Two old drugs, NVP-AEW541 and GSK-J4, repurposed against the Toxoplasma gondii RH strain
Abstract Background Toxoplasma gondii is a zoonotic pathogen that causes toxoplasmosis and leads to serious public health problems in developing countries. However, current clinical therapeutic drugs have some disadvantages, such as serious side effects, a long course of treatment and the emergence...
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| Format: | Article |
| Language: | English |
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BMC
2020-05-01
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| Series: | Parasites & Vectors |
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| Online Access: | http://link.springer.com/article/10.1186/s13071-020-04094-2 |
| _version_ | 1818047915939069952 |
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| author | Shuxian Liu Mimi Wu Qianqian Hua Daiqiang Lu Yuan Tian Helin Yu Linyan Cheng Yinqi Chen Jiaxin Cao Xin Hu Feng Tan |
| author_facet | Shuxian Liu Mimi Wu Qianqian Hua Daiqiang Lu Yuan Tian Helin Yu Linyan Cheng Yinqi Chen Jiaxin Cao Xin Hu Feng Tan |
| author_sort | Shuxian Liu |
| collection | DOAJ |
| description | Abstract Background Toxoplasma gondii is a zoonotic pathogen that causes toxoplasmosis and leads to serious public health problems in developing countries. However, current clinical therapeutic drugs have some disadvantages, such as serious side effects, a long course of treatment and the emergence of drug-resistant strains. The urgent need to identify novel anti-Toxoplasma drugs has initiated the effective strategy of repurposing well-characterized drugs. As a principled screening for the identification of effective compounds against Toxoplasma gondii, in the current study, a collection of 666 compounds were screened for their ability to significantly inhibit Toxoplasma growth. Methods The inhibition of parasite growth was determined using a luminescence-based β-galactosidase activity assay. Meanwhile, the effect of compounds on the viability of host cells was measured using CCK8. To assess the inhibition of the selected compounds on discrete steps of the T. gondii lytic cycle, the invasion, intracellular proliferation and egress abilities were evaluated. Finally, a murine infection model of toxoplasmosis was used to monitor the protective efficacy of drugs against acute infection of a highly virulent RH strain. Results A total of 68 compounds demonstrated more than 70% parasite growth inhibition. After excluding compounds that impaired host cell viability, we further characterized two compounds, NVP-AEW541 and GSK-J4 HCl, which had IC50 values for parasite growth of 1.17 μM and 2.37 μM, respectively. In addition, both compounds showed low toxicity to the host cell. Furthermore, we demonstrated that NVP-AEW541 inhibits tachyzoite invasion, while GSK-J4 HCl inhibits intracellular tachyzoite proliferation by halting cell cycle progression from G1 to S phase. These findings prompted us to analyse the efficacy of the two compounds in vivo by using established mouse models of acute toxoplasmosis. In addition to prolonging the survival time of mice acutely infected with T. gondii, both compounds had a remarkable ability to reduce the parasite burden of tissues. Conclusions Our findings suggest that both NVP-AEW541 and GSK-J4 could be potentially repurposed as candidate drugs against T. gondii infection. |
| first_indexed | 2024-12-10T10:13:23Z |
| format | Article |
| id | doaj.art-0f51cfef9dfe4f9684d4fb340feaaa0f |
| institution | Directory Open Access Journal |
| issn | 1756-3305 |
| language | English |
| last_indexed | 2024-12-10T10:13:23Z |
| publishDate | 2020-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Parasites & Vectors |
