Novel pantothenate derivatives for anti-malarial chemotherapy

Helmi E. Pett, Patrick A.M. Jansen, Pedro H.H. Hermkens, Peter N.M. Botman, Christien A. Beuckens-Schortinghuis, Richard H. Blaauw, Wouter Graumans, Marga Van De Vegte-Bolmer, Karin M.J. Koolen, Floris P.J.T. Rutjes, Koen J. Dechering, Robert W. Sauerwein, Joost Schalkwijk*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

8 Citations (Scopus)

Abstract

Abstract 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.

Original languageEnglish
Article number169
JournalMalaria Journal
Volume14
Issue number1
DOIs
Publication statusPublished - 1 Dec 2015
Externally publishedYes

Keywords

  • Anti-malarial
  • Coenzyme A
  • Malaria
  • Pantothenamide
  • Pantothenate
  • Pantothenic acid
  • Pantothenone
  • Plasmodium falciparum

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