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Curr Med Chem. 2018 Sep 26. doi: 10.2174/0929867325666180926151059. [Epub ahead of print]

The thiol-polyamine metabolism of Trypanosoma cruzi: molecular targets and drug repurposing strategies.

Author information

1
Medicinal Chemistry, Department of Biological Sciences, Faculty of Exact Sciences, University of La Plata, La Plata. Argentina.
2
Instituto de Ciencias y Tecnologia Dr. Cesar Milstein (ICT Milstein) - CONICET. Ciudad Autonoma de Buenos Aires. Argentina.
3
Institut Pasteur de Montevideo, Mataojo 2020, Montevideo 11400. Uruguay.

Abstract

Chagas´ disease continues to be a challenging and neglected public health problem in many American countries. The etiologic agent, Trypanosoma cruzi, develops intracellularly in the mammalian host, which hinders treatment efficacy. Progress in the knowledge of parasite biology and host-pathogen interaction has not been paralleled by the development of novel, safe and effective therapeutic options. It is then urgent to seek for novel therapeutic candidates and to implement drug discovery strategies that may accelerate the discovery process. The most appealing targets for pharmacological intervention are those essential for the pathogen and, whenever possible, absent or significantly different from the host homolog. The thiol-polyamine metabolism of T. cruzi offers interesting candidates for a rational design of selective drugs. In this respect, here we critically review the state of the art of the thiol-polyamine metabolism of T. cruzi and the pharmacological potential of its components. On the other hand, drug repurposing emerged as a valid strategy to identify new biological activities for drugs in clinical use, while significantly shortening the long time and high cost associated with de novo drug discovery approaches. Thus, we also discuss the different drug repurposing strategies available with a special emphasis in their applications to the identification of drug candidates targeting essential components of the thiol-polyamine metabolism of T. cruzi.

KEYWORDS:

Chagas disease; approved drugs; bioinformatics; drug repositioning; drug repurposing.; polyamines; screening; spermidine; therapy; trypanothione

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