Planejamento racional de novos agentes quimioterápicos: Identificação e estudos cinéticos de novos inibidores da gliceraldeído-3-fosfato desidrogenase glicossomal de Trypanosoma cruzi

Zottis, Aderson

doi:10.11606/T.76.2009.tde-23042009-145454

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Doctoral Thesis

DOI

https://doi.org/10.11606/T.76.2009.tde-23042009-145454

Document

Doctoral Thesis

Author

Zottis, Aderson (Catálogo USP)

Full name

Aderson Zottis

E-mail

Institute/School/College

Instituto de Física de São Carlos

Knowledge Area

Applied Physics

Date of Defense

2009-03-26

Published

São Carlos, 2009

Supervisor

Andricopulo, Adriano Defini (Catálogo USP)
Oliva, Glaucius - (Co-supervisor) (Catálogo USP)

Committee

Andricopulo, Adriano Defini (President)
Honorio, Káthia Maria
Silva, Albérico Borges Ferreira da
Yunes, Rosendo Augusto
Zucolotto, Valtencir

Title in Portuguese

Planejamento racional de novos agentes quimioterápicos: Identificação e estudos cinéticos de novos inibidores da gliceraldeído-3-fosfato desidrogenase glicossomal de Trypanosoma cruzi

Keywords in Portuguese

Trypanosoma cruzi
Doença de Chagas.
Ensaio virtual
GAPDH
Inibidores

Abstract in Portuguese

As doenças negligenciadas são conseqüências marcantes do subdesenvolvimento que atinge diversas regiões do planeta. Dentre estas, destaca-se a Doença de Chagas, causada pelo parasita Trypanosoma cruzi, a qual afeta aproximadamente um quarto da população da América Latina e para qual os fármacos utilizados apresentam baixa eficácia, toxidez e sérios efeitos colaterais. Este quadro é agravado pela emergência de cepas resistentes, o que indica a grande necessidade de desenvolvimento de novos agentes quimioterápicos contra esta doença. A enzima gliceraldeído-3-fosfato desidrogenase (GAPDH) da via glicolítica do T. cruzi é um alvo macromolecular interessante devido ao seu papel essencial no metabolismo de tripanossomatídeos. Constitui o objetivo desta tese o desenvolvimento, a padronização e a validação de ensaios enzimáticos para a realização de extensivas triagens bioquímicas de modo a contribuir para a identificação de novos inibidores da GAPDH pertencentes a diversas classes químicas. Os compostos estudados são provenientes de síntese orgânica e de complexos inorgânicos de Rutênio, bem como de origem natural. Paralelamente, a realização do ensaio virtual em larga escala a partir de uma base de dados dirigida e da estrutura da GAPDH de T. cruzi resultou na identificação de um inibidor inédito da proteína alvo. Estudos do mecanismo de ação enzimático levaram à elucidação da modalidade de alguns inibidores identificados nesse estudo.

Title in English
Rational design of new chemotherapeutic agents: identification and kinetic studies of new inhibitors of glycosomal glyceraldehyde-3-phosphate dehydrogenase from Trypanosoma cruzi

Keywords in English
Trypanosoma cruzi
Chagas' Disease
GAPDH
Inhibitors
Virtual screening

Abstract in English

Parasitic diseases are a major global cause of illness, long-term disability, and death, with severe socio-economic consequences for millions of people worldwide. In Latin America, nearly one fourth of the population is infected by Trypanosoma cruzi, the causative agent of Chagas disease. The limited existing drug therapies suffer from a combination of drawbacks including poor efficacy, resistance and serious side effects. Therefore, there is an urgent need for new drugs that can overcome resistance and are safe and effective for use in human. The crucial dependence on glycolysis as a source of energy makes the glycolytic parasite enzymes promising targets for drug design. In this context, the enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was identified as an attractive target for drug design. The development of standard enzymatic assays combined with extensive biological screening was the aim of this work and it has been contributing for the identification of novel GAPDH inhibitors. These compounds belong to several chemical classes from different sources, including organic synthesis, inorganic complexes and natural products. In addition, a virtual screening approach was applied in a focused database, previously filtered by drug-like properties, in order to identify new hits. This strategy resulted in the discovery of a novel scaffold with significant inhibitory activity against T. cruzi GAPDH. Kinetic and inhibition assays were conducted to shed light on the mechanism of action of the promising inhibitors.

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Publishing Date
2009-04-28

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