Targeting L-Proline uptake as new strategy for anti-chagas drug development
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2020-08-25
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Frontiers Media
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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
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
Palabras clave
Chagas Disease, Proline Uptake, Trypanosoma cruzi Epimastigotes, Cytotoxicity, Target Validation