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 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 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.
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 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 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.
Authors: D H Souza; R C Garratt; A P Araújo; B G Guimarães; W D Jesus; P A Michels; V Hannaert; G Oliva Journal: FEBS Lett Date: 1998-03-13 Impact factor: 4.124
Authors: Douglas T Hess; Akio Matsumoto; Sung-Oog Kim; Harvey E Marshall; Jonathan S Stamler Journal: Nat Rev Mol Cell Biol Date: 2005-02 Impact factor: 94.444
Authors: Simone da S. S. Borges; Celso U. Davanzo; Eduardo E. Castellano; Julio Z-Schpector; Sebastião C. Silva; Douglas W. Franco Journal: Inorg Chem Date: 1998-06-01 Impact factor: 5.165
Authors: Marcio Wilker Soares Campelo; Reinaldo Barreto Oriá; Luiz Gonzaga de França Lopes; Gerly Anne de Castro Brito; Armenio Aguiar dos Santos; Raquel Cavalcante de Vasconcelos; Francisco Ordelei Nascimento da Silva; Beatrice Nuto Nobrega; Moisés Tolentino Bento-Silva; Paulo Roberto Leitão de Vasconcelos Journal: Neurochem Res Date: 2011-12-10 Impact factor: 3.996
Authors: Alisson L Matsuo; Luis S Silva; Ana C Torrecilhas; Bruno S Pascoalino; Thiago C Ramos; Elaine G Rodrigues; Sergio Schenkman; Antonio C F Caires; Luiz R Travassos Journal: Antimicrob Agents Chemother Date: 2010-05-17 Impact factor: 5.191
Authors: Antonio R L Teixeira; Mariana M Hecht; Maria C Guimaro; Alessandro O Sousa; Nadjar Nitz Journal: Clin Microbiol Rev Date: 2011-07 Impact factor: 26.132
Authors: Tanira M Bastos; Marília I F Barbosa; Monize M da Silva; José W da C Júnior; Cássio S Meira; Elisalva T Guimaraes; Javier Ellena; Diogo R M Moreira; Alzir A Batista; Milena B P Soares Journal: Antimicrob Agents Chemother Date: 2014-08-04 Impact factor: 5.191
Authors: Aurideia P de Sousa; Ana C S Gondim; Eduardo H S Sousa; Mayron A de Vasconcelos; Edson H Teixeira; Beatriz Pinheiro Bezerra; Alejandro Pedro Ayala; Patrícia H R Martins; Luiz Gonzaga de França Lopes; Alda K M Holanda Journal: J Biol Inorg Chem Date: 2020-03-14 Impact factor: 3.358
Authors: Edinilton Muniz Carvalho; Lisa A Ridnour; Florêncio Sousa Gouveia Júnior; Pedro Henrique Bezerra Cabral; Nilberto Robson Falcão do Nascimento; David A Wink; Douglas W Franco; Mayara Jane Campos de Medeiros; Daniel de Lima Pontes; Elisane Longhinotti; Tércio de Freitas Paulo; Vania Bernardes-Génisson; Remi Chauvin; Eduardo Henrique Silva Sousa; Luiz Gonzaga de França Lopes Journal: J Inorg Biochem Date: 2020-06-20 Impact factor: 4.155