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ALTERATIONS ON THE GROWTH AND ULTRASTRUCTURE OF LEISHMANIA CHAGASI INDUCED BY SQUALENE SYNTHASE INHIBITORS
Ultraestrutura
Quimioterapia
Ergosterol
Inibidores da biossíntese de esteróis
Squalene synthase
Sterol biosynthesis inhibitors
Ergosterol
Chemotherapy
Ultrastructure
Author
Affilliation
Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Laboratório de Ultraestrutura Celular Hertha Meyer. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Departamento de Biologia. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Laboratório de Ultraestrutura Celular Hertha Meyer. Rio de Janeiro, RJ, Brasil.
Cardiff University. Welsh School of Pharmacy. Cardiff, UK.
Cardiff University. Welsh School of Pharmacy. Cardiff, UK.
Cardiff University. Welsh School of Pharmacy. Cardiff, UK.
Instituto Venezolano de Investigaciones Científicas. Centro de Biofísica y Bioquímica. Laboratorio de Química Biológica. Venezuela.
Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Laboratório de Ultraestrutura Celular Hertha Meyer. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Departamento de Biologia. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Laboratório de Ultraestrutura Celular Hertha Meyer. Rio de Janeiro, RJ, Brasil.
Cardiff University. Welsh School of Pharmacy. Cardiff, UK.
Cardiff University. Welsh School of Pharmacy. Cardiff, UK.
Cardiff University. Welsh School of Pharmacy. Cardiff, UK.
Instituto Venezolano de Investigaciones Científicas. Centro de Biofísica y Bioquímica. Laboratorio de Química Biológica. Venezuela.
Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Laboratório de Ultraestrutura Celular Hertha Meyer. Rio de Janeiro, RJ, Brasil.
Abstract
Leishmaniasis 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.
Keywords in Portuguese
LeishmaniaUltraestrutura
Quimioterapia
Ergosterol
Inibidores da biossíntese de esteróis
Keywords
LeishmaniaSqualene synthase
Sterol biosynthesis inhibitors
Ergosterol
Chemotherapy
Ultrastructure
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