Novel pantothenate derivatives for anti-malarial chemotherapy.

Autor:	Pett HE; Department of Medical Microbiology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. helmi.pett@radboudumc.nl., Jansen PA; Department of Dermatology and Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. patrick.jansen@radboudumc.nl., Hermkens PH; Pansynt B V, Nijmegen, The Netherlands. pedro.hermkens@ziggo.nl., Botman PN; Chiralix B V, Nijmegen, The Netherlands. peter.botman@chiralix.com., Beuckens-Schortinghuis CA; Chiralix B V, Nijmegen, The Netherlands. christien.beuckens@chiralix.com., Blaauw RH; Chiralix B V, Nijmegen, The Netherlands. richard.blaauw@chiralix.com., Graumans W; Department of Medical Microbiology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. wouter.graumans@radboudumc.nl., van de Vegte-Bolmer M; Department of Medical Microbiology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. marga.vandevegte-bolmer@radboudumc.nl., Koolen KM; TropIQ Health Sciences, Nijmegen, The Netherlands. k.koolen@tropiq.nl., Rutjes FP; Radboud University Nijmegen, Institute for Molecules and Materials, Nijmegen, The Netherlands. f.rutjes@science.ru.nl.; Pansynt B V, Nijmegen, The Netherlands. f.rutjes@science.ru.nl., Dechering KJ; TropIQ Health Sciences, Nijmegen, The Netherlands. k.dechering@tropiq.nl., Sauerwein RW; Department of Medical Microbiology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. robert.sauerwein@radboudumc.nl.; TropIQ Health Sciences, Nijmegen, The Netherlands. robert.sauerwein@radboudumc.nl., Schalkwijk J; Department of Dermatology and Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. joost.schalkwijk@radboudumc.nl.; Pansynt B V, Nijmegen, The Netherlands. joost.schalkwijk@radboudumc.nl.
Jazyk:	angličtina
Zdroj:	Malaria journal [Malar J] 2015 Apr 18; Vol. 14, pp. 169. Date of Electronic Publication: 2015 Apr 18.
DOI:	10.1186/s12936-015-0673-8
Abstrakt:	Background: A 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. Methods: A 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. Results: The 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. Conclusions: Growth 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.
Databáze:	MEDLINE
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