| Author | Araújo, Julianna Siciliano de | |
| Author | Silva, Patrícia Bernardino da | |
| Author | Batista, Marcos Meuser | |
| Author | Peres, Raiza Brandão | |
| Author | Cardoso-Santos, Camila | |
| Author | Kalejaiye, Titilola D. | |
| Author | Munday, Jane C. | |
| Author | De Heuvel, Erik | |
| Author | Sterk, Geert Jan | |
| Author | Augustyns, Koen | |
| Author | Salado, Irene G. | |
| Author | Matheeussen, An | |
| Author | De Esch, Iwan | |
| Author | De Koning, Harry P. | |
| Author | Leurs, Rob | |
| Author | Maes, Louis | |
| Author | Soeiro, Maria de Nazaré Correia | |
| Access date | 2020-03-23T20:00:15Z | |
| Available date | 2020-03-23T20:00:15Z | |
| Document date | 2020 | |
| Citation | ARAÚJO, Julianna Siciliano de et al. Evaluation of phthalazinone phosphodiesterase inhibitors with improved activity and selectivity against Trypanosoma cruzi. Journal of Antimicrobial Chemotherapy, v. 75, n. 4, p. 958-967, Apr. 2020. | |
| ISSN | 0305-7453 | |
| URI | https://www.arca.fiocruz.br/handle/icict/40465 | |
| Description | Produção científica do Laboratório de Biologia Celular. | pt_BR |
| Sponsorship | This work was supported by grants from Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) (203636, 200381). | |
| Sponsorship | Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (400102/2011–0, 302435/2012–3, 470582/2013–8) and Fundação Oswaldo Cruz. | |
| Sponsorship | Maria de Nazaré Correia Soeiro is a research fellow of CNPq and Cientista do Nosso Estado (CNE). | |
| Sponsorship | The PDE4NPD project is supported by the European Union 7th Framework Program (FP7/2007–2013) (grant agreement 602666). | |
| Language | eng | en_US |
| Publisher | Oxford | |
| Rights | open access | |
| Title | Evaluation of phthalazinone phosphodiesterase inhibitors with improved activity and selectivity against Trypanosoma cruzi | en_US |
| Type | Article | |
| DOI | 10.1093/jac/dkz516 | |
| Abstract | Background: Chagas' disease, caused by the protozoan parasite Trypanosoma cruzi, needs urgent alternative therapeutic options as the treatments currently available display severe limitations, mainly related to efficacy and toxicity. Objectives: As phosphodiesterases (PDEs) have been claimed as novel targets against T. cruzi, our aim was to evaluate the biological aspects of 12 new phthalazinone PDE inhibitors against different T. cruzi strains and parasite forms relevant for human infection. Methods: In vitro trypanocidal activity of the inhibitors was assessed alone and in combination with benznidazole. Their effects on parasite ultrastructural and cAMP levels were determined. PDE mRNA levels from the different T. cruzi forms were measured by quantitative reverse transcription PCR. Results: Five TcrPDEs were found to be expressed in all parasite stages. Four compounds displayed strong effects against intracellular amastigotes. Against bloodstream trypomastigotes (BTs), three were at least as potent as benznidazole. In vitro combination therapy with one of the most active inhibitors on both parasite forms (NPD-040) plus benznidazole demonstrated a quite synergistic profile (xΣ FICI = 0.58) against intracellular amastigotes but no interaction (xΣ FICI = 1.27) when BTs were assayed. BTs treated with NPD-040 presented disrupted Golgi apparatus, a swollen flagellar pocket and signs of autophagy. cAMP measurements of untreated parasites showed that amastigotes have higher ability to efflux this second messenger than BTs. NPD-001 and NPD-040 increase the intracellular cAMP content in both BTs and amastigotes, which is also released into the extracellular milieu. Conclusions: The findings demonstrate the potential of PDE inhibitors as anti-T. cruzi drug candidates. | en_US |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil. | |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil. | |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil. | |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil. | |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil. | |
| Affilliation | University of Glasgow. College of Medical, Veterinary & Life Sciences. Institute of Infection, Immunity & Inflammation. Glasgow, UK. | |
| Affilliation | University of Glasgow. College of Medical, Veterinary & Life Sciences. Institute of Infection, Immunity & Inflammation. Glasgow, UK. | |
| Affilliation | Vrije Universiteit Amsterdam. Amsterdam Institute for Molecules, Medicines & Systems. Medicinal Chemistry. Amsterdam, The Netherlands. | |
| Affilliation | Vrije Universiteit Amsterdam. Amsterdam Institute for Molecules, Medicines & Systems. Medicinal Chemistry. Amsterdam, The Netherlands. | |
| Affilliation | University of Antwerp. Laboratory of Medicinal Chemistry. Antwerp, Belgium. | |
| Affilliation | University of Antwerp. Laboratory of Medicinal Chemistry. Antwerp, Belgium. | |
| Affilliation | University of Antwerp. Laboratory for Microbiology, Parasitology and Hygiene. Antwerp, Belgium. | |
| Affilliation | Vrije Universiteit Amsterdam. Amsterdam Institute for Molecules, Medicines & Systems. Medicinal Chemistry. Amsterdam, The Netherlands. | |
| Affilliation | University of Glasgow. College of Medical, Veterinary & Life Sciences. Institute of Infection, Immunity & Inflammation. Glasgow, UK. | |
| Affilliation | Vrije Universiteit Amsterdam. Amsterdam Institute for Molecules, Medicines & Systems. Medicinal Chemistry. Amsterdam, The Netherlands. | |
| Affilliation | University of Antwerp. Laboratory for Microbiology, Parasitology and Hygiene. Antwerp, Belgium. | |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil. | |
| Subject | Chagas disease | en_US |
| Subject | Polymerase chain reaction | en_US |
| Subject | Phosphodiesterase inhibitors | en_US |
| Subject | Blalock-taussig shunt | en_US |
| Subject | Benznidazole | en_US |
| Subject | Combined modality therapy | en_US |
| Subject | Golgi apparatus | en_US |
| Subject | Parasites | en_US |
| Subject | Trypanosoma cruzi | en_US |
| Subject | Infections | en_US |
| Subject | Cyclic ampcyclic amp measurement | en_US |
| Subject | Diethylstilbestrol monophosphate | en_US |
| Subject | Toxic effect | en_US |
| Subject | Trypomastigote form of protozoa | en_US |
| e-ISSN | 1460-2091 | |
