljon

Date Published: 18th Nov 2022

Publication Type: Journal Article

Powered by
 (v.1.18.0)
About FAIRDOMHub | Funding and Programmes | Credits | Terms & Conditions | Imprint | Cookie preferences
Copyright © 2008 - 2026 The University of Manchester and HITS gGmbH
Metadata is licensed under Creative Commons Attribution 4.0 International (CC-BY-4.0)