Structure- and function-based design of Plasmodium-selective proteasome inhibitors
The proteasome is a multi-component protease complex responsible for regulating key processes such as the cell cycle and antigen presentation. Compounds that target the proteasome are potentially valuable tools for the treatment of pathogens that depend on proteasome function for survival and replic...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Stanley C Xie [verfasserIn] |
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| Format: |
Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2016 |
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| Übergeordnetes Werk: |
Enthalten in: Nature - London : Macmillan Publishers Limited, part of Springer Nature, 1869, 530(2016), 7589, Seite 233 |
|---|---|
| Übergeordnetes Werk: |
volume:530 ; year:2016 ; number:7589 ; pages:233 |
| Links: |
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| DOI / URN: |
10.1038/nature16936 |
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| Katalog-ID: |
OLC1971894575 |
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| 520 | |a The proteasome is a multi-component protease complex responsible for regulating key processes such as the cell cycle and antigen presentation. Compounds that target the proteasome are potentially valuable tools for the treatment of pathogens that depend on proteasome function for survival and replication. In particular, proteasome inhibitors have been shown to be toxic for the malaria parasite Plasmodium falciparum at all stages of its life cycle. Most compounds that have been tested against the parasite also inhibit the mammalian proteasome, resulting in toxicity that precludes their use as therapeutic agents. Therefore, better definition of the substrate specificity and structural properties of the Plasmodium proteasome could enable the development of compounds with sufficient selectivity to allow their use as anti-malarial agents. To accomplish this goal, here we use a substrate profiling method to uncover differences in the specificities of the human and P. falciparum proteasome. We design inhibitors based on amino-acid preferences specific to the parasite proteasome, and find that they preferentially inhibit the β2-subunit. We determine the structure of the P. falciparum 20S proteasome bound to the inhibitor using cryo-electron microscopy and single-particle analysis, to a resolution of 3.6 Å. These data reveal the unusually open P. falciparum β2 active site and provide valuable information about active-site architecture that can be used to further refine inhibitor design. Furthermore, consistent with the recent finding that the proteasome is important for stress pathways associated with resistance of artemisinin family anti-malarials, we observe growth inhibition synergism with low doses of this β2-selective inhibitor in artemisinin-sensitive and -resistant parasites. Finally, we demonstrate that a parasite-selective inhibitor could be used to attenuate parasite growth in vivo without appreciable toxicity to the host. Thus, the Plasmodium proteasome is a chemically tractable target that could be exploited by next-generation anti-malarial agents. | ||
| 650 | 4 | |a Parasites | |
| 650 | 4 | |a Protease inhibitors | |
| 650 | 4 | |a Drug dosages | |
| 650 | 4 | |a Erythrocytes | |
| 650 | 4 | |a Proteins | |
| 650 | 4 | |a Malaria | |
| 650 | 4 | |a Proteases | |
| 650 | 4 | |a Ligands | |
| 650 | 4 | |a Plasmodium falciparum - drug effects | |
| 650 | 4 | |a Plasmodium - enzymology | |
| 650 | 4 | |a Plasmodium chabaudi - physiology | |
| 650 | 4 | |a Plasmodium chabaudi - enzymology | |
| 650 | 4 | |a Plasmodium falciparum - growth & development | |
| 650 | 4 | |a Artemisinins - pharmacology | |
| 650 | 4 | |a Antimalarials - pharmacology | |
| 650 | 4 | |a Substrate Specificity - drug effects | |
| 650 | 4 | |a Proteasome Inhibitors - adverse effects | |
| 650 | 4 | |a Plasmodium chabaudi - drug effects | |
| 650 | 4 | |a Antimalarials - adverse effects | |
| 650 | 4 | |a Proteasome Inhibitors - toxicity | |
| 650 | 4 | |a Proteasome Endopeptidase Complex - ultrastructure | |
| 650 | 4 | |a Proteasome Inhibitors - chemistry | |
