Identification of proteases that regulate erythrocyte rupture by the malaria parasite Plasmodium falciparum

Arastu‐Kapur, Shirin; Ponder, Elizabeth L.; Fonović, Urša Pečar; Yeoh, Sharon; Yuan, Fang; Fonović, Marko; Grainger, Munira; Phillips, Carolyn I; Powers, James C.; Bogyo, Matthew

doi:10.1038/nchembio.70

Cited by 246 publications

(319 citation statements)

References 40 publications

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“…First, DPAP1 is highly expressed in blood-stage parasites and is localized to the parasite DV where it catalyzes the final stages of hemoglobin degradation (23). Thus, reactive Fe II is present in the DV, and the desired release of free ML in this compartment can be detected with an activity-based probe (ABP) for DPAP activity (24,25). Secondly, the free amino group in ML is essential as it serves to mimic the N terminus of DPAP substrates.…”

Section: Resultsmentioning

confidence: 99%

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Ferrous iron-dependent drug delivery enables controlled and selective release of therapeutic agents in vivo

Deu¹,

Chen

Lauterwasser

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The precise targeting of cytotoxic agents to specific cell types or cellular compartments is of significant interest in medicine, with particular relevance for infectious diseases and cancer. Here, we describe a method to exploit aberrant levels of mobile ferrous iron (Fe II ) for selective drug delivery in vivo. This approach makes use of a 1,2,4-trioxolane moiety, which serves as an Fe II -sensitive "trigger," making drug release contingent on Fe II -promoted trioxolane fragmentation. We demonstrate in vivo validation of this approach with the Plasmodium berghei model of murine malaria. Malaria parasites produce high concentrations of mobile ferrous iron as a consequence of their catabolism of host hemoglobin in the infected erythrocyte. Using activity-based probes, we successfully demonstrate the Fe II -dependent and parasite-selective delivery of a potent dipeptidyl aminopeptidase inhibitor. We find that delivery of the compound in its Fe II -targeted form leads to more sustained target inhibition with greatly reduced off-target inhibition of mammalian cathepsins. This selective drug delivery translates into improved efficacy and tolerability. These findings demonstrate the utility of a purely chemical means to achieve selective drug targeting in vivo. This approach may find useful application in parasitic infections and more broadly in any disease state characterized by aberrant production of reactive ferrous iron.iron-mediated delivery | targeted prodrugs | dipeptidyl peptidase | combination therapy

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Section: Resultsmentioning

confidence: 99%

“…*This Direct Submission article had a prearranged editor. To validate our approach in parasites, we used a potent and irreversible inhibitor of the parasite cysteine protease dipeptidyl aminopeptidase 1 (DPAP1) (23)(24)(25) as our "drug" species. Several factors drove the selection of the DPAP inhibitor ML4118S (24) (herein denoted ML) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Ferrous iron-dependent drug delivery enables controlled and selective release of therapeutic agents in vivo

Deu¹,

Chen

Lauterwasser

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…As our in vitro biochemical data show that the increase in [Ca 2 þ ] activates only a fraction of SUB1, it is likely to be that other stimuli could also participate in the full activation of the parasite enzyme. In this respect, two natural candidates are pH, which is known to regulate the activation of the PCs furin and PC1/3 (refs 5,6), and the parasite di-peptidyl peptidase DPAP3 that has been proposed to participate in SUB1 activation 49 .…”

Section: Post 3′ Utr Pbsub1mentioning

confidence: 99%

A novel Plasmodium-specific prodomain fold regulates the malaria drug target SUB1 subtilase

et al. 2014

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The Plasmodium subtilase SUB1 plays a pivotal role during the egress of malaria parasites from host hepatocytes and erythrocytes. Here we report the crystal structure of full-length SUB1 from the human-infecting parasite Plasmodium vivax, revealing a bacterial-like catalytic domain in complex with a Plasmodium-specific prodomain. The latter displays a novel architecture with an amino-terminal insertion that functions as a 'belt', embracing the catalytic domain to further stabilize the quaternary structure of the pre-protease, and undergoes calcium-dependent autoprocessing during subsequent activation. Although dispensable for recombinant enzymatic activity, the SUB1 'belt' could not be deleted in Plasmodium berghei, suggesting an essential role of this domain for parasite development in vivo. The SUB1 structure not only provides a valuable platform to develop new anti-malarial candidates against this promising drug target, but also defines the Plasmodium-specific 'belt' domain as a key calcium-dependent regulator of SUB1 during parasite egress from host cells.

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“…Chemical biology approaches are increasingly being used to glean new insights into P. falciparum biology. Activity based probes have been used to identify and investigate the role of falcipain-1 in parasite invasion of RBCs (16) and that of the subtilisin-family serine protease, PfSUB1, and cysteine protease dipeptidyl peptidase in parasite release from infected RBCs (17). Similarly, selected enzyme targets are also being screened against large chemical libraries to identify specific inhibitors that can be used to modulate the activity of this target in situ and potentially serve as lead compounds in drug discovery efforts.…”

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confidence: 99%

Inhibiting Plasmodium falciparum growth and heme detoxification pathway using heme-binding DNA aptamers

Niles¹,

DeRisi

Marletta

2009

Proc. Natl. Acad. Sci. U.S.A.

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The human parasite Plasmodium falciparum enzymatically digests hemoglobin during its intra-erythrocytic developmental stages in acidic food vacuole compartments. The released heme is rapidly detoxified by polymerization into the chemically inert pigment, hemozoin. Several heme-binding anti-malarial compounds, such as chloroquine, efficiently inhibit this process, and this is believed to be the predominant mechanism by which these drugs induce parasite toxicity. In an effort to expand the biochemical tools available for exploration of this pathogen's basic biology, we chose this heme-detoxification pathway as a model system for exploring the suitability of DNA aptamers for modulating this essential parasite biochemical pathway. In this report, we demonstrate that heme-binding DNA aptamers efficiently inhibit in vitro hemozoin formation catalyzed by either a model lipid system or parasite-derived extracts just as or more potently than chloroquine. Furthermore, when parasites are grown in red cells loaded with heme-binding aptamers, their growth is significantly inhibited relative to parasites exposed to non-heme-binding DNA oligonucleotides. Both the timing of parasite-induced toxicity and the concentration of heme-binding aptamer required for inducing toxicity correlate well with the uptake of red cell cytosolic components by the parasite, and the requirement for compounds with similar in vitro hemozoin inhibitory potency to preconcentrate within the parasite before observing toxicity. Thus, these hemebinding aptamers recapitulate the in vitro hemozoin inhibition activity and induce parasite toxicity in a manner consistent with inhibition of this pathway. Altogether, these data demonstrate that aptamers can be versatile tools with applicability in functionally dissecting important P. falciparum-specific pathways both in vitro and in vivo.

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Identification of proteases that regulate erythrocyte rupture by the malaria parasite Plasmodium falciparum

Cited by 246 publications

References 40 publications

Ferrous iron-dependent drug delivery enables controlled and selective release of therapeutic agents in vivo

Ferrous iron-dependent drug delivery enables controlled and selective release of therapeutic agents in vivo

A novel Plasmodium-specific prodomain fold regulates the malaria drug target SUB1 subtilase

Inhibiting Plasmodium falciparum growth and heme detoxification pathway using heme-binding DNA aptamers

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