International Journal for Parasitology: Drugs and Drug Resistance最新文献

{"title":"The phosphatase inhibitor BVT-948 can be used to efficiently screen functional sexual development proteins in the malaria parasite Plasmodium berghei","authors":"Xitong Jia ,&nbsp;Yong Wang ,&nbsp;Meilian Wang ,&nbsp;Hui Min ,&nbsp;Zehou Fang ,&nbsp;Haifeng Lu ,&nbsp;Jiao Li ,&nbsp;Yaming Cao ,&nbsp;Lunhao Bai ,&nbsp;Jinghan Lu","doi":"10.1016/j.ijpddr.2024.100563","DOIUrl":"10.1016/j.ijpddr.2024.100563","url":null,"abstract":"<div><h3>Background</h3><p>Studying and discovering the molecular mechanism of <em>Plasmodium</em> sexual development is crucial for the development of transmission blocking drugs and malaria eradication. The aim of this study was to investigate the feasibility of using phosphatase inhibitors as a tool for screening proteins essential for <em>Plasmodium</em> sexual development and to discover proteins affecting the sexual development of malaria parasites.</p></div><div><h3>Methods</h3><p>Differences in protein phosphorylation among <em>Plasmodium</em> gametocytes incubated with BVT-948 under <em>in vitro</em> ookinete culture conditions were evaluated using phosphoproteomic methods. Gene Ontology (GO) analysis was performed to predict the mechanism by which BVT-948 affected gametocyte–ookinete conversion. The functions of 8 putative proteins involved in <em>Plasmodium berghei</em> sexual development were evaluated. Bioinformatic analysis was used to evaluate the possible mechanism of PBANKA_0100800 in gametogenesis and subsequent sexual development.</p></div><div><h3>Results</h3><p>The phosphorylation levels of 265 proteins decreased while those of 67 increased after treatment with BVT-948. Seven of the 8 genes selected for phenotype screening play roles in <em>P. berghei</em> sexual development, and 4 of these were associated with gametocytogenesis. PBANKA_0100800 plays essential roles in gametocyte–ookinete conversion and transmission to mosquitoes.</p></div><div><h3>Conclusions</h3><p>Seven proteins identified by screening affect <em>P. berghei</em> sexual development, suggesting that phosphatase inhibitors can be used for functional protein screening.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"26 ","pages":"Article 100563"},"PeriodicalIF":4.1,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320724000447/pdfft?md5=9f49542e884503e417896ae68e574d58&pid=1-s2.0-S2211320724000447-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “Efficacy of flukicides against Fasciola hepatica and first report of triclabendazole resistance on German sheep farms” [Int. J. Parasitol. Drugs Drug Resist. 23 (2023) 94–105]","authors":"Alexandra Kahl ,&nbsp;Georg von Samson-Himmelstjerna ,&nbsp;Christina Helm ,&nbsp;Jane Hodgkinson ,&nbsp;Diana Williams ,&nbsp;Wiebke Weiher ,&nbsp;Werner Terhalle ,&nbsp;Stephan Steuber ,&nbsp;Martin Ganter ,&nbsp;Jürgen Krücken","doi":"10.1016/j.ijpddr.2024.100562","DOIUrl":"10.1016/j.ijpddr.2024.100562","url":null,"abstract":"","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"26 ","pages":"Article 100562"},"PeriodicalIF":4.1,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142017334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluating the amoeba thioredoxin reductase selenoprotein as potential drug target for treatment of Acanthamoeba infections","authors":"Alvie Loufouma-Mbouaka ,&nbsp;Attila Andor ,&nbsp;David Leitsch ,&nbsp;Jorge Pérez-Serrano ,&nbsp;Elias S.J. Arnér ,&nbsp;Julia Walochnik ,&nbsp;Tania Martín-Pérez","doi":"10.1016/j.ijpddr.2024.100564","DOIUrl":"10.1016/j.ijpddr.2024.100564","url":null,"abstract":"<div><div>The genus <em>Acanthamoeba</em> comprises facultative pathogens, causing <em>Acanthamoeba</em> keratitis (AK) and granulomatous amoebic encephalitis (GAE). In both diseases, treatment options are limited, and drug development is challenging. This study aimed to investigate the role of the large thioredoxin reductase selenoprotein of <em>Acanthamoeba</em> (AcTrxR-L) as a potential drug target assessing the effects of the thioredoxin reductase inhibitors auranofin, TRi-1, and TRi-2 on AcTrxR-L activity and on the viability of <em>Acanthamoeba</em> trophozoites. Recombinant expression and purification of AcTrxR-L as a selenoprotein allowed assessments