title: Anacardic acid derivatives as inhibitors of glyceraldehyde-3-phosphate dehydrogenase from Trypanosoma cruzi.
abstract: Chagas' disease, a parasitic infection caused by the flagellate protozoan Trypanosoma cruzi, is a major public health problem affecting millions of individuals in Latin America. On the basis of the essential role in the life cycle of T. cruzi, the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has been considered an attractive target for the development of novel antitrypanosomatid agents. In the present work, we describe the inhibitory effects of a small library of natural and synthetic anacardic acid derivatives against the target enzyme. The most potent inhibitors, 6-n-pentadecyl- and 6-n-dodecylsalicilic acids, have IC(50) values of 28 and 55 microM, respectively. The inhibition was not reversed or prevented by the addition of Triton X-100, indicating that aggregate-based inhibition did not occur. In addition, detailed mechanistic characterization of the effects of these compounds on the T. cruzi GAPDH-catalyzed reaction showed clear noncompetitive inhibition with respect to both substrate and cofactor.
authors.affiliation: Departamento de Química, Universidade Federal de São Carlos, 13565-905 São Carlos, SP, Brazil.
authors.forename: Junia M
authors.initials: JM
authors.lastname: Pereira
authors.forename: Richele P
authors.initials: RP
authors.lastname: Severino
authors.forename: Paulo C
authors.initials: PC
authors.lastname: Vieira
authors.forename: João B
authors.initials: JB
authors.lastname: Fernandes
authors.forename: M Fátima G F
authors.initials: MF
authors.lastname: da Silva
authors.forename: Aderson
authors.initials: A
authors.lastname: Zottis
authors.forename: Adriano D
authors.initials: AD
authors.lastname: Andricopulo
authors.forename: Glaucius
authors.initials: G
authors.lastname: Oliva
authors.forename: Arlene G
authors.initials: AG
authors.lastname: Corrêa
mesh_terms: D048729:Anacardic Acids / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D002384:Catalysis; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D007700:Kinetics; D013329:Structure-Activity Relationship; D014349:Trypanosoma cruzi / Q000201:enzymology*
chemical_list: D048729:Anacardic Acids; D004791:Enzyme Inhibitors; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases