A new class of mechanism-based inhibitors for Trypanosoma cruzi trans-sialidase and their influence on parasite virulence
Autor: | Mauro Sola-Penna, Arlan S. Gonçalves, Shin-Ichiro Nishimura, Bianca Cruz Neves, Hiroshi Hinou, José O. Previato, Leonardo Freire-de-Lima, Isadora A. Oliveira, Sebastiao T. Carvalho, Francisco R Sousa, Samuel Pita, Lucia Mendonça-Previato, Masaki Kurogochi, Adriane R. Todeschini |
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Rok vydání: | 2010 |
Předmět: |
Chagas disease
Trypanosoma cruzi Mutant Virulence Neuraminidase Molecular Dynamics Simulation Biochemistry Host-Parasite Interactions Pathogenesis chemistry.chemical_compound Structure-Activity Relationship medicine Structure–activity relationship Animals Enzyme Inhibitors Glycoproteins chemistry.chemical_classification biology Dose-Response Relationship Drug Molecular Structure biology.organism_classification medicine.disease Virology Sialic acid Enzyme chemistry Biocatalysis Sialic Acids |
Zdroj: | Glycobiology. 20(8) |
ISSN: | 1460-2423 |
Popis: | One of the most interesting aspects of Trypanosoma cruzi is its adaptation to obtain sialic acid from its host, fulfilling this need exclusively through the reaction catalyzed by enzymatically active trans-sialidase (aTS), thought to play an important role in the pathogenesis of Chagas' disease. Herein, we report that 2-difluoromethyl-4-nitrophenyl-3,5-dideoxy-d-glycero-alpha-d-galacto-2-nonulopyranosid acid (NeuNAcFNP) inactivates aTS time- and dose-dependently, and this inhibition was not relieved removing the inhibitor. Also, NeuNAcFNP causes a decrease in infection of mammalian cells. Characterization of labeled aTS by matrix-assisted laser desorption/ionization time-of-flight/time-of-flight mass spectrometry revealed that inactivation of the enzyme occurs through formation of a covalent bond between Arg245 and Asp247 and the inhibitor aglycone. Participation of Asp247 in the catalytic mechanism was proved by constructing a TSD247A mutant, which presents only residual activity. Molecular dynamic simulations indicate that the D247A mutation results in a more open catalytic cleft. In summary, NeuNAcFNP is the first reported mechanism-based inhibitor of aTS, representing a new template for drug design and opening new possibilities for chemotherapy of Chagas' disease, as well as for the elucidation of aTS function in T. cruzi pathogenesis and biology. |
Databáze: | OpenAIRE |
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