Inhibition of isoleucyl-tRNA synthetase as a potential treatment for human African Trypanosomiasis.
J Biol Chem
; 288(20): 14256-14263, 2013 May 17.
Article
em En
| MEDLINE
| ID: mdl-23548908
ABSTRACT
Trypanosoma brucei sp. causes human African trypanosomiasis (HAT; African sleeping sickness). The parasites initially proliferate in the hemolymphatic system and then invade the central nervous system, which is lethal if not treated. New drugs are needed for HAT because the approved drugs are few, toxic, and difficult to administer, and drug resistance is spreading. We showed by RNAi knockdown that T. brucei isoleucyl-tRNA synthetase is essential for the parasites in vitro and in vivo in a mouse model of infection. By structure prediction and experimental analysis, we also identified small molecules that inhibit recombinant isoleucyl-tRNA synthetase and that are lethal to the parasites in vitro and highly selective compared with mammalian cells. One of these molecules acts as a competitive inhibitor of the enzyme and cures mice of the infection. Because members of this class of molecules are known to cross the blood-brain barrier in humans and to be tolerated, they may be attractive as leading candidates for drug development for HAT.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Tripanossomicidas
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Trypanosoma brucei brucei
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Tripanossomíase Africana
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Inibidores Enzimáticos
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Isoleucina-tRNA Ligase
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
J Biol Chem
Ano de publicação:
2013
Tipo de documento:
Article