Carlla Assis Araujo-Silva , Katharina Vögerl , Ferdinand Breu , Manfred Jung , Andreia Luiza Oliveira Costa , Wanderley De Souza , Franz Bracher , Erica S. Martins-Duarte , Rossiane C. Vommaro
{"title":"源自羟基氨基甲酸酯的强效化合物可抑制弓形虫蝌蚪的内生。","authors":"Carlla Assis Araujo-Silva , Katharina Vögerl , Ferdinand Breu , Manfred Jung , Andreia Luiza Oliveira Costa , Wanderley De Souza , Franz Bracher , Erica S. Martins-Duarte , Rossiane C. Vommaro","doi":"10.1016/j.exppara.2024.108727","DOIUrl":null,"url":null,"abstract":"<div><p>Toxoplasmosis is a zoonosis that is a worldwide health problem, commonly affecting fetal development and immunodeficient patients. Treatment is carried out with a combination of pyrimethamine and sulfadiazine, which can cause cytopenia and intolerance and does not lead to a parasitological cure of the infection. Lysine deacetylases (KDACs), which remove an acetyl group from lysine residues in histone and non-histone proteins are found in the <em>Toxoplasma gondii</em> genome. Previous work showed the hydroxamate-type KDAC inhibitors Tubastatin A (TST) and Vorinostat (Suberoylanilide Hydroxamic Acid, SAHA) were effective against <em>T. gondii</em>. In the present study, the effects of three hydroxamates (<strong>KV-24</strong>, <strong>KV-30</strong>, <strong>KV-46</strong>), which were originally designed to inhibit human KDAC6, showed different effects against <em>T. gondii</em>. These compounds contain a heterocyclic cap group and a benzyl linker bearing the hydroxamic acid group in <em>para</em>-position. All compounds showed selective activity against <em>T. gondii</em> proliferation, inhibiting tachyzoite proliferation with IC<sub>50</sub> values in a nanomolar range after 48h treatment. Microscopy analyses showed that after treatment, tachyzoites presented mislocalization of the apicoplast, disorganization of the inner membrane complex, and arrest in the completion of new daughter cells. The number of dividing cells with incomplete endodyogeny increased significantly after treatment, indicating the compounds can interfere in the late steps of cell division. The results obtained in this work that these new hydroxamates should be considered for future <em>in vivo</em> tests and the development of new compounds for treating toxoplasmosis.</p></div>","PeriodicalId":12117,"journal":{"name":"Experimental parasitology","volume":null,"pages":null},"PeriodicalIF":1.4000,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Potent hydroxamate-derived compounds arrest endodyogeny of Toxoplasma gondii tachyzoites\",\"authors\":\"Carlla Assis Araujo-Silva , Katharina Vögerl , Ferdinand Breu , Manfred Jung , Andreia Luiza Oliveira Costa , Wanderley De Souza , Franz Bracher , Erica S. Martins-Duarte , Rossiane C. Vommaro\",\"doi\":\"10.1016/j.exppara.2024.108727\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Toxoplasmosis is a zoonosis that is a worldwide health problem, commonly affecting fetal development and immunodeficient patients. Treatment is carried out with a combination of pyrimethamine and sulfadiazine, which can cause cytopenia and intolerance and does not lead to a parasitological cure of the infection. Lysine deacetylases (KDACs), which remove an acetyl group from lysine residues in histone and non-histone proteins are found in the <em>Toxoplasma gondii</em> genome. Previous work showed the hydroxamate-type KDAC inhibitors Tubastatin A (TST) and Vorinostat (Suberoylanilide Hydroxamic Acid, SAHA) were effective against <em>T. gondii</em>. In the present study, the effects of three hydroxamates (<strong>KV-24</strong>, <strong>KV-30</strong>, <strong>KV-46</strong>), which were originally designed to inhibit human KDAC6, showed different effects against <em>T. gondii</em>. These compounds contain a heterocyclic cap group and a benzyl linker bearing the hydroxamic acid group in <em>para</em>-position. All compounds showed selective activity against <em>T. gondii</em> proliferation, inhibiting tachyzoite proliferation with IC<sub>50</sub> values in a nanomolar range after 48h treatment. Microscopy analyses showed that after treatment, tachyzoites presented mislocalization of the apicoplast, disorganization of the inner membrane complex, and arrest in the completion of new daughter cells. The number of dividing cells with incomplete endodyogeny increased significantly after treatment, indicating the compounds can interfere in the late steps of cell division. The results obtained in this work that these new hydroxamates should be considered for future <em>in vivo</em> tests and the development of new compounds for treating toxoplasmosis.</p></div>\",\"PeriodicalId\":12117,\"journal\":{\"name\":\"Experimental parasitology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":1.4000,\"publicationDate\":\"2024-03-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Experimental parasitology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0014489424000304\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"PARASITOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Experimental parasitology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0014489424000304","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"PARASITOLOGY","Score":null,"Total":0}
Potent hydroxamate-derived compounds arrest endodyogeny of Toxoplasma gondii tachyzoites
Toxoplasmosis is a zoonosis that is a worldwide health problem, commonly affecting fetal development and immunodeficient patients. Treatment is carried out with a combination of pyrimethamine and sulfadiazine, which can cause cytopenia and intolerance and does not lead to a parasitological cure of the infection. Lysine deacetylases (KDACs), which remove an acetyl group from lysine residues in histone and non-histone proteins are found in the Toxoplasma gondii genome. Previous work showed the hydroxamate-type KDAC inhibitors Tubastatin A (TST) and Vorinostat (Suberoylanilide Hydroxamic Acid, SAHA) were effective against T. gondii. In the present study, the effects of three hydroxamates (KV-24, KV-30, KV-46), which were originally designed to inhibit human KDAC6, showed different effects against T. gondii. These compounds contain a heterocyclic cap group and a benzyl linker bearing the hydroxamic acid group in para-position. All compounds showed selective activity against T. gondii proliferation, inhibiting tachyzoite proliferation with IC50 values in a nanomolar range after 48h treatment. Microscopy analyses showed that after treatment, tachyzoites presented mislocalization of the apicoplast, disorganization of the inner membrane complex, and arrest in the completion of new daughter cells. The number of dividing cells with incomplete endodyogeny increased significantly after treatment, indicating the compounds can interfere in the late steps of cell division. The results obtained in this work that these new hydroxamates should be considered for future in vivo tests and the development of new compounds for treating toxoplasmosis.
期刊介绍:
Experimental Parasitology emphasizes modern approaches to parasitology, including molecular biology and immunology. The journal features original research papers on the physiological, metabolic, immunologic, biochemical, nutritional, and chemotherapeutic aspects of parasites and host-parasite relationships.