| spelling | doaj.art-0f51cfef9dfe4f9684d4fb340feaaa0f2022-12-22T01:53:04ZengBMCParasites & Vectors1756-33052020-05-0113111310.1186/s13071-020-04094-2Two old drugs, NVP-AEW541 and GSK-J4, repurposed against the Toxoplasma gondii RH strainShuxian Liu0Mimi Wu1Qianqian Hua2Daiqiang Lu3Yuan Tian4Helin Yu5Linyan Cheng6Yinqi Chen7Jiaxin Cao8Xin Hu9Feng Tan10Department of Parasitology, School of Basic Medical Sciences, Wenzhou Medical UniversityDepartment of Parasitology, School of Basic Medical Sciences, Wenzhou Medical UniversityClinical Laboratory, Dongyang People’s HospitalDepartment of Parasitology, School of Basic Medical Sciences, Wenzhou Medical UniversityDepartment of Parasitology, School of Basic Medical Sciences, Wenzhou Medical UniversityDepartment of Parasitology, School of Basic Medical Sciences, Wenzhou Medical UniversitySchool of the First Clinical Medical Sciences, Wenzhou Medical UniversitySchool of the Second Clinical Medical Sciences, Wenzhou Medical UniversitySchool of Ophthalmology & Optometry, Wenzhou Medical UniversitySchool of Medical Laboratory Science and School of Life Science, Wenzhou Medical UniversityDepartment of Parasitology, School of Basic Medical Sciences, Wenzhou Medical UniversityAbstract Background Toxoplasma gondii is a zoonotic pathogen that causes toxoplasmosis and leads to serious public health problems in developing countries. However, current clinical therapeutic drugs have some disadvantages, such as serious side effects, a long course of treatment and the emergence of drug-resistant strains. The urgent need to identify novel anti-Toxoplasma drugs has initiated the effective strategy of repurposing well-characterized drugs. As a principled screening for the identification of effective compounds against Toxoplasma gondii, in the current study, a collection of 666 compounds were screened for their ability to significantly inhibit Toxoplasma growth. Methods The inhibition of parasite growth was determined using a luminescence-based β-galactosidase activity assay. Meanwhile, the effect of compounds on the viability of host cells was measured using CCK8. To assess the inhibition of the selected compounds on discrete steps of the T. gondii lytic cycle, the invasion, intracellular proliferation and egress abilities were evaluated. Finally, a murine infection model of toxoplasmosis was used to monitor the protective efficacy of drugs against acute infection of a highly virulent RH strain. Results A total of 68 compounds demonstrated more than 70% parasite growth inhibition. After excluding compounds that impaired host cell viability, we further characterized two compounds, NVP-AEW541 and GSK-J4 HCl, which had IC50 values for parasite growth of 1.17 μM and 2.37 μM, respectively. In addition, both compounds showed low toxicity to the host cell. Furthermore, we demonstrated that NVP-AEW541 inhibits tachyzoite invasion, while GSK-J4 HCl inhibits intracellular tachyzoite proliferation by halting cell cycle progression from G1 to S phase. These findings prompted us to analyse the efficacy of the two compounds in vivo by using established mouse models of acute toxoplasmosis. In addition to prolonging the survival time of mice acutely infected with T. gondii, both compounds had a remarkable ability to reduce the parasite burden of tissues. Conclusions Our findings suggest that both NVP-AEW541 and GSK-J4 could be potentially repurposed as candidate drugs against T. gondii infection.http://link.springer.com/article/10.1186/s13071-020-04094-2NVP-AEW541GSK-J4Toxoplasma gondiiInvasionIntracellular replicationIn vivo |
| spellingShingle | Shuxian Liu Mimi Wu Qianqian Hua Daiqiang Lu Yuan Tian Helin Yu Linyan Cheng Yinqi Chen Jiaxin Cao Xin Hu Feng Tan Two old drugs, NVP-AEW541 and GSK-J4, repurposed against the Toxoplasma gondii RH strain Parasites & Vectors NVP-AEW541 GSK-J4 Toxoplasma gondii Invasion Intracellular replication In vivo |
| title | Two old drugs, NVP-AEW541 and GSK-J4, repurposed against the Toxoplasma gondii RH strain |
| title_full | Two old drugs, NVP-AEW541 and GSK-J4, repurposed against the Toxoplasma gondii RH strain |
| title_fullStr | Two old drugs, NVP-AEW541 and GSK-J4, repurposed against the Toxoplasma gondii RH strain |
| title_full_unstemmed | Two old drugs, NVP-AEW541 and GSK-J4, repurposed against the Toxoplasma gondii RH strain |
| title_short | Two old drugs, NVP-AEW541 and GSK-J4, repurposed against the Toxoplasma gondii RH strain |
| title_sort | two old drugs nvp aew541 and gsk j4 repurposed against the toxoplasma gondii rh strain |
| topic | NVP-AEW541 GSK-J4 Toxoplasma gondii Invasion Intracellular replication In vivo |
| url | http://link.springer.com/article/10.1186/s13071-020-04094-2 |
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