Journal
FRONTIERS IN CHEMISTRY
Volume 8, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fchem.2020.00696
Keywords
Chagas disease; proline uptake; T; cruziepimastigotes; cytotoxicity; target validation
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Funding
- UNR (Universidad Nacional de Rosario) [Bio503]
- Agencia Nacional de Promocion Cientifica y Tecnologica (ANPCyT) [PICT-2017-2096]
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo [2016/06034-2]
- Conselho Nacional de Pesquisas Cientificas e Tecnologicas (CNPq) [404769/2018-7, 308351/2013-4]
- UK Research and Innovation via the Global Challenges Research Fund [MR/P027989/1]
- CONICET
- MRC [MR/P027989/1] Funding Source: UKRI
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L-Proline is an important amino acid for the pathogenic protists belonging toTrypanosomaandLeishmaniagenera. InTrypanosoma 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 forT. 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 forin vitroscreening againstT. cruziepimastigotes 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.
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