Evaluating the amoeba thioredoxin reductase selenoprotein as potential drug target for treatment of Acanthamoeba infections
The genus Acanthamoeba comprises facultative pathogens, causing Acanthamoeba 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...
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Elsevier
2024-12-01
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| Series: | International Journal for Parasitology: Drugs and Drug Resistance |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211320724000459 |
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| author | Alvie Loufouma-Mbouaka Attila Andor David Leitsch Jorge Pérez-Serrano Elias S.J. Arnér Julia Walochnik Tania Martín-Pérez |
| author_facet | Alvie Loufouma-Mbouaka Attila Andor David Leitsch Jorge Pérez-Serrano Elias S.J. Arnér Julia Walochnik Tania Martín-Pérez |
| author_sort | Alvie Loufouma-Mbouaka |
| collection | DOAJ |
| description | The genus Acanthamoeba comprises facultative pathogens, causing Acanthamoeba 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 Acanthamoeba (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 Acanthamoeba 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 Acanthamoeba 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 Acanthamoeba infections. Further research is warranted to elucidate the role of AcTrxR-L in Acanthamoeba pathogenesis and to develop effective therapeutic strategies targeting this redox enzyme. |
| format | Article |
| id | doaj-art-a321e913316c4f588aebb3207daad9b2 |
| institution | OA Journals |
| issn | 2211-3207 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | International Journal for Parasitology: Drugs and Drug Resistance |
| spelling | doaj-art-a321e913316c4f588aebb3207daad9b22025-08-20T01:59:04ZengElsevierInternational Journal for Parasitology: Drugs and Drug Resistance2211-32072024-12-012610056410.1016/j.ijpddr.2024.100564Evaluating the amoeba thioredoxin reductase selenoprotein as potential drug target for treatment of Acanthamoeba infectionsAlvie Loufouma-Mbouaka0Attila Andor1David Leitsch2Jorge Pérez-Serrano3Elias S.J. Arnér4Julia Walochnik5Tania Martín-Pérez6Institute of Specific Prophylaxis and Tropical Medicine, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090, Vienna, AustriaDepartment of Selenoprotein Research and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, Hungary; Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, SwedenInstitute of Specific Prophylaxis and Tropical Medicine, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090, Vienna, AustriaDepartment of Biomedicine and Biotechnology, Faculty of Pharmacy, University of Alcalá, 28871, Alcalá de Henares, SpainDepartment of Selenoprotein Research and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, Hungary; Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, SwedenInstitute of Specific Prophylaxis and Tropical Medicine, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090, Vienna, AustriaInstitute of Specific Prophylaxis and Tropical Medicine, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090, Vienna, Austria; Corresponding author.The genus Acanthamoeba comprises facultative pathogens, causing Acanthamoeba 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 Acanthamoeba (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 Acanthamoeba 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 Acanthamoeba 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 Acanthamoeba infections. Further research is warranted to elucidate the role of AcTrxR-L in Acanthamoeba pathogenesis and to develop effective therapeutic strategies targeting this redox enzyme.http://www.sciencedirect.com/science/article/pii/S2211320724000459Acanthamoeba castellaniiRedox systemThioredoxin reductaseSelenoproteinAuranofinThioredoxin reductase inhibitor |
| spellingShingle | Alvie Loufouma-Mbouaka Attila Andor David Leitsch Jorge Pérez-Serrano Elias S.J. Arnér Julia Walochnik Tania Martín-Pérez Evaluating the amoeba thioredoxin reductase selenoprotein as potential drug target for treatment of Acanthamoeba infections International Journal for Parasitology: Drugs and Drug Resistance Acanthamoeba castellanii Redox system Thioredoxin reductase Selenoprotein Auranofin Thioredoxin reductase inhibitor |
| title | Evaluating the amoeba thioredoxin reductase selenoprotein as potential drug target for treatment of Acanthamoeba infections |
| title_full | Evaluating the amoeba thioredoxin reductase selenoprotein as potential drug target for treatment of Acanthamoeba infections |
| title_fullStr | Evaluating the amoeba thioredoxin reductase selenoprotein as potential drug target for treatment of Acanthamoeba infections |
| title_full_unstemmed | Evaluating the amoeba thioredoxin reductase selenoprotein as potential drug target for treatment of Acanthamoeba infections |
| title_short | Evaluating the amoeba thioredoxin reductase selenoprotein as potential drug target for treatment of Acanthamoeba infections |
| title_sort | evaluating the amoeba thioredoxin reductase selenoprotein as potential drug target for treatment of acanthamoeba infections |
| topic | Acanthamoeba castellanii Redox system Thioredoxin reductase Selenoprotein Auranofin Thioredoxin reductase inhibitor |
| url | http://www.sciencedirect.com/science/article/pii/S2211320724000459 |
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