PLoS Neglected Tropical Diseases (Apr 2016)

Validation of N-myristoyltransferase as Potential Chemotherapeutic Target in Mammal-Dwelling Stages of Trypanosoma cruzi.

  • Linda J Herrera,
  • Stephen Brand,
  • Andres Santos,
  • Lilian L Nohara,
  • Justin Harrison,
  • Neil R Norcross,
  • Stephen Thompson,
  • Victoria Smith,
  • Carolina Lema,
  • Armando Varela-Ramirez,
  • Ian H Gilbert,
  • Igor C Almeida,
  • Rosa A Maldonado

DOI
https://doi.org/10.1371/journal.pntd.0004540
Journal volume & issue
Vol. 10, no. 4
p. e0004540

Abstract

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BACKGROUND:Trypanosoma cruzi causes Chagas disease, an endemic and debilitating illness in Latin America. Lately, owing to extensive population movements, this neglected tropical disease has become a global health concern. The two clinically available drugs for the chemotherapy of Chagas disease have rather high toxicity and limited efficacy in the chronic phase of the disease, and may induce parasite resistance. The development of new anti-T. cruzi agents is therefore imperative. The enzyme N-myristoyltransferase (NMT) has recently been biochemically characterized, shown to be essential in Leishmania major, Trypanosoma brucei, and T. cruzi¸ and proposed as promising chemotherapeutic target in these trypanosomatids. METHODOLOGY/PRINCIPAL FINDINGS:Here, using high-content imaging we assayed eight known trypanosomatid NMT inhibitors, against mammal-dwelling intracellular amastigote and trypomastigote stages and demonstrated that three of them (compounds 1, 5, and 8) have potent anti-proliferative effect at submicromolar concentrations against T. cruzi, with very low toxicity against human epithelial cells. Moreover, metabolic labeling using myristic acid, azide showed a considerable decrease in the myristoylation of proteins in parasites treated with NMT inhibitors, providing evidence of the on-target activity of the inhibitors. CONCLUSIONS/SIGNIFICANCE:Taken together, our data point out to the potential use of NMT inhibitors as anti-T. cruzi chemotherapy.