of its enzymatic activity, with reduction of various substrates, including different thioredoxin isoforms. Auranofin demonstrated potent inhibition towards AcTrxR-L, followed by TRi-1, and TRi-2 exhibiting lower effectiveness. The inhibitors showed variable activity against trophozoites in culture, with TRi-1 and TRi-2 resulting in strongly impaired trophozoite viability. Cytotoxicity tests with human corneal epithelial cells revealed lower susceptibility to all compounds compared to <em>Acanthamoeba</em> trophozoites, underscoring their potential as future amoebicidal agents. Altogether, this study highlights the druggability of AcTrxR-L and suggests it to be a promising drug target for the treatment of <em>Acanthamoeba</em> infections. Further research is warranted to elucidate the role of AcTrxR-L in <em>Acanthamoeba</em> pathogenesis and to develop effective therapeutic strategies targeting this redox enzyme.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"26 ","pages":"Article 100564"},"PeriodicalIF":4.1,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142319637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A multiplexed high throughput screening assay using flow cytometry identifies glycolytic molecular probes in bloodstream form Trypanosoma brucei","authors":"Daniel H. Call ,&nbsp;John Asafo Adjei ,&nbsp;Ryan Pilgrim ,&nbsp;James W. Jeong ,&nbsp;E. Vance Willis ,&nbsp;Ronald A. Zegarra ,&nbsp;Nicholas L. Tapia ,&nbsp;Madalyn Osterhaus ,&nbsp;Jacob A. Vance ,&nbsp;Charles M. Voyton ,&nbsp;James A. Call ,&nbsp;Sabrina S. Pizarro ,&nbsp;James C. Morris ,&nbsp;Kenneth A. Christensen","doi":"10.1016/j.ijpddr.2024.100557","DOIUrl":"10.1016/j.ijpddr.2024.100557","url":null,"abstract":"<div><p>Kinetoplastid organisms, including <em>Trypanosoma brucei</em>, are a significant health burden in many tropical and semitropical countries. Much of their metabolism is poorly understood. To better study kinetoplastid metabolism, chemical probes that inhibit kinetoplastid enzymes are needed. To discover chemical probes, we have developed a high-throughput flow cytometry screening assay that simultaneously measures multiple glycolysis-relevant metabolites in live <em>T. brucei</em> bloodstream form parasites. We transfected parasites with biosensors that measure glucose, ATP, or glycosomal pH. The glucose and ATP sensors were FRET biosensors, while the pH sensor was a GFP-based biosensor. The pH sensor exhibited a different fluorescent profile from the FRET sensors, allowing us to simultaneously measure pH and either glucose or ATP. Cell viability was measured in tandem with the biosensors using thiazole red. We pooled sensor cell lines, loaded them onto plates containing a compound library, and then analyzed them by flow cytometry. The library was analyzed twice, once with the pooled pH and glucose sensor cell lines and once with the pH and ATP sensor cell lines. Multiplexing sensors provided some internal validation of active compounds and gave potential clues for each compound's target(s). We demonstrated this using the glycolytic inhibitor 2-deoxyglucose and the alternative oxidase inhibitor salicylhydroxamic acid. Individual biosensor-based assays exhibited a Z′-factor value acceptable for high-throughput screening, including when multiplexed. We tested assay performance in a pilot screen of 14,976 compounds from the Life Chemicals Compound Library. We obtained hit rates from 0.2 to 0.4% depending on the biosensor, with many compounds impacting multiple sensors. We rescreened 44 hits, and 28 (64%) showed repeatable activity for one or more sensors. One compound exhibited EC₅₀ values in the low micromolar range against two sensors. We expect this method will enable the discovery of glycolytic chemical probes to improve metabolic studies in kinetoplastid parasites.