Novel ruthenium complexes as potential drugs for Chagas's disease: enzyme inhibition and in vitro/in vivo trypanocidal activity

作者：Nogueira Silva Jean Jerley; Matta Guedes Paulo Marcos; Zottis Aderson; Balliano Tatiane Luciano; Nascimento Silva Francisco Ordelei; Franca Lopes Luiz Gonzaga; Ellena Javier; Oliva Glaucius; Andricopulo Adriano Defini; Franco Douglas Wagner; Silva Joao Santana^*

来源：British Journal of Pharmacology, 2010, 160(2): 260-269.

DOI：10.1111/j.1476-5381.2009.00524.x

• NO donors
• Trypanosoma cruzi
• medicinal inorganic chemistry
• GAPDH
• ruthenium

Background and purpose:
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.
Experimental approach:
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.
Key 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 mu M). 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 center dot kg-1, yielded survival rates of 80 and 60%, respectively, in infected mice, and eradicated any amastigotes from their myocardial tissue.
Conclusions and implications:
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.
This article is commented on by Machado et al., pp. 258-259 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2010.00662.x and to view a related paper in this issue by Guedes et al. visit http://dx.doi.org/10.1111/j.1476-5381.2010.00576.x.

• 出版日期2010-5