Aziridine-2,3-dicarboxylate inhibitors targeting the major cysteine protease of Trypanosoma brucei as lead trypanocidal agents

Host-Parasite Interactions in Trypanosomiasis: on the Way to an Antidisease Strategy

“…Progress in proteomics and genomics will further allow rapid evolution in the field, as several new proteases are already available in gene databanks. Simultaneously, important efforts are being undertaken for the development of CP-inhibiting molecules for T. congolense, T. brucei brucei, and T. brucei rhodesiense (34,35,48,49,59,82,157).…”

Aziridine-2,3-Dicarboxylate-Based Cysteine Cathepsin Inhibitors Induce Cell Death inLeishmania majorAssociated with Accumulation of Debris in Autophagy-Related Lysosome-Like Vacuoles

“…Derivatives containing aziridine-2-carboxylic acid and aziridine-2,3-dicarboxylic acid as electrophilic building blocks were synthesized to develop new selective inhibitors (25,26). In further investigations, aziridine-based inhibitors containing aziridine-2,3-dicarboxylates [Azi(OBn) 2 s] showed selective inhibition of cathepsin L-like enzymes, for instance, rhodesain, the major trypanosomal papain-like CP of the parasite Trypanosoma brucei rhodesiense (41), and falcipain-2 and falcipain-3 from the malaria parasite Plasmodium falciparum (29). In addition, aziridine-2,3-dicarboxylate-based inhibitors had antiparasitic activity against Trypanosoma brucei brucei and P. falciparum in vitro (29,41).…”

“…In further investigations, aziridine-based inhibitors containing aziridine-2,3-dicarboxylates [Azi(OBn) 2 s] showed selective inhibition of cathepsin L-like enzymes, for instance, rhodesain, the major trypanosomal papain-like CP of the parasite Trypanosoma brucei rhodesiense (41), and falcipain-2 and falcipain-3 from the malaria parasite Plasmodium falciparum (29). In addition, aziridine-2,3-dicarboxylate-based inhibitors had antiparasitic activity against Trypanosoma brucei brucei and P. falciparum in vitro (29,41). Finally, this promising series of peptidomimetic aziridine-2,3-dicarboxylate inhibitors was demonstrated to exert significant antileishmanial activity.…”

“…Aziridine-2,3-dicarboxylate CP inhibitors 13b and 13e ( Fig. 1) were synthesized as described previously (41). Proteolytic activities were determined by degradation of the fluoropeptide Z-Phe-Arg-4-methyl-coumarin-7-amide (Z-Phe-Arg-AMC; Bachem, Bubendorf, Switzerland), a substrate of the leishmanial cathepsin B-like enzyme (CPC) and cathepsin-L like enzymes (CPA, CPB) (30,31,32), using fluorescence proteinase activity assays.…”

Inhibition of cysteine proteases by a natural biflavone: behavioral evaluation of fukugetin as papain and cruzain inhibitor

“…It is involved in intracellular replication and differentiation, and is essential at all stages of the parasite's life cycle. Inhibitors of cruzain [3][4][5][6] display considerable antitrypanosomal activity 7,8 and some classes have been shown to cure T. cruzi infection in mouse models [7][8][9][10] . Since currently available therapeutics is practically ineffective in the acute phase of the disease besides being highly toxic to be safely administered for long periods, efforts have been made with a view to characterizing new therapeutic targets, among which the proteolytic apparatus of T. cruzi is a possible candidate 11 .…”