AUTHOR=Fargnoli Lucía , Panozzo-Zénere Esteban A. , Pagura Lucas , Barisón María Julia , Cricco Julia A. , Silber Ariel M. , Labadie Guillermo R. 

TITLE=Targeting L-Proline Uptake as New Strategy for Anti-chagas Drug Development

JOURNAL=Frontiers in Chemistry

VOLUME=8

YEAR=2020

URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2020.00696

DOI=10.3389/fchem.2020.00696

ISSN=2296-2646

ABSTRACT=<p>L-Proline is an important amino acid for the pathogenic protists belonging to <italic>Trypanosoma</italic> and <italic>Leishmania</italic> genera. In <italic>Trypanosoma cruzi</italic>, 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 <italic>T. cruzi</italic>. 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 <italic>in vitro</italic> screening against <italic>T. cruzi</italic> 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.</p>