title: Development of a New Antileishmanial Aziridine-2,3-Dicarboxylate-Based Inhibitor with High Selectivity for Parasite Cysteine Proteases.
abstract: Leishmaniasis is one of the major neglected tropical diseases of the world. Druggable targets are the parasite cysteine proteases (CPs) of clan CA, family C1 (CAC1). In previous studies, we identified two peptidomimetic compounds, the aziridine-2,3-dicarboxylate compounds 13b and 13e, in a series of inhibitors of the cathepsin L (CL) subfamily of the papain clan CAC1. Both displayed antileishmanial activity in vitro while not showing cytotoxicity against host cells. In further investigations, the mode of action was characterized in Leishmania major. It was demonstrated that aziridines 13b and 13e mainly inhibited the parasitic cathepsin B (CB)-like CPC enzyme and, additionally, mammalian CL. Although these compounds induced cell death of Leishmania promastigotes and amastigotes in vitro, the induction of a proleishmanial T helper type 2 (Th2) response caused by host CL inhibition was observed in vivo. Therefore, we describe here the synthesis of a new library of more selective peptidomimetic aziridine-2,3-dicarboxylates discriminating between host and parasite CPs. The new compounds are based on 13b and 13e as lead structures. One of the most promising compounds of this series is compound s9, showing selective inhibition of the parasite CPs LmaCatB (a CB-like enzyme of L. major; also named L. major CPC) and LmCPB2.8 (a CL-like enzyme of Leishmania mexicana) while not affecting mammalian CL and CB. It displayed excellent leishmanicidal activities against L. major promastigotes (50% inhibitory concentration [IC50] = 37.4 μM) and amastigotes (IC50 = 2.3 μM). In summary, we demonstrate a new selective aziridine-2,3-dicarboxylate, compound s9, which might be a good candidate for future in vivo studies.
authors.affiliation: Institute of Pharmacy and Food Chemistry, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Caroline
authors.initials: C
authors.lastname: Schad
authors.affiliation: Institute for Molecular Infection Biology, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Baum
authors.affiliation: Institute for Molecular Infection Biology, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Frank
authors.affiliation: Rudolf Virchow Center for Experimental Biomedicine, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Dietzel
authors.affiliation: Rudolf Virchow Center for Experimental Biomedicine, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Mattern
authors.affiliation: Laboratory of Molecular Physiology, Institute of Experimental Medicine, Faculty of Medicine, Universidad Central de Venezuela, Caracas, Venezuela.
authors.forename: Carlos
authors.initials: C
authors.lastname: Gomes
authors.affiliation: Laboratory of Molecular Physiology, Institute of Experimental Medicine, Faculty of Medicine, Universidad Central de Venezuela, Caracas, Venezuela.
authors.forename: Alicia
authors.initials: A
authors.lastname: Ponte-Sucre
authors.affiliation: Institute for Molecular Infection Biology, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Heidrun
authors.initials: H
authors.lastname: Moll
authors.affiliation: Institute for Molecular Infection Biology, University of Wuerzburg, Wuerzburg, Germany uta.schurigt@gmx.de schirmei@uni-mainz.de.
authors.forename: Uta
authors.initials: U
authors.lastname: Schurigt
authors.affiliation: Institute of Pharmacy and Biochemistry, University of Mainz, Mainz, Germany uta.schurigt@gmx.de schirmei@uni-mainz.de.
authors.forename: Tanja
authors.initials: T
authors.lastname: Schirmeister
mesh_terms: D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology*; D001388:Aziridines / Q000737:chemistry / Q000494:pharmacology*; D002401:Cathepsin B / Q000037:antagonists & inhibitors*; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D018320:Leishmania major / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D007896:Leishmaniasis / Q000188:drug therapy* / Q000276:immunology / Q000469:parasitology; D010206:Papain / Q000037:antagonists & inhibitors*; D018418:Th2 Cells / Q000276:immunology
chemical_list: D000981:Antiprotozoal Agents; D001388:Aziridines; D015853:Cysteine Proteinase Inhibitors; C495385:aziridine-2,3-dicarboxylate; D002401:Cathepsin B; D010206:Papain