Novel pantothenate derivatives for anti-malarial chemotherapy

Malaria Journal

Research

Christien A Beuckens-Schortinghuis¹  Richard H Blaauw¹  Peter NM Botman¹  Patrick AM Jansen²  Joost Schalkwijk³  Marga van de Vegte-Bolmer⁴  Wouter Graumans⁴  Helmi E Pett⁴  Robert W Sauerwein⁵  Pedro HH Hermkens⁶  Floris PJT Rutjes⁷  Koen J Dechering⁸  Karin MJ Koolen⁸ 

[1] Chiralix B V, Nijmegen, The Netherlands;Department of Dermatology and Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands;Department of Dermatology and Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands;Pansynt B V, Nijmegen, The Netherlands;Department of Medical Microbiology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands;Department of Medical Microbiology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands;TropIQ Health Sciences, Nijmegen, The Netherlands;Pansynt B V, Nijmegen, The Netherlands;Radboud University Nijmegen, Institute for Molecules and Materials, Nijmegen, The Netherlands;Pansynt B V, Nijmegen, The Netherlands;TropIQ Health Sciences, Nijmegen, The Netherlands;

关键词: Malaria;    Anti-malarial;    Plasmodium falciparum;    Pantothenate;    Pantothenic acid;    Pantothenamide;    Pantothenone;    Coenzyme A;   

DOI  :  10.1186/s12936-015-0673-8

 received in 2014-12-01, accepted in 2015-04-04,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundA number of synthetic pantothenate derivatives, such as pantothenamides, are known to inhibit the growth of the human malaria parasite Plasmodium falciparum, by interfering with the parasite Coenzyme A (CoA) biosynthetic pathway. The clinical use of pantothenamides is limited by their sensitivity to breakdown by ubiquitous human pantetheinases of the vanin family.MethodsA number of pantothenate derivatives (pantothenones) with potent and specific inhibitory activity against mammalian vanins were tested in a proliferation assay of asexual P. falciparum blood stages alone, and in combination with pantothenamides.ResultsThe vanin inhibitors were found to protect pantothenamides against breakdown by plasma vanins, thereby preserving the in vitro anti-malarial activity. Moreover, some of the vanin inhibitors showed in vitro anti-malarial activity in the low micromolar range. The most potent antimalarial in this series of compounds (RR8), was found to compete with pantothenate in a combination proliferation assay. No correlation, however, was found between anti-vanin and anti-malarial activity, nor was pantetheinase activity detected in P. falciparum extracts.ConclusionsGrowth inhibition is most likely due to competition with pantothenate, rather than pantetheinase inhibition. As vanin inhibitors of the pantothenone class are stable in biological fluids and are non-toxic to mammalian cells, they may represent novel pantothenate-based anti-malarials, either on their own or in combination with pantothenamides.

【 授权许可】

Unknown   
© Pett et al.; licensee BioMed Central. 2015. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.