Alterations on the growth and ultrastructure of Leishmania chagasi induced by squalene synthase inhibitors

dc.creatorGranthon, Ana Claudia
dc.creatorBraga, Marina V.
dc.creatorRodrigues, Juliany C.F.
dc.creatorCammerer, Simon
dc.creatorLorente, Silvia Orenes
dc.creatorGilbert, Ian H.
dc.creatorUrbina, Julio A.
dc.creatorSouza, Wanderley de
dc.date2020-02-06T15:57:27Z
dc.date2020-02-06T15:57:27Z
dc.date2007
dc.date.accessioned2023-09-26T20:55:25Z
dc.date.available2023-09-26T20:55:25Z
dc.identifierGRANTHON, Ana Claudia et al. Alterations on the growth and ultrastructure of Leishmania chagasi induced by squalene synthase inhibitors. Veterinary Parasitology, v. 146, p. 25-34, 2007.
dc.identifier0304-4017
dc.identifierhttps://www.arca.fiocruz.br/handle/icict/39780
dc.identifier10.1016/j.vetpar.2006.12.022
dc.identifier1873-2550
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/8866225
dc.descriptionLeishmaniasis is an important disease in widely dispersed regions of the world. In South America, visceral leishmaniasis (VL) is mainly caused by Leishmania chagasi. The morbidity associated with the infection is high, and death may occur in some untreated patients. Treatment has been based upon pentavalent antimonial drugs for more than half a century and problems, including development of resistance to antimonials and lack of efficacy against VL/HIV co-infections, have emphasized the need for new drugs. Squalene synthase (SQS) is an essential enzyme for the biosynthesis of protozoal sterol molecules. In this work, nineteen synthetic quinuclidines, potentially inhibitors of SQS, were tested against promastigote forms of L. chagasi and the IC50 values of the compounds were determined. The most active compounds had IC50 values of around 30 nM and induced complete growth arrest and cell lysis at sub-micromolar concentrations. We analyzed the morphological structure of the parasites treated with these compounds by transmission electron microscopy of thin sections. Treated parasites showed significant ultrastructural changes, which varied from discrete alterations to total destruction of the cells, depending on the drug concentration and the time of incubation. One important change observed was a typical swelling of the unique and highly branched mitochondrion, where the inner membrane lost its organization. There was an increase in the number of autophagosomal structures. Changes in the organization of the nuclear chromatin and alterations in the flagellar pocket and flagellar membrane were also observed.
dc.formatapplication/pdf
dc.languageeng
dc.publisherElsevier
dc.rightsopen access
dc.subjectFarnesil-Difosfato Farnesiltransferase
dc.subjectLeishmania
dc.subjectUltraestrutura
dc.subjectQuimioterapia
dc.subjectErgosterol
dc.subjectInibidores da biossíntese de esteróis
dc.subjectLeishmania
dc.subjectSqualene synthase
dc.subjectSterol biosynthesis inhibitors
dc.subjectErgosterol
dc.subjectChemotherapy
dc.subjectUltrastructure
dc.titleAlterations on the growth and ultrastructure of Leishmania chagasi induced by squalene synthase inhibitors
dc.typeArticle


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