| 650 | 4 | |a Plasmodium - drug effects | |
| 650 | 4 | |a Antimalarials - toxicity | |
| 650 | 4 | |a Protein Subunits - antagonists & inhibitors | |
| 650 | 4 | |a Proteasome Inhibitors - pharmacology | |
| 650 | 4 | |a Plasmodium falciparum - enzymology | |
| 650 | 4 | |a Protein Subunits - metabolism | |
| 650 | 4 | |a Proteasome Endopeptidase Complex - metabolism | |
| 650 | 4 | |a Antimalarials - chemistry | |
| 650 | 4 | |a Protein Subunits - chemistry | |
| 650 | 4 | |a Proteasome Endopeptidase Complex - chemistry | |
| 650 | 4 | |a Plasmodium - growth & development | |
| 650 | 4 | |a Ubiquitin-proteasome system | |
| 650 | 4 | |a Health aspects | |
| 650 | 4 | |a Plasmodium | |
| 700 | 0 | |a Euna Yoo |4 oth | |
| 700 | 0 | |a Charles S Craik |4 oth | |
| 700 | 0 | |a Paula C A da Fonseca |4 oth | |
| 700 | 0 | |a Wouter A van der Linden |4 oth | |
| 700 | 0 | |a Hao Li |4 oth | |
| 700 | 0 | |a Anthony J O'Donoghue |4 oth | |
| 700 | 0 | |a Matthew Bogyo |4 oth | |
| 700 | 0 | |a Ian T Foe |4 oth | |
| 700 | 0 | |a Leann Tilley |4 oth | |
| 773 | 0 | 8 | |i Enthalten in |t Nature |d London : Macmillan Publishers Limited, part of Springer Nature, 1869 |g 530(2016), 7589, Seite 233 |w (DE-627)129292834 |w (DE-600)120714-3 |w (DE-576)014473941 |x 0028-0836 |7 nnns |
| 773 | 1 | 8 | |g volume:530 |g year:2016 |g number:7589 |g pages:233 |
| 856 | 4 | 1 | |u http://dx.doi.org/10.1038/nature16936 |3 Volltext |
| 856 | 4 | 2 | |u http://www.ncbi.nlm.nih.gov/pubmed/26863983 |
| 856 | 4 | 2 | |u http://search.proquest.com/docview/1765089218 |
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2016 |
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2016 |
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10.1038/nature16936 doi PQ20160307 (DE-627)OLC1971894575 (DE-599)GBVOLC1971894575 (PRQ)g1990-16376b6a17142b84c4c2c38814c3d1d64e83fb92d09f3ecdc67baa79fba438700 (KEY)0072945020160000530758900233structureandfunctionbaseddesignofplasmodiumselecti DE-627 ger DE-627 rakwb eng 070 500 DNB 500 AVZ BIODIV fid Stanley C Xie verfasserin aut Structure- and function-based design of Plasmodium-selective proteasome inhibitors 2016 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier The proteasome is a multi-component protease complex responsible for regulating key processes such as the cell cycle and antigen presentation. Compounds that target the proteasome are potentially valuable tools for the treatment of pathogens that depend on proteasome function for survival and replication. In particular, proteasome inhibitors have been shown to be toxic for the malaria parasite Plasmodium falciparum at all stages of its life cycle. Most compounds that have been tested against the parasite also inhibit the mammalian proteasome, resulting in toxicity that precludes their use as therapeutic agents. Therefore, better definition of the substrate specificity and structural properties of the Plasmodium proteasome could enable the development of compounds with sufficient selectivity to allow their use as anti-malarial agents. To accomplish this goal, here we use a substrate profiling method to uncover differences in the specificities of the human and P. falciparum proteasome. We design inhibitors based on amino-acid preferences specific to the parasite proteasome, and find that they preferentially inhibit the β2-subunit. We determine the structure of the P. falciparum 20S proteasome bound to the inhibitor using cryo-electron microscopy and single-particle analysis, to a resolution of 3.6 Å. These data reveal the unusually open P. falciparum β2 active site and provide valuable information about active-site architecture that can be used to further refine inhibitor design. Furthermore, consistent with the recent finding that the proteasome is important for stress pathways associated with resistance of artemisinin family anti-malarials, we observe growth inhibition synergism with low doses of this β2-selective inhibitor in artemisinin-sensitive and -resistant parasites. Finally, we demonstrate that a parasite-selective inhibitor could be used to attenuate parasite growth in vivo without appreciable toxicity to the host. Thus, the Plasmodium