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 (Lead / Corresponding author), Rosa A. Maldonado (Lead / Corresponding author)

Research output: Contribution to journalArticle

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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. 

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.

Original languageEnglish
Article numbere0004540
Number of pages20
JournalPLoS Neglected Tropical Diseases
Volume10
Issue number4
DOIs
Publication statusPublished - 29 Apr 2016

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Trypanosoma cruzi
Mammals
Chagas Disease
Parasites
Neglected Diseases
Leishmania major
Drug Therapy
Trypanosoma brucei brucei
Azides
Latin America
Myristic Acid
Chronic Disease
Epithelial Cells
glycylpeptide N-tetradecanoyltransferase
Enzymes
Pharmaceutical Preparations
Population
Proteins
Thomsen-Friedenreich antibodies

Cite this

Herrera, Linda J. ; Brand, Stephen ; Santos, Andres ; Nohara, Lilian L. ; Harrison, Justin ; Norcross, Neil R. ; Thompson, Stephen ; Smith, Victoria ; Lema, Carolina ; Varela-Ramirez, Armando ; Gilbert, Ian H. ; Almeida, Igor C. ; Maldonado, Rosa A. / Validation of N-myristoyltransferase as Potential Chemotherapeutic Target in Mammal-Dwelling Stages of Trypanosoma cruzi. In: PLoS Neglected Tropical Diseases. 2016 ; Vol. 10, No. 4.
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Validation of N-myristoyltransferase as Potential Chemotherapeutic Target in Mammal-Dwelling Stages of Trypanosoma cruzi. / Herrera, Linda J.; Brand, Stephen; Santos, Andres; Nohara, Lilian L.; Harrison, Justin; Norcross, Neil R.; Thompson, Stephen; Smith, Victoria; Lema, Carolina; Varela-Ramirez, Armando; Gilbert, Ian H.; Almeida, Igor C. (Lead / Corresponding author); Maldonado, Rosa A. (Lead / Corresponding author).

In: PLoS Neglected Tropical Diseases, Vol. 10, No. 4, e0004540, 29.04.2016.

Research output: Contribution to journalArticle

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T1 - Validation of N-myristoyltransferase as Potential Chemotherapeutic Target in Mammal-Dwelling Stages of Trypanosoma cruzi

AU - Herrera, Linda J.

AU - Brand, Stephen

AU - Santos, Andres

AU - Nohara, Lilian L.

AU - Harrison, Justin

AU - Norcross, Neil R.

AU - Thompson, Stephen

AU - Smith, Victoria

AU - Lema, Carolina

AU - Varela-Ramirez, Armando

AU - Gilbert, Ian H.

AU - Almeida, Igor C.

AU - Maldonado, Rosa A.

PY - 2016/4/29

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N2 - 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.

AB - 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.

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DO - 10.1371/journal.pntd.0004540

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