Reference : 2-Octadecynoic acid as a dual life stage inhibitor of Plasmodium infections and plasm...

	Document type :	Scientific journals : Article
	Discipline(s) :	Human health sciences : Multidisciplinary, general & others
	To cite this reference:	http://hdl.handle.net/10993/26936

Title :	2-Octadecynoic acid as a dual life stage inhibitor of Plasmodium infections and plasmodial FAS-II enzymes
Language :	-
Author, co-author :	Carballeira, N. M. [Department of Chemistry, University of Puerto Rico, PO Box 23346, San Juan 00931-3346, Puerto Rico]
	Bwalya, A. G. [Department of Biological and Pharmaceutical Chemistry, University of London, School of Pharmacy, London WC1N 1AX, United Kingdom]
	Itoe, M. A. [Instituto de Medicina Molecular, Universidade de Lisboa, Lisbon 1649-028, Portugal]
	Andricopulo, A. D. [Laboratório de Química Medicinal e Computacional, Centro de Pesquisa e Inovação em Biodiversidade e Fármacos, Universidade de São Paulo, São Carlos, SP 13563-120, Brazil]
	Cordero-Maldonado, M. L. [Chemical Biology Group, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4362 Esch-sur-Alzette, Luxembourg]
	Kaiser, M. [Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, CH-4002 Basel, Switzerland, University of Basel, Petersplatz 1, CH-4003 Basel, Switzerland]
	Mota, M. M. [Instituto de Medicina Molecular, Universidade de Lisboa, Lisbon 1649-028, Portugal]
	Crawford, Alexander Dettmar [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) >]
	Guido, R. V. C. [Laboratório de Química Medicinal e Computacional, Centro de Pesquisa e Inovação em Biodiversidade e Fármacos, Universidade de São Paulo, São Carlos, SP 13563-120, Brazil]
	Tasdemir, D. [Department of Biological and Pharmaceutical Chemistry, University of London, School of Pharmacy, London WC1N 1AX, United Kingdom, School of Chemistry, National University of Ireland, Galway, Ireland]
Publication date :	2014
Journal title :	Bioorganic & Medicinal Chemistry Letters
Publisher :	Elsevier Ltd
Volume :	24
Issue/season :	17
Pages :	4151-4157
Peer reviewed :	Yes
ISSN :	0960894X
Keywords :	[en] Acetylenic fatty acids ; Blood stage ; Liver stage ; Malaria ; Plasmodium ; Type II fatty acid synthase ; IC 50 ; Plasmodium berghei ; Plasmodium falciparum ; Danio rerio ; Mammalia ; Plasmodium berghei ; Plasmodium falciparum ; Animals ; Antimalarials ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Fatty Acid Synthase, Type II ; Fatty Acids, Unsaturated ; Humans ; Models, Molecular ; Plasmodium berghei ; Plasmodium falciparum ; Structure-Activity Relationship ; Zebrafish
Abstract :	[en] The malaria parasite Plasmodium goes through two life stages in the human host, a non-symptomatic liver stage (LS) followed by a blood stage with all clinical manifestation of the disease. In this study, we investigated a series of 2-alkynoic fatty acids (2-AFAs) with chain lengths between 14 and 18 carbon atoms for dual in vitro activity against both life stages. 2-Octadecynoic acid (2-ODA) was identified as the best inhibitor of Plasmodium berghei parasites with ten times higher potency (IC50 = 0.34 μg/ml) than the control drug. In target determination studies, the same compound inhibited three Plasmodium falciparum FAS-II (PfFAS-II) elongation enzymes PfFabI, PfFabZ, and PfFabG with the lowest IC50 values (0.28-0.80 μg/ml, respectively). Molecular modeling studies provided insights into the molecular aspects underlying the inhibitory activity of this series of 2-AFAs and a likely explanation for the considerably different inhibition potentials. Blood stages of P. falciparum followed a similar trend where 2-ODA emerged as the most active compound, with 20 times less potency. The general toxicity and hepatotoxicity of 2-AFAs were evaluated by in vitro and in vivo methods in mammalian cell lines and zebrafish models, respectively. This study identifies 2-ODA as the most promising antiparasitic 2-AFA, particularly towards P. berghei parasites. © 2014 Elsevier Ltd. All rights reserved.
Research centres :	Luxembourg Centre for Systems Biomedicine (LCSB): Chemical Biology (Crawford Group)
Funders :	ERC-2012-StG-20111109, ERC, National Institutes of Health; NIH, National Institutes of Health
Permalink :	http://hdl.handle.net/10993/26936
DOI :	10.1016/j.bmcl.2014.07.050

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