Leishmania major:Molecular Modeling of Cysteine Proteases and Prediction of New Nonpeptide Inhibitors

Cysteine Proteinases and the Pathogenesis of Amebiasis

“…Plasmodial proteases hydrolyze globin to free acids for the growth of intraerythrocytic parasites (92), and the protease inhibitors that block hemoglobin degradation block the development of cultured malaria parasites (95). Cysteine proteinase inhibitors also block the intracellular development of T. cruzi (23) and Leishmania (102). Although E. histolytica is not an intracellular parasite, when its trophozoites were incubated with a diazopeptidyl inhibitor, growth was decreased by 50% (22), suggesting that cysteine proteinases are important for the acquisition of nutrients, even from a liquid medium.…”

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

“…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. These assays were carried out in black 96-well microtiter plates (Nunc GmbH, Langenselbold, Germany).…”

Cysteine protease inhibitors as chemotherapy: Lessons from a parasite target

“…To address the need for new, cost-effective leads for the chemotherapy of leishmaniasis, we have applied strategies of structure-based drug design (2). An attractive target for new chemotherapy is a family of cathepsin L-like (cpL) and cathepsin B-like (cpB) cysteine proteases found in all species of Leishmania examined, and required for parasite growth or virulence (3)(4)(5).…”

“…Deletion of the cpB gene ''cpc'' led to reduced survival of parasites in macrophages (3,6). While structurally distinct, Leishmania cpL and cpB overlap in substrate specificity (2). Inhibitors that would effectively target both types of cysteine proteases in Leishmania, while maintaining some selectivity versus homologous host enzymes, would be ideal drug leads.…”

“…Reversible inhibitors were discovered through a structure-based drug design screen and subsequent combinatorial synthetic optimization using models of both Leishmania major cpB and cpL (2). The irreversible inhibitors are pseudopeptide substrate analogues that take advantage of the unique reactivity of the active site sulfhydryl of cysteine proteases to confer specificity for this enzyme family but maintain activity against both cpL and cpB proteases (7,8).…”