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"26 ","pages":"Article 100557"},"PeriodicalIF":4.1,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320724000381/pdfft?md5=ee9ca1f5f6eea35ce2b8b29b0d76d4d1&pid=1-s2.0-S2211320724000381-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142008764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antileishmanial and synergic effects of Rhanterium epapposum essential oil and its main compounds alone and combined with glucantime against Leishmania major infection","authors":"Abdullah D. Alanazi ,&nbsp;Areej Jameel Alghabban","doi":"10.1016/j.ijpddr.2024.100571","DOIUrl":"10.1016/j.ijpddr.2024.100571","url":null,"abstract":"<div><div>Cutaneous leishmaniasis (CL) is a widespread disease affecting both humans and animals globally. Currently, common treatments (e.g., glucantime (GC) for CL treatment have many side effects that limit their use. The current experimental study aims to assess the <em>in vitro, in vivo</em>, and potential mechanisms of action of <em>Rhanterium epapposum</em> essential oil (REE) and its main compounds β-Myrcene (MC), camphene (CP), and limonene (LN) alone and in combination against <em>Leishmania major</em>. In vitro effects of REE and its main compounds were evaluated on amastigote forms, infection in macrophages cells stimulation of nitric oxide (NO), and stimulation of the cellular immunity in macrophages. In vivo efficacy of REE and its main constituents was also assessed in mice with CL through evaluating parasite burden, oxidative stress and proinflammatory-related genes. A concentration-dependent reduction in the average number of amastigotes was observed, with statistical significance (p &lt; 0.001); whereas the results revealed synergistic effects when REE, MC and LN were combined with GC. REE and main compounds mainly in combination elicited a dose-dependent elevation in NO production and the expression levels of inducible nitric oxide synthase (iNOS), interferon gamma (IFN-γ), and tumor necrosis factor (TNF-α) genes in macrophages. Notably, mice treated with a combination of REE, MC, and GC showed the complete recovery of CL lesions after 28 days of treatment and resulted in a reduction of tissue malondialdehyde levels and a significant increase (p &lt; 0.001) in the gene expression levels of the antioxidant enzymes. Topical treating CL-infected mice with REE and its main compounds alone particularly in conjunction with GC, significantly increased (p &lt; 0.001) the expression levels of IFN-γ and interleukin (IL-12), while also causing a notable reduction in IL-4 expression. The findings of the current experimental research revealed the high <em>in vitro</em> and <em>in vivo</em> antileishmanial efficacy of REE and its main compounds MC, CP, and LN mainly in combination with GC; which indicated the high synergic effects of these compounds.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"26 ","pages":"Article 100571"},"PeriodicalIF":4.1,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In vitro and in vivo activity evaluation and mode of action of broxaldine on Toxoplasma gondii","authors":"Yanhua Qiu ,&nbsp;Bintao Zhai ,&nbsp;Yubin Bai ,&nbsp;Hongling Lin ,&nbsp;Lingyu Wu ,&nbsp;Wei Luo ,&nbsp;Mengyan Shi ,&nbsp;Shulin Chen ,&nbsp;Jiyu Zhang","doi":"10.1016/j.ijpddr.2024.100552","DOIUrl":"10.1016/j.ijpddr.2024.100552","url":null,"abstract":"<div><p><em>Toxoplasma gondii</em> (<em>T. gondii</em>) is a highly successful global parasite, infecting about one-third of the world's population and significantly affecting human life and the economy. However, current drugs for toxoplasmosis treatment have considerable side effects, and there is no specific drug to meet current needs. This study aims to evaluate the anti-<em>T. gondii</em> activity of broxaldine (BRO) <em>in vitro</em> and <em>in vivo</em> and explore its mechanism of action. Our results showed that compared to the control group, the invasion rate of tachyzoites in the 4 μg/mL BRO group was only 14.31%, and the proliferation rate of tachyzoites in host cells was only 1.23%. Furthermore, BRO disrupted the lytic cycle of <em>T. gondii</em> and reduced the size and number of cysts <em>in vitro</em>. A mouse model of acute toxoplasmosis reported a 41.5% survival rate after BRO treatment, with reduced parasite load in tissues and blood. The subcellular structure of <em>T. gondii</em> was observed, including disintegration of <em>T. gondii</em>, mitochondrial swelling, increased liposomes, and the presence of autophagic lysosomes. Further investigation revealed enhanced autophagy, increased neutral lipids, and decreased mitochondrial membrane potential in <em>T. gondii</em> treated with BRO. The results also showed a significant decrease in ATP levels. Overall, BRO demonstrates good anti-<em>T. gondii</em> activity <em>in vitro</em> and <em>in vivo</em>; therefore, it has the potential to be used as a lead compound for anti-<em>T. gondii</em> treatment.