title: Aziridine-2,3-dicarboxylates, peptidomimetic cysteine protease inhibitors with antileishmanial activity.
abstract: Chemotherapy of leishmaniasis is mainly based on antimonials. However, they are extremely toxic and cause serious side effects, and there is a worldwide increasing frequency of chemoresistance to antimonials. These issues emphasize the urgent need for affordable alternative drugs against leishmaniasis. Leishmania cysteine proteases are essential for parasite growth, differentiation, pathogenicity, and virulence and are thus attractive targets for combating leishmaniasis. Herein we demonstrate that the cysteine protease inhibitors aziridine-2,3-dicarboxylates 13b and 13e impaired promastigote growth at mid-micromolar concentrations and decreased the infection rate of peritoneal macrophages at concentrations 8- to 13-fold lower than those needed to inhibit parasite replication. Simultaneous treatment of infected cells with compound 13b and gamma interferon resulted in an even further reduction of the concentration needed for a significant decrease in macrophage infection rate. Notably, treatment with the compounds alone modulated the cytokine secretion of infected macrophages, with increased levels of interleukin-12 and tumor necrosis factor alpha. Furthermore, the decreased infection rate in the presence of compound 13b correlated with increased nitric oxide production by macrophages. Importantly, at the concentrations used herein, compounds 13b and 13e were not toxic against fibroblasts, macrophages, or dendritic cells. Together, these results suggest that the aziridine-2,3-dicarboxylates 13b and 13e are potential antileishmanial lead compounds with low toxicity against host cells and selective antiparasitic effects.
authors.affiliation: Institute for Molecular Infection Biology, University of Würzburg, Röntgenring 11, 97070 Würzburg, Germany.
authors.forename: Alicia
authors.initials: A
authors.lastname: Ponte-Sucre
authors.forename: Radim
authors.initials: R
authors.lastname: Vicik
authors.forename: Martina
authors.initials: M
authors.lastname: Schultheis
authors.forename: Tanja
authors.initials: T
authors.lastname: Schirmeister
authors.forename: Heidrun
authors.initials: H
authors.lastname: Moll
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D001388:Aziridines / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D001854:Bone Marrow Cells; D002460:Cell Line; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000469:parasitology; D018320:Leishmania major / Q000187:drug effects* / Q000254:growth & development; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D041681:NIH 3T3 Cells
chemical_list: D000981:Antiprotozoal Agents; D001388:Aziridines; D015853:Cysteine Proteinase Inhibitors; D016207:Cytokines; C495385:aziridine-2,3-dicarboxylate