proteasome is a chemically tractable target that could be exploited by next-generation anti-malarial agents. Parasites Protease inhibitors Drug dosages Erythrocytes Proteins Malaria Proteases Ligands Plasmodium falciparum - drug effects Plasmodium - enzymology Plasmodium chabaudi - physiology Plasmodium chabaudi - enzymology Plasmodium falciparum - growth & development Artemisinins - pharmacology Antimalarials - pharmacology Substrate Specificity - drug effects Proteasome Inhibitors - adverse effects Plasmodium chabaudi - drug effects Antimalarials - adverse effects Proteasome Inhibitors - toxicity Proteasome Endopeptidase Complex - ultrastructure Proteasome Inhibitors - chemistry Plasmodium - drug effects Antimalarials - toxicity Protein Subunits - antagonists & inhibitors Proteasome Inhibitors - pharmacology Plasmodium falciparum - enzymology Protein Subunits - metabolism Proteasome Endopeptidase Complex - metabolism Antimalarials - chemistry Protein Subunits - chemistry Proteasome Endopeptidase Complex - chemistry Plasmodium - growth & development Ubiquitin-proteasome system Health aspects Plasmodium Euna Yoo oth Charles S Craik oth Paula C A da Fonseca oth Wouter A van der Linden oth Hao Li oth Anthony J O'Donoghue oth Matthew Bogyo oth Ian T Foe oth Leann Tilley oth Enthalten in Nature London : Macmillan Publishers Limited, part of Springer Nature, 1869 530(2016), 7589, Seite 233 (DE-627)129292834 (DE-600)120714-3 (DE-576)014473941 0028-0836 nnns volume:530 year:2016 number:7589 pages:233 http://dx.doi.org/10.1038/nature16936 Volltext http://www.ncbi.nlm.nih.gov/pubmed/26863983 http://search.proquest.com/docview/1765089218 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-SPO SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-FOR GBV_ILN_11 GBV_ILN_22 GBV_ILN_30 GBV_ILN_40 GBV_ILN_47 GBV_ILN_55 GBV_ILN_59 GBV_ILN_60 GBV_ILN_62 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_101 GBV_ILN_110 GBV_ILN_120 GBV_ILN_154 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_290 GBV_ILN_294 GBV_ILN_601 GBV_ILN_647 GBV_ILN_754 GBV_ILN_2001 GBV_ILN_2002 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2015 GBV_ILN_2016 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2026 GBV_ILN_2095 GBV_ILN_2116 GBV_ILN_2120 GBV_ILN_2121 GBV_ILN_2219 GBV_ILN_2221 GBV_ILN_2279 GBV_ILN_2286 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4125 GBV_ILN_4219 GBV_ILN_4251 GBV_ILN_4277 GBV_ILN_4302 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4317 GBV_ILN_4320 GBV_ILN_4324 GBV_ILN_4700 AR 530 2016 7589 233 |
| spelling |
10.1038/nature16936 doi PQ20160307 (DE-627)OLC1971894575 (DE-599)GBVOLC1971894575 (PRQ)g1990-16376b6a17142b84c4c2c38814c3d1d64e83fb92d09f3ecdc67baa79fba438700 (KEY)0072945020160000530758900233structureandfunctionbaseddesignofplasmodiumselecti DE-627 ger DE-627 rakwb eng 070 500 DNB 500 AVZ BIODIV fid Stanley C Xie verfasserin aut Structure- and function-based design of Plasmodium-selective proteasome inhibitors 2016 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier The proteasome is a multi-component protease complex responsible for regulating key processes such as the cell cycle and antigen presentation. Compounds that target the proteasome are potentially valuable tools for the treatment of pathogens that depend on proteasome function for survival and replication. In particular, proteasome inhibitors have been shown to be toxic for the malaria parasite Plasmodium falciparum at all stages of its life cycle. Most compounds that have been tested against the parasite also inhibit the mammalian proteasome, resulting in toxicity that precludes their use as therapeutic agents. Therefore, better definition of the substrate specificity and structural properties of the Plasmodium proteasome could enable the development of compounds with sufficient selectivity to allow their use as anti-malarial agents. To accomplish this goal, here we use a substrate profiling method to uncover differences in the specificities of the human and P. falciparum proteasome. We design inhibitors based on amino-acid preferences specific to the parasite proteasome, and find that they preferentially inhibit the β2-subunit. We