article
Targeting L-Proline uptake as new strategy for anti-chagas drug development
Autor
Fargnoli, Lucía
Panozzo Zénere, Esteban Andrés
Pagura, Lucas
Barisón, María Julia
Cricco, Julia Alejandra
Silber, Ariel M.
Labadie, Guillermo Roberto
Institución
Resumen
L-Proline is an important amino acid for the pathogenic protists belonging to
Trypanosoma and Leishmania genera. In Trypanosoma cruzi, the etiological agent of
Chagas disease, this amino acid is involved in fundamental biological processes such as
ATP production, differentiation of the insect and intracellular stages, the host cell infection
and the resistance to a variety of stresses. In this study, we explore the L-Proline uptake
as a chemotherapeutic target for T. cruzi. Novel inhibitors have been proposed containing
the amino acid with a linker and a variable region able to block the transporter. A series of
sixteen 1,2,3-triazolyl-proline derivatives have been prepared for in vitro screening against
T. cruzi epimastigotes and proline uptake assays. We successfully obtained inhibitors
that interfere with the amino acid internalization, which validated our design targeting the
metabolite’s transport. The presented structures are one of few examples of amino acid
transporter inhibitors. The unprecedent application of this strategy on the development of
new chemotherapy against Chagas disease, opens a new horizon on antiparasitic drug
development against parasitic diseases and other pathologies. Para citar este articulo: Fargnoli L, Panozzo-Zénere EA,
Pagura L, Barisón MJ, Cricco JA,
Silber AM and Labadie GR (2020)
Targeting L-Proline Uptake as New
Strategy for Anti-chagas Drug
Development. Front. Chem. 8:696.
doi: 10.3389/fchem.2020.00696 Fil: Fargnoli, Lucía. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario (IQUIR -CONICET); Argentina. Fil: Panozzo Zénere, Esteban Andrés. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario (IQUIR -CONICET); Argentina. Fil: Pagura, Lucas. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario (IBR -CONICET); Argentina. Fil: Barisón, María Julia. Universidade de São Paulo. Instituto de Ciências Biomédicas. Departamento de Parasitologia. Laboratory of Biochemistry of Tryps (LaBTryps); Brazil. Fil: Cricco, Julia Alejandra. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario (IBR -CONICET); Argentina. Fil: Silber, Ariel M. Universidade de São Paulo. Instituto de Ciências Biomédicas. Departamento de Parasitologia. Laboratory of Biochemistry of Tryps (LaBTryps); Brazil. Fil: Labadie, Guillermo Roberto. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario (IQUIR -CONICET); Argentina. Fil: Labadie, Guillermo Roberto. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Química Orgánica; Argentina.