| Role of Plasmodium falciparum digestive vacuole plasmepsins in the specificity and antimalarial mode of action of cysteine and aspartic protease inhibitors. | |
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MedLine Citation:
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PMID: 19752273 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Hemoglobin (Hb) degradation is essential for the growth of the intraerythrocytic stages of malarial parasites. This process, which occurs inside an acidic digestive vacuole (DV), is thought to involve the action of four aspartic proteases, termed plasmepsins (PMs). These enzymes have received considerable attention as potential antimalarial drug targets. Leveraging the availability of a set of PM-knockout lines generated in Plasmodium falciparum, we report here that a wide range of previously characterized or novel aspartic protease inhibitors exert their antimalarial activities independently of their effect on the DV PMs. We also assayed compounds previously shown to inhibit cysteine proteases residing in the DV. The most striking observation was a ninefold increase in the potency of the calpain inhibitor N-acetyl-leucinyl-leucinyl-norleucinal (ALLN) against parasites lacking all four DV PMs. Genetic ablation of PM III or PM IV also decreased the level of parasite resistance to the beta-hematin binding antimalarial chloroquine. On the basis of the findings of drug susceptibility and isobologram assays, as well as the findings of studies of the inhibition of Hb degradation, morphological analyses, and stage specificity, we conclude that the DV PMs and falcipain cysteine proteases act cooperatively in Hb hydrolysis. We also identify several aspartic protease inhibitors, designed to target DV PMs, which appear to act on alternative targets early in the intraerythrocytic life cycle. These include the potent diphenylurea compound GB-III-32, which was found to be fourfold less potent against a P. falciparum line overexpressing plasmepsin X than against the parental nontransformed parasite line. The identification of the mode of action of these inhibitors will be important for future antimalarial drug discovery efforts focusing on aspartic proteases. |
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Authors:
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Pedro A Moura; John B Dame; David A Fidock |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2009-09-14 |
Journal Detail:
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Title: Antimicrobial agents and chemotherapy Volume: 53 ISSN: 1098-6596 ISO Abbreviation: Antimicrob. Agents Chemother. Publication Date: 2009 Dec |
Date Detail:
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Created Date: 2009-11-17 Completed Date: 2010-02-01 Revised Date: 2010-09-28 |
Medline Journal Info:
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Nlm Unique ID: 0315061 Medline TA: Antimicrob Agents Chemother Country: United States |
Other Details:
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Languages: eng Pagination: 4968-78 Citation Subset: IM |
Affiliation:
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Department of Microbiology, Columbia University, New York, NY 10032, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antimalarials / pharmacology*, therapeutic use Aspartic Acid Endopeptidases / genetics, physiology* Cysteine Endopeptidases / metabolism Cysteine Proteinase Inhibitors / pharmacology*, therapeutic use Hemoglobins / metabolism Hydrolysis Leupeptins / pharmacology, therapeutic use Malaria, Falciparum / drug therapy Parasitic Sensitivity Tests Plasmodium falciparum / drug effects*, pathogenicity Protease Inhibitors / pharmacology*, therapeutic use |
| Grant Support | |
ID/Acronym/Agency:
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GM 04791/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antimalarials; 0/Cysteine Proteinase Inhibitors; 0/Hemoglobins; 0/Leupeptins; 0/Protease Inhibitors; 110044-82-1/acetylleucyl-leucyl-norleucinal; EC 3.4.22.-/Cysteine Endopeptidases; EC 3.4.22.-/falcipain; EC 3.4.23.-/Aspartic Acid Endopeptidases; EC 3.4.23.38/plasmepsin |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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