determine the structure of the P. falciparum 20S proteasome bound to the inhibitor using cryo-electron microscopy and single-particle analysis, to a resolution of 3.6 Å. These data reveal the unusually open P. falciparum β2 active site and provide valuable information about active-site architecture that can be used to further refine inhibitor design. Furthermore, consistent with the recent finding that the proteasome is important for stress pathways associated with resistance of artemisinin family anti-malarials, we observe growth inhibition synergism with low doses of this β2-selective inhibitor in artemisinin-sensitive and -resistant parasites. Finally, we demonstrate that a parasite-selective inhibitor could be used to attenuate parasite growth in vivo without appreciable toxicity to the host. Thus, the Plasmodium proteasome is a chemically tractable target that could be exploited by next-generation anti-malarial agents. Parasites Protease inhibitors Drug dosages Erythrocytes Proteins Malaria Proteases Ligands Plasmodium falciparum - drug effects Plasmodium - enzymology Plasmodium chabaudi - physiology Plasmodium chabaudi - enzymology Plasmodium falciparum - growth & development Artemisinins - pharmacology Antimalarials - pharmacology Substrate Specificity - drug effects Proteasome Inhibitors - adverse effects Plasmodium chabaudi - drug effects Antimalarials - adverse effects Proteasome Inhibitors - toxicity Proteasome Endopeptidase Complex - ultrastructure Proteasome Inhibitors - chemistry Plasmodium - drug effects Antimalarials - toxicity Protein Subunits - antagonists & inhibitors Proteasome Inhibitors - pharmacology Plasmodium falciparum - enzymology Protein Subunits - metabolism Proteasome Endopeptidase Complex - metabolism Antimalarials - chemistry Protein Subunits - chemistry Proteasome Endopeptidase Complex - chemistry Plasmodium - growth & development Ubiquitin-proteasome system Health aspects Plasmodium Euna Yoo oth Charles S Craik oth Paula C A da Fonseca oth Wouter A van der Linden oth Hao Li oth Anthony J O'Donoghue oth Matthew Bogyo oth Ian T Foe oth Leann Tilley oth Enthalten in Nature London : Macmillan Publishers Limited, part of Springer Nature, 1869 530(2016), 7589, Seite 233 (DE-627)129292834 (DE-600)120714-3 (DE-576)014473941 0028-0836 nnns volume:530 year:2016 number:7589 pages:233 http://dx.doi.org/10.1038/nature16936 Volltext http://www.ncbi.nlm.nih.gov/pubmed/26863983 http://search.proquest.com/docview/1765089218 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-SPO SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-FOR GBV_ILN_11 GBV_ILN_22 GBV_ILN_30 GBV_ILN_40 GBV_ILN_47 GBV_ILN_55 GBV_ILN_59 GBV_ILN_60 GBV_ILN_62 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_101 GBV_ILN_110 GBV_ILN_120 GBV_ILN_154 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_290 GBV_ILN_294 GBV_ILN_601 GBV_ILN_647 GBV_ILN_754 GBV_ILN_2001 GBV_ILN_2002 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2015 GBV_ILN_2016 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2026 GBV_ILN_2095 GBV_ILN_2116 GBV_ILN_2120 GBV_ILN_2121 GBV_ILN_2219 GBV_ILN_2221 GBV_ILN_2279 GBV_ILN_2286 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4125 GBV_ILN_4219 GBV_ILN_4251 GBV_ILN_4277 GBV_ILN_4302 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4317 GBV_ILN_4320 GBV_ILN_4324 GBV_ILN_4700 AR 530 2016 7589 233 |
| allfields_unstemmed |
10.1038/nature16936 doi PQ20160307 (DE-627)OLC1971894575 (DE-599)GBVOLC1971894575 (PRQ)g1990-16376b6a17142b84c4c2c38814c3d1d64e83fb92d09f3ecdc67baa79fba438700 (KEY)0072945020160000530758900233structureandfunctionbaseddesignofplasmodiumselecti DE-627 ger DE-627 rakwb eng 070 500 DNB 500 AVZ BIODIV fid Stanley C Xie verfasserin aut Structure- and function-based design of Plasmodium-selective proteasome inhibitors 2016 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier The proteasome is a multi-component protease complex responsible for regulating key processes such as the cell cycle and antigen presentation. Compounds that target the proteasome are potentially valuable tools for the treatment of pathogens that depend on proteasome function for survival and replication. In