Novel ruthenium complexes as potential drugs for Chagas's disease: enzyme inhibition and in vitro/in vivo trypanocidal activity.
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.
Silva
Jean Jerley Nogueira
JJ
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>
Guedes
Paulo Marcos Matta
PM
Zottis
Aderson
A
Balliano
Tatiane Luciano
TL
Nascimento Silva
Francisco Ordelei
FO
França Lopes
Luiz Gonzaga
LG
Ellena
Javier
J
Oliva
Glaucius
G
Andricopulo
Adriano Defini
AD
Franco
Douglas Wagner
DW
Silva
João Santana
JS
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
D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D017975:Ruthenium Compounds; D014344:Trypanocidal Agents; D009569:Nitric Oxide; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases