Examination of multiple Trypanosoma cruzi targets in a new drug discovery approach for Chagas disease

Bioorg Med Chem. 2022 Mar 15:58:116577. doi: 10.1016/j.bmc.2021.116577. Epub 2022 Feb 1.

Abstract

Chagas disease (CD) is a centenarian neglected parasitosis caused by the protozoan Trypanosoma cruzi (T. cruzi). Despite the continuous efforts of many organizations and institutions, CD is still an important human health problem worldwide. A lack of a safe and affordable treatment has led drug discovery programmes to focus, for years, on the search for molecules enabling interference with enzymes that are essential for T. cruzi survival. In this work, the authors want to offer a brief overview of the different validated targets that are involved in diverse parasite pathways: glycolysis, sterol synthesis, the de novo biosynthesis of pyrimidine nucleotides, the degradative processing of peptides and proteins, oxidative stress damage and purine salvage and nucleotide synthesis and metabolism. Their structural aspects, function, active sites, etc. were studied and considered with the aim of defining molecular bases in the search for new effective treatments for CD. This review also compiles, as much as possible, all the inhibitors reported to date against these T. cruzi targets, serving as a reference for future research in this field.

Keywords: CYP51; Cruzain; Dihydrofolate reductase; Dihydroorotate dehydrogenase; Pteridine reductase; Sterol 14α-demethylase; Superoxide dismutase; Thymidylate synthase; Triosephosphate isomerase; Trypanosoma cruzi; Trypanothione reductase.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Chagas Disease / drug therapy*
  • Chagas Disease / metabolism
  • Drug Discovery*
  • Humans
  • Molecular Structure
  • Oxidative Stress / drug effects
  • Parasitic Sensitivity Tests
  • Trypanocidal Agents / chemical synthesis
  • Trypanocidal Agents / chemistry
  • Trypanocidal Agents / pharmacology*
  • Trypanosoma cruzi / drug effects*

Substances

  • Trypanocidal Agents