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"25 ","pages":"Article 100552"},"PeriodicalIF":4.1,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320724000332/pdfft?md5=ea67480b952bf320577dc0399ea13b71&pid=1-s2.0-S2211320724000332-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141579582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Robenidine derivatives as potential antischistosomal drug candidates","authors":"Christian N. Lotz ,&nbsp;Alina Krollenbrock ,&nbsp;Lea Imhof ,&nbsp;Michael Riscoe ,&nbsp;Jennifer Keiser","doi":"10.1016/j.ijpddr.2024.100546","DOIUrl":"https://doi.org/10.1016/j.ijpddr.2024.100546","url":null,"abstract":"<div><p>Schistosomiasis caused by <em>Schistosoma</em> spp. is a disease that causes a considerable health burden to millions of people worldwide. The limited availability of effective drugs on the market and the increased risk of resistance development due to extensive usage, highlight the urgent need for new antischistosomal drugs. Recent studies have shown that robenidine derivatives, containing an aminoguanidine core, exhibit promising activities against <em>Plasmodium falciparum</em>, motivating further investigation into their efficacy against <em>Schistosoma mansoni,</em> due to their similar habitat and the resulting related cellular mechanisms like the heme detoxification pathway. The conducted phenotypic screening of robenidine and 80 derivatives against newly transformed schistosomula and adult <em>Schistosoma mansoni</em> yielded 11 candidates with low EC₅₀ values for newly transformed schistosomula (1.12–4.63 μM) and adults (2.78–9.47 μM). The structure-activity relationship revealed that electron-withdrawing groups at the phenyl moiety, as well as the presence of methyl groups adjacent to the guanidine moiety, enhanced the activity of derivatives against both stages of <em>Schistosoma mansoni</em>. The two compounds <em>2,2′-Bis[(3-cyano-4-fluorophenyl)methylene] carbonimidic Dihydrazide Hydrochloride</em> (<strong>1</strong>) and <em>2,2′-Bis[(4-difluoromethoxyphenyl) ethylidene] carbonimidic Dihydrazide Hydrochloride</em> (<strong>19</strong>), were selected for an in vivo study in <em>Schistosoma mansoni</em>-infected mice based on their potency, cytotoxicity, pharmacokinetic-, and physicochemical properties, but failed to reduce the worm burden significantly (worm burden reduction &lt;20%). Thus, robenidine derivatives require further refinements to obtain higher antischistosomal specificity and in vivo activity.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"25 ","pages":"Article 100546"},"PeriodicalIF":4.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320724000277/pdfft?md5=07fc6d729d2617e9566802c376d81c41&pid=1-s2.0-S2211320724000277-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140906878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phylogenetic and transcriptomic study of aldo-keto reductases in Haemonchus contortus and their inducibility by flubendazole","authors":"Karolína Štěrbová,&nbsp;Lucie Raisová Stuchlíková,&nbsp;Nikola Rychlá,&nbsp;Kateřina Kohoutová,&nbsp;Markéta Babičková,&nbsp;Lenka Skálová,&nbsp;Petra Matoušková","doi":"10.1016/j.ijpddr.2024.100555","DOIUrl":"https://doi.org/10.1016/j.ijpddr.2024.100555","url":null,"abstract":"<div><p>Aldo-keto reductases (AKRs), a superfamily of NADP(H)-dependent oxidoreductases, catalyze the oxidoreduction of a wide variety of eobiotic and xenobiotic aldehydes and ketones. In mammals, AKRs play essential roles in hormone and xenobiotic metabolism, oxidative stress, and drug resistance, but little is known about these enzymes in the parasitic nematode <em>Haemonchus contortus</em>. In the present study, 22 AKR genes existing in the <em>H. contortus</em> genome were investigated and a phylogenetic analysis with comparison to AKRs in <em>Caenorhabditis elegans</em>, sheep and humans was conducted. The constitutive transcription levels of all AKRs were measured in eggs, larvae, and adults of <em>H. contortus</em>, and their