Potent hydroxamate-derived compounds arrest endodyogeny of Toxoplasma gondii tachyzoites.

Autor:	Araujo-Silva CA; Laboratório de Ultraestrutura Celular Hertha Meyer, Instituto de Biofísica Carlos Chagas Filho, Av. Carlos Chagas Filho, Centro de Pesquisa em medicina de Precisão, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro, RJ, 21941-904, Brazil; Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagens, Universidade Federal do Rio de Janeiro, Brazil., Vögerl K; Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians University, Munich, Germany., Breu F; Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians University, Munich, Germany., Jung M; Institute of Pharmaceutical Sciences, University of Freiburg, Germany., Costa ALO; Laboratório de Quimioterapia de Protozoários Egler Chiari, Departamento de Parasitologia, ICB, Universidade Federal de Minas Gerais, Avenida Presidente Antônio Carlos, 6.627 -Pampulha, Belo Horizonte, MG, 31270-901, Brazil., De Souza W; Laboratório de Ultraestrutura Celular Hertha Meyer, Instituto de Biofísica Carlos Chagas Filho, Av. Carlos Chagas Filho, Centro de Pesquisa em medicina de Precisão, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro, RJ, 21941-904, Brazil; Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagens, Universidade Federal do Rio de Janeiro, Brazil., Bracher F; Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians University, Munich, Germany., Martins-Duarte ES; Laboratório de Quimioterapia de Protozoários Egler Chiari, Departamento de Parasitologia, ICB, Universidade Federal de Minas Gerais, Avenida Presidente Antônio Carlos, 6.627 -Pampulha, Belo Horizonte, MG, 31270-901, Brazil. Electronic address: ericamduarte@icb.ufmg.br., Vommaro RC; Laboratório de Ultraestrutura Celular Hertha Meyer, Instituto de Biofísica Carlos Chagas Filho, Av. Carlos Chagas Filho, Centro de Pesquisa em medicina de Precisão, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro, RJ, 21941-904, Brazil; Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagens, Universidade Federal do Rio de Janeiro, Brazil. Electronic address: vommaro@biof.ufrj.br.
Jazyk:	angličtina
Zdroj:	Experimental parasitology [Exp Parasitol] 2024 Apr; Vol. 259, pp. 108727. Date of Electronic Publication: 2024 Mar 01.
DOI:	10.1016/j.exppara.2024.108727
Abstrakt:	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 IC 50 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. Competing Interests: Declaration of competing interest The authors have none. (Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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