Aziridine-2,3-Dicarboxylate-Based Cysteine Cathepsin Inhibitors Induce Cell Death in<i>Leishmania major</i>Associated with Accumulation of Debris in Autophagy-Related Lysosome-Like Vacuoles

Schurigt, Uta; Schad, Caroline; Glowa, Christin; Baum, Ulrike; Thomale, Katja; Schnitzer, Johannes K.; Martina, Stefano; Schaschke, Norbert; Schirmeister, Tanja; Moll, Heidrun

doi:10.1128/aac.00327-10

Cited by 43 publications

(52 citation statements)

References 48 publications

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“…Preliminary experiments using L. major promastigote full-lysate in a cysteine-cathepsin fluorescence activity assay [16,34] showed protease inhibitory activity of compound 1 and 15 and, thus, point to this target.…”

Section: Discussionmentioning

confidence: 96%

Antileishmanial Lead Structures from Nature: Analysis of Structure-Activity Relationships of a Compound Library Derived from Caffeic Acid Bornyl Ester

et al. 2014

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Bioassay-guided fractionation of a chloroform extract of Valeriana wallichii (V. wallichii) rhizomes lead to the isolation and identification of caffeic acid bornyl ester (1) as the active component against Leishmania major (L. major) promastigotes (IC 50 = 48.8 µM). To investigate the structure-activity relationship (SAR), a library of compounds based on 1 was synthesized and tested in vitro against L. major and L. donovani promastigotes, and L. major amastigotes. Cytotoxicity was determined using a murine J774.1 cell line and bone marrow derived macrophages (BMDM). Some compounds showed antileishmanial activity in the concentration range of pentamidine and miltefosine which are the standard drugs in use. In the L. major amastigote assay compounds 15, 19 and 20 showed good activity with relatively low cytotoxicity against BMDM, resulting in acceptable selectivity indices. Molecules with adjacent phenolic hydroxyl groups exhibited elevated cytotoxicity against murine cell lines J774.1 and BMDM. The Michael system seems not to be essential for antileishmanial activity. Based on the results compound 27 can be regarded as new lead structure for further structure optimization.

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Section: Discussionmentioning

confidence: 96%

Antileishmanial Lead Structures from Nature: Analysis of Structure-Activity Relationships of a Compound Library Derived from Caffeic Acid Bornyl Ester

et al. 2014

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“…Moreover, cell shrinkage, loss of plasma membrane integrity along with blebbing, chromatin condensation, and dilation of mitochondria, hallmarks of apoptotic cell death (51), were observed. Lack of extensive round lysosome-like cytoplasmic intracellular vacuoles, chromatin condensation, and the absence of intact plasma membrane with insignificant cell shrinkage and swelling, along with insignificant changes in nuclear and mitochondrial integrity, observed herein, are indicative of apoptotic rather than autophagic cell death (50). Further, increases in annexin V positivity and intracellular ROS generation, upregulation of hydroxyl radicals, downregulation of GSH levels, elevation of lipid peroxide levels, a decrease in mitochondrial membrane potential, and elevation of late-stage apoptosis markers such as protease activation and DNA nucleosomal fragmentation in the treated promastigotes support induction of apoptosis-like PCD (20).…”

Section: Discussionmentioning

confidence: 53%

“…Treatment with PP-10 at IC 50 doses for 1.5 and 2 h produced 33% and 17% apoptotic (annexin V-positive) cells at early apoptotic and late apoptotic phases of promastigote cell death, respectively. In contrast, 8% and 31.4% necrotic cells (PI positive) were observed at 2 h and 3.5 h posttreatment with PP-10 at IC 50 and IC 90 doses, respectively. 50 dose of PP-10 to investigate the generation of ROS.…”

Section: -mentioning

confidence: 86%

“…In contrast, 8% and 31.4% necrotic cells (PI positive) were observed at 2 h and 3.5 h posttreatment with PP-10 at IC 50 and IC 90 doses, respectively. 50 dose of PP-10 to investigate the generation of ROS. The increase in the fluorescence intensity of the treated cells in comparison to untreated controls (0.2% DMSO) demonstrates that the IC 50 dose of PP-10 induces early apoptosis for up to 1.5 h due to the physiological production of ROS by the mitochondrion (Fig.…”

Section: -mentioning

confidence: 86%

“…3Bc, lane 3) in isolated nuclei obtained from log-phase culture of leishmanial cells treated with PP-10 at the IC 50 dose for 2 h. The effect of fragmentation became more marked at 3.5 h posttreatment (lane 2). The cleavage patterns of genomic DNA characterized by fragmentation are typical of internucleosomal DNA digestion by an endogenous nuclease and a hallmark of apoptosis.…”

Section: Ros Generation Caused By Oxidative Stress Influences Depletimentioning

confidence: 98%

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Discovery of Safe and Orally Effective 4-Aminoquinaldine Analogues as Apoptotic Inducers with Activity against Experimental Visceral Leishmaniasis

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Novel antileishmanials are urgently required to overcome emergence of drug resistance, cytotoxic effects, and difficulties in oral delivery. Toward this, we investigated a series of novel 4-aminoquinaldine derivatives, a new class of molecules, as potential antileishmanials. 4-Aminoquinaldine derivatives presented inhibitory effects on L. donovani promastigotes and amastigotes (50% inhibitory concentration range, 0.94 to 127 M). Of these, PP-9 and PP-10 were the most effective in vitro and demonstrated strong efficacies in vivo through the intraperitoneal route. They were also found to be effective against both sodium antimony gluconate-sensitive and -resistant Leishmania donovani strains in BALB/c mice when treated orally, resulting in more than 95% protection. Investigation of their mode of action revealed that killing by PP-10 involved moderate inhibition of dihydrofolate reductase and elicitation of the apoptotic cascade. Our studies implicate that PP-10 augments reactive oxygen species generation, evidenced from decreased glutathione levels and increased lipid peroxidation. Subsequent disruption of Leishmania promastigote mitochondrial membrane potential and activation of cytosolic proteases initiated the apoptotic pathway, resulting in DNA fragmentation and parasite death. Our results demonstrate that PP-9 and PP-10 are promising lead compounds with the potential for treating visceral leishmaniasis (VL) through the oral route.

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Turnover of Glycosomes in Trypanosomes – Perspectives for Drug Discovery

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Comprehensive Analysis of Parasite Biology: From Metabolism to Drug Discovery

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

Cited by 43 publications

References 48 publications

Antileishmanial Lead Structures from Nature: Analysis of Structure-Activity Relationships of a Compound Library Derived from Caffeic Acid Bornyl Ester

Antileishmanial Lead Structures from Nature: Analysis of Structure-Activity Relationships of a Compound Library Derived from Caffeic Acid Bornyl Ester

Discovery of Safe and Orally Effective 4-Aminoquinaldine Analogues as Apoptotic Inducers with Activity against Experimental Visceral Leishmaniasis

Turnover of Glycosomes in Trypanosomes – Perspectives for Drug Discovery

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