title: Hemolytic and antimalarial effects of tight-binding glyoxalase 1 inhibitors on the host-parasite unit of erythrocytes infected with Plasmodium falciparum.
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.
authors.affiliation: Department of Parasitology, Ruprecht-Karls University, D-69120 Heidelberg, Germany.
authors.forename: Cletus A
authors.initials: CA
authors.lastname: Wezena
authors.affiliation: Department of Parasitology, Ruprecht-Karls University, D-69120 Heidelberg, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Urscher
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Vince
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Swati S
authors.initials: SS
authors.lastname: More
authors.affiliation: Department of Parasitology, Ruprecht-Karls University, D-69120 Heidelberg, Germany. Electronic address: marcel.deponte@gmx.de.
authors.forename: Marcel
authors.initials: M
authors.lastname: Deponte
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis; D004912:Erythrocytes / Q000187:drug effects* / Q000469:parasitology; D005978:Glutathione / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000187:drug effects / Q000378:metabolism; D006461:Hemolysis / Q000187:drug effects; D006790:Host-Parasite Interactions / Q000187:drug effects*; D006801:Humans; D007791:Lactoylglutathione Lyase / Q000037:antagonists & inhibitors* / Q000235:genetics; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000235:genetics / Q000469:parasitology; D010963:Plasmodium falciparum / Q000187:drug effects / Q000472:pathogenicity
chemical_list: D004791:Enzyme Inhibitors; D017127:Glycation End Products, Advanced; D007791:Lactoylglutathione Lyase; D005978:Glutathione
keywords: Erythrocyte; Glyoxalase; Inhibitor; Malaria; Pharmacokinetics; Redox