title: Validation of N-myristoyltransferase as Potential Chemotherapeutic Target in Mammal-Dwelling Stages of Trypanosoma cruzi.
abstract: 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.
  
  
  RESULTS
  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
  Taken together, our data point out to the potential use of NMT inhibitors as anti-T. cruzi chemotherapy.
authors.affiliation: The Border Biomedical Research Center, Department of Biological Sciences, University of Texas at El Paso, El Paso, Texas, United States of America.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Herrera
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Brand
authors.affiliation: The Border Biomedical Research Center, Department of Biological Sciences, University of Texas at El Paso, El Paso, Texas, United States of America.
authors.forename: Andres
authors.initials: A
authors.lastname: Santos
authors.affiliation: The Border Biomedical Research Center, Department of Biological Sciences, University of Texas at El Paso, El Paso, Texas, United States of America.
authors.forename: Lilian L
authors.initials: LL
authors.lastname: Nohara
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, United Kingdom.
authors.forename: Justin
authors.initials: J
authors.lastname: Harrison
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, United Kingdom.
authors.forename: Neil R
authors.initials: NR
authors.lastname: Norcross
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Thompson
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, United Kingdom.
authors.forename: Victoria
authors.initials: V
authors.lastname: Smith
authors.affiliation: The Border Biomedical Research Center, Department of Biological Sciences, University of Texas at El Paso, El Paso, Texas, United States of America.
authors.forename: Carolina
authors.initials: C
authors.lastname: Lema
authors.affiliation: The Border Biomedical Research Center, Department of Biological Sciences, University of Texas at El Paso, El Paso, Texas, United States of America.
authors.forename: Armando
authors.initials: A
authors.lastname: Varela-Ramirez
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, United Kingdom.
authors.forename: Ian H
authors.initials: IH
authors.lastname: Gilbert
authors.affiliation: The Border Biomedical Research Center, Department of Biological Sciences, University of Texas at El Paso, El Paso, Texas, United States of America.
authors.forename: Igor C
authors.initials: IC
authors.lastname: Almeida
authors.affiliation: The Border Biomedical Research Center, Department of Biological Sciences, University of Texas at El Paso, El Paso, Texas, United States of America.
authors.forename: Rosa A
authors.initials: RA
authors.lastname: Maldonado
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics*; D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D021261:Parasitic Sensitivity Tests; D014349:Trypanosoma cruzi / Q000201:enzymology* / Q000235:genetics*
chemical_list: D000981:Antiprotozoal Agents; D004791:Enzyme Inhibitors; D000217:Acyltransferases; C050480:glycylpeptide N-tetradecanoyltransferase