expression was compared in a drug-sensitive strain (ISE) and a benzimidazole-resistant strain (IRE) previously derived from the sensitive strain by imposing benzimidazole selection pressure. In addition, the inducibility of AKRs by exposure of <em>H. contortus</em> adults to benzimidazole anthelmintic flubendazole <em>in vitro</em> was tested. Phylogenetic analysis demonstrated that the majority of AKR genes in <em>H. contortus</em> lack orthologues in the sheep genome, which is a favorable finding for considering AKRs as potential drug targets. Large differences in the expression levels of individual AKRs were observed, with AKR1, AKR3, AKR8, and AKR10 being the most highly expressed at most developmental stages. Significant changes in the expression of AKRs during the life cycle and pronounced sex differences were found. Comparing the IRE and ISE strains, three AKRs were upregulated, and seven AKRs were downregulated in adults. In addition, the expression of three AKRs was induced by flubendazole exposure in adults of the ISE strain. Based on these results, AKR1, AKR2, AKR3, AKR5, AKR10 and AKR19 in particular merit further investigation and functional characterization with respect to their potential involvement in drug biotransformation and anthelmintic resistance in <em>H. contortus</em>.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"25 ","pages":"Article 100555"},"PeriodicalIF":4.1,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320724000368/pdfft?md5=c93325ee1e10575c2febe46eaf79a324&pid=1-s2.0-S2211320724000368-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141593798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Erratum to “Uncovering the antimalarial potential of toad venoms through a bioassay-guided fractionation process” [Int. J. Parasitol.: Drugs Drug Resist. 20 (2022) 97–107]","authors":"","doi":"10.1016/j.ijpddr.2023.10.002","DOIUrl":"10.1016/j.ijpddr.2023.10.002","url":null,"abstract":"","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"25 ","pages":"Article 100510"},"PeriodicalIF":4.1,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320723000325/pdfft?md5=0d8e8e74e09173394e44da7777759996&pid=1-s2.0-S2211320723000325-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41235103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Treating cryptosporidiosis: A review on drug discovery strategies","authors":"Anne-Charlotte Lenière,&nbsp;Alexis Vlandas,&nbsp;Jérôme Follet","doi":"10.1016/j.ijpddr.2024.100542","DOIUrl":"https://doi.org/10.1016/j.ijpddr.2024.100542","url":null,"abstract":"<div><p>Despite several decades of research on therapeutics, cryptosporidiosis remains a major concern for human and animal health. Even though this field of research to assess antiparasitic drug activity is highly active and competitive, only one molecule is authorized to be used in humans. However, this molecule was not efficacious in immunocompromised people and the lack of animal therapeutics remains a cause of concern. Indeed, the therapeutic arsenal needs to be developed for both humans and animals. Our work aims to clarify research strategies that historically were diffuse and poorly directed. This paper reviews <em>in vitro</em> and <em>in vivo</em> methodologies to assess the activity of future therapeutic compounds by screening drug libraries or through drug repurposing. It focuses on High Throughput Screening methodologies (HTS) and discusses the lack of knowledge of target mechanisms. In addition, an overview of several specific metabolic pathways and enzymatic activities used as targets against <em>Cryptosporidium</em> is provided. These metabolic processes include glycolytic pathways, fatty acid production, kinase activities, tRNA elaboration, nucleotide synthesis, gene expression and mRNA maturation. As a conclusion, we highlight emerging future strategies for screening natural compounds and assessing drug resistance issues.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"25 ","pages":"Article 100542"},"PeriodicalIF":4.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S221132072400023X/pdfft?md5=2c999fcac43efe99f255fbf85f5d4e5d&pid=1-s2.0-S221132072400023X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140645476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}