Novel pantothenate derivatives for anti-malarial chemotherapy.
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.
Department of Medical Microbiology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. helmi.pett@radboudumc.nl.
Helmi E
HE
Pett
Department of Dermatology and Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. patrick.jansen@radboudumc.nl.
Patrick A M
PA
Jansen
Pansynt B V, Nijmegen, The Netherlands. pedro.hermkens@ziggo.nl.
Pedro H H
PH
Hermkens
Chiralix B V, Nijmegen, The Netherlands. peter.botman@chiralix.com.
Peter N M
PN
Botman
Chiralix B V, Nijmegen, The Netherlands. christien.beuckens@chiralix.com.
Christien A
CA
Beuckens-Schortinghuis
Chiralix B V, Nijmegen, The Netherlands. richard.blaauw@chiralix.com.
Richard H
RH
Blaauw
Department of Medical Microbiology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. wouter.graumans@radboudumc.nl.
Wouter
W
Graumans
Department of Medical Microbiology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. marga.vandevegte-bolmer@radboudumc.nl.
Marga
M
van de Vegte-Bolmer
TropIQ Health Sciences, Nijmegen, The Netherlands. k.koolen@tropiq.nl.
Karin M J
KM
Koolen
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.
Floris P J T
FP
Rutjes
TropIQ Health Sciences, Nijmegen, The Netherlands. k.dechering@tropiq.nl.
Koen J
KJ
Dechering
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.
Robert W
RW
Sauerwein
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.
Joost
J
Schalkwijk
D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy; D010205:Pantothenic Acid / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000254:growth & development
D000962:Antimalarials; D010205:Pantothenic Acid