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

• Published in: PLoS neglected tropical diseases 2016-04, Vol.10 (4), p.e0004540
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Acyltransferases - antagonists & inhibitors; Acyltransferases - genetics; Analysis; Animals; Antiprotozoal Agents - pharmacology; Antiprotozoal Agents - toxicity; Biology and Life Sciences; Care and treatment; Cell Line; Cell Survival - drug effects; Chemotherapy; Chronic illnesses; Cytotoxicity; Enzyme activation; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - toxicity; Enzymes; Epithelial Cells - drug effects; Epithelial Cells - physiology; Humans; Mammals; Medicine and Health Sciences; Parasites; Parasitic Sensitivity Tests; Peptides; Physical Sciences; Proteins; Protozoa; Researchers; Signal transduction; Studies; Tropical diseases; Trypanosoma cruzi; Trypanosoma cruzi - enzymology; Trypanosoma cruzi - genetics
• ISSN: 1935-2735; 1935-2727; 1935-2735
• DOI: 10.1371/journal.pntd.0004540

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. 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. Taken together, our data point out to the potential use of NMT inhibitors as anti-T. cruzi chemotherapy.