Chemical validation of GPI biosynthesis as a drug target against African sleeping sickness

AUTOR(ES)

Smith, Terry K

FONTE

Nature Publishing Group

RESUMO

It has been suggested that compounds affecting glycosylphosphatidylinositol (GPI) biosynthesis in bloodstream form Trypanosoma brucei should be trypanocidal. We describe cell-permeable analogues of a GPI intermediate that are toxic to this parasite but not to human cells. These analogues are metabolized by the T. brucei GPI pathway, but not by the human pathway. Closely related nonmetabolizable analogues have no trypanocidal activity. This represents the first direct chemical validation of the GPI biosynthetic pathway as a drug target against African human sleeping sickness. The results should stimulate further inhibitor design and synthesis and encourage the search for inhibitors in natural product and synthetic compound libraries.

Documentos Relacionados

• Glycosylphosphatidylinositol biosynthesis validated as a drug target for African sleeping sickness
• African sleeping sickness
• Trypanosoma brucei CTP synthetase: A target for the treatment of African sleeping sickness
• Galactose metabolism is essential for the African sleeping sickness parasite Trypanosoma brucei
• Peptide Deformylase as an Antibacterial Drug Target: Target Validation and Resistance Development