title: Novel ruthenium complexes as potential drugs for Chagas's disease: enzyme inhibition and in vitro/in vivo trypanocidal activity.
abstract: OBJECTIVE
  The discovery of the pharmacological functions of nitric oxide has led to the development of NO donor compounds as therapeutic agents. A new generation of ruthenium NO donors, cis-[Ru(NO)(bpy)(2)L]X(n), has been developed, and our aim was to show that these complexes are able to lyse Trypanosoma cruzi in vitro and in vivo.
  
  
  METHODS
  NO donors were incubated with T. cruzi and their anti-T. cruzi activities evaluated as the percentage of lysed parasites compared to the negative control. In vivo, trypanocidal activity was evaluated by observing the levels of parasitaemia, survival rate and elimination of amastigotes in mouse myocardial tissue. The inhibition of GAPDH was monitored by the biochemical reduction of NAD(+) to NADH.
  
  
  RESULTS
  The NO donors cis-[Ru(NO)(bpy)(2)L]X(n) presented inhibitory effects on T. cruzi GAPDH (IC(50) ranging from 89 to 153 microM). The crystal structure of the enzyme shows that the inhibitory mechanism is compatible with S-nitrosylation of the active cysteine (cys166) site. Compounds cis-[Ru(NO)(bpy)(2)imN](PF(6))(3) and cis-[Ru(NO)(bpy)(2)SO(3)]PF(6), at a dose of 385 nmol.kg(-1), yielded survival rates of 80 and 60%, respectively, in infected mice, and eradicated any amastigotes from their myocardial tissue.
  
  
  CONCLUSIONS
  The ruthenium compounds exhibited potent in vitro and in vivo trypanocidal activities at doses up to 1000-fold lower than the clinical dose for benznidazole. Furthermore, one mechanism of action of these compounds is via the S-nitrosylation of Cys166 of T. cruzi GAPDH. Thus, these compounds show huge potential as candidates for the development of new drugs for the treatment of Chagas's disease.
authors.affiliation: Departamento de Física e Informática, Instituto de Física de São Carlos, Universidade de São Paulo, São Carlos, SP, Brazil. jjerley@usp.br <jjerley@usp.br>
authors.forename: Jean Jerley Nogueira
authors.initials: JJ
authors.lastname: Silva
authors.forename: Paulo Marcos Matta
authors.initials: PM
authors.lastname: Guedes
authors.forename: Aderson
authors.initials: A
authors.lastname: Zottis
authors.forename: Tatiane Luciano
authors.initials: TL
authors.lastname: Balliano
authors.forename: Francisco Ordelei
authors.initials: FO
authors.lastname: Nascimento Silva
authors.forename: Luiz Gonzaga
authors.initials: LG
authors.lastname: França Lopes
authors.forename: Javier
authors.initials: J
authors.lastname: Ellena
authors.forename: Glaucius
authors.initials: G
authors.lastname: Oliva
authors.forename: Adriano Defini
authors.initials: AD
authors.lastname: Andricopulo
authors.forename: Douglas Wagner
authors.initials: DW
authors.lastname: Franco
authors.forename: João Santana
authors.initials: JS
authors.lastname: Silva
mesh_terms: D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy* / Q000469:parasitology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology; D005260:Female; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000037:antagonists & inhibitors; D020128:Inhibitory Concentration 50; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D017975:Ruthenium Compounds / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000201:enzymology
chemical_list: D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D017975:Ruthenium Compounds; D014344:Trypanocidal Agents; D009569:Nitric Oxide; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases