Hemolytic and antimalarial effects of tight-binding glyoxalase 1 inhibitors on the host-parasite unit of erythrocytes infected with Plasmodium falciparum

Cletus A. Wezena, Miriam Urscher, Robert Vince, Swati S More, Marcel Deponte

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Glyoxalases prevent the formation of advanced glycation end products by converting glycolysis-derived methylglyoxal to d-lactate with the help of glutathione. Vander Jagt and colleagues previously showed that erythrocytes release about thirty times more d-lactate after infection with the human malaria parasite Plasmodium falciparum. Functional glyoxalases in the host-parasite unit might therefore be crucial for parasite survival. Here, we determined the antimalarial and hemolytic activity of two tight-binding glyoxalase inhibitors using infected and uninfected erythrocytes. In addition, we synthesized and analyzed a set of diester derivates of both tight-binding inhibitors resulting in up to threefold lower IC50 values and an altered methemoglobin formation and hemolytic activity depending on the type of ester. Inhibitor treatments of uninfected erythrocytes revealed an extremely slow inactivation of the host cell glyoxalase, irrespective of inhibitor modifications, and a potential dispensability of the host cell enzyme for parasite survival. Our study highlights the benefits and drawbacks of different esterifications of glutathione-derived inhibitors and demonstrates the suitability of glyoxalase inhibitors as a tool for deciphering the relevance and mode of action of different glyoxalase systems in a host-parasite unit.

Original languageEnglish (US)
Pages (from-to)348-353
Number of pages6
JournalRedox Biology
Volume8
DOIs
StatePublished - Aug 1 2016

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Antimalarials
Plasmodium falciparum
Parasites
Erythrocytes
Glutathione
Lactic Acid
Pyruvaldehyde
Methemoglobin
Advanced Glycosylation End Products
Falciparum Malaria
Esterification
Glycolysis
Inhibitory Concentration 50
Esters
Enzymes
Infection

Keywords

  • Erythrocyte
  • Glyoxalase
  • Inhibitor
  • Malaria
  • Pharmacokinetics
  • Redox

Cite this

Hemolytic and antimalarial effects of tight-binding glyoxalase 1 inhibitors on the host-parasite unit of erythrocytes infected with Plasmodium falciparum. / Wezena, Cletus A.; Urscher, Miriam; Vince, Robert; More, Swati S; Deponte, Marcel.

In: Redox Biology, Vol. 8, 01.08.2016, p. 348-353.

Research output: Contribution to journalArticle

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