Anti-Trypanosoma cruzi Activity of Metabolism Modifier Compounds
Martinez-Peinado, Nieves (Institut de Salut Global de Barcelona)
Cortés Serra, Núria (Institut de Salut Global de Barcelona)
Sherman, Julian (New York University School of Medicine. Department of Microbiology)
Rodriguez, Ana (New York University School of Medicine. Department of Microbiology)
Gascon, Joaquim (Barcelona Institute for Global Health (ISGlobal))
Alberola, Jordi (Universitat Autònoma de Barcelona. Departament de Farmacologia, de Terapèutica i de Toxicologia)
Pinazo, Maria-Jesus (Institut de Salut Global de Barcelona)
Rodríguez-Cortés, Alhelí (Universitat Autònoma de Barcelona. Departament de Farmacologia, de Terapèutica i de Toxicologia)
Alonso-Padilla, Julio (Institut de Salut Global de Barcelona)
Martori Muntsant, Clara (Universitat Autònoma de Barcelona. Departament de Farmacologia, de Terapèutica i de Toxicologia)

Data:	2021
Resum:	Chagas disease is caused by the protozoan parasite Trypanosoma cruzi and affects over 6 million people worldwide. Development of new drugs to treat this disease remains a priority since those currently available have variable efficacy and frequent adverse effects, especially during the long regimens required for treating the chronic stage of the disease. T. cruzi modulates the host cell-metabolism to accommodate the cell cytosol into a favorable growth environment and acquire nutrients for its multiplication. In this study we evaluated the specific anti-T. cruzi activity of nine bio-energetic modulator compounds. Notably, we identified that 17-DMAG, which targets the ATP-binding site of heat shock protein 90 (Hsp90), has a very high (sub-micromolar range) selective inhibition of the parasite growth. This inhibitory effect was also highly potent (IC50 = 0. 27 μmol L−1) against the amastigote intracellular replicative stage of the parasite. Moreover, molecular docking results suggest that 17-DMAG may bind T. cruzi Hsp90 homologue Hsp83 with good affinity. Evaluation in a mouse model of chronic T. cruzi infection did not show parasite growth inhibition, highlighting the difficulties encountered when going from in vitro assays onto preclinical drug developmental stages.
Ajuts:	Agència de Gestió d'Ajuts Universitaris i de Recerca 2017SGR00924 Instituto de Salud Carlos III RD12/0018/0010 Ministerio de Ciencia e Innovación PI18/01054 Ministerio de Ciencia e Innovación CEX2018-000806-S
Nota:	Altres ajuts: GC/PERIS/2016-2010/SLT008/18/00132
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Trypanosoma cruzi ; Chagas disease ; Metabolism drugs ; Phenotypic assays ; Cytotoxicity assays ; Chronic in vivo model ; Dorsomorphin ; 17-DMAG
Publicat a:	International journal of molecular sciences, Vol. 22 Núm. 2 (2021) , p. 688, ISSN 1422-0067

DOI: 10.3390/ijms22020688
PMID: 33445756

16 p, 2.8 MB

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