6533b85cfe1ef96bd12bc05d

RESEARCH PRODUCT

Development of a New Antileishmanial Aziridine-2,3-Dicarboxylate-Based Inhibitor with High Selectivity for Parasite Cysteine Proteases

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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 Lma CatB (a CB-like enzyme of L. major ; also named L. major CPC) and Lm CPB2.8 (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 [IC 50 ] = 37.4 μM) and amastigotes (IC 50 = 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.