particular, proteasome inhibitors have been shown to be toxic for the malaria parasite Plasmodium falciparum at all stages of its life cycle. Most compounds that have been tested against the parasite also inhibit the mammalian proteasome, resulting in toxicity that precludes their use as therapeutic agents. Therefore, better definition of the substrate specificity and structural properties of the Plasmodium proteasome could enable the development of compounds with sufficient selectivity to allow their use as anti-malarial agents. To accomplish this goal, here we use a substrate profiling method to uncover differences in the specificities of the human and P. falciparum proteasome. We design inhibitors based on amino-acid preferences specific to the parasite proteasome, and find that they preferentially inhibit the β2-subunit. We determine the structure of the P. falciparum 20S proteasome bound to the inhibitor using cryo-electron microscopy and single-particle analysis, to a resolution of 3.6 Å. These data reveal the unusually open P. falciparum β2 active site and provide valuable information about active-site architecture that can be used to further refine inhibitor design. Furthermore, consistent with the recent finding that the proteasome is important for stress pathways associated with resistance of artemisinin family anti-malarials, we observe growth inhibition synergism with low doses of this β2-selective inhibitor in artemisinin-sensitive and -resistant parasites. Finally, we demonstrate that a parasite-selective inhibitor could be used to attenuate parasite growth in vivo without appreciable toxicity to the host. Thus, the Plasmodium proteasome is a chemically tractable target that could be exploited by next-generation anti-malarial agents. Parasites Protease inhibitors Drug dosages Erythrocytes Proteins Malaria Proteases Ligands Plasmodium falciparum - drug effects Plasmodium - enzymology Plasmodium chabaudi - physiology Plasmodium chabaudi - enzymology Plasmodium falciparum - growth & development Artemisinins - pharmacology Antimalarials - pharmacology Substrate Specificity - drug effects Proteasome Inhibitors - adverse effects Plasmodium chabaudi - drug effects Antimalarials - adverse effects Proteasome Inhibitors - toxicity Proteasome Endopeptidase Complex - ultrastructure Proteasome Inhibitors - chemistry Plasmodium - drug effects Antimalarials - toxicity Protein Subunits - antagonists & inhibitors Proteasome Inhibitors - pharmacology Plasmodium falciparum - enzymology Protein Subunits - metabolism Proteasome Endopeptidase Complex - metabolism Antimalarials - chemistry Protein Subunits - chemistry Proteasome Endopeptidase Complex - chemistry Plasmodium - growth & development Ubiquitin-proteasome system Health aspects Plasmodium Euna Yoo oth Charles S Craik oth Paula C A da Fonseca oth Wouter A van der Linden oth Hao Li oth Anthony J O'Donoghue oth Matthew Bogyo oth Ian T Foe oth Leann Tilley oth Enthalten in Nature London : Macmillan Publishers Limited, part of Springer Nature, 1869 530(2016), 7589, Seite 233 (DE-627)129292834 (DE-600)120714-3 (DE-576)014473941 0028-0836 nnns volume:530 year:2016 number:7589 pages:233 http://dx.doi.org/10.1038/nature16936 Volltext http://www.ncbi.nlm.nih.gov/pubmed/26863983 http://search.proquest.com/docview/1765089218 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-SPO SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-FOR GBV_ILN_11 GBV_ILN_22 GBV_ILN_30 GBV_ILN_40 GBV_ILN_47 GBV_ILN_55 GBV_ILN_59 GBV_ILN_60 GBV_ILN_62 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_101 GBV_ILN_110 GBV_ILN_120 GBV_ILN_154 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_290 GBV_ILN_294 GBV_ILN_601 GBV_ILN_647 GBV_ILN_754 GBV_ILN_2001 GBV_ILN_2002 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2015 GBV_ILN_2016 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2026 GBV_ILN_2095 GBV_ILN_2116 GBV_ILN_2120 GBV_ILN_2121 GBV_ILN_2219 GBV_ILN_2221 GBV_ILN_2279 GBV_ILN_2286 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4125 GBV_ILN_4219 GBV_ILN_4251 GBV_ILN_4277 GBV_ILN_4302 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4317 GBV_ILN_4320 GBV_ILN_4324 GBV_ILN_4700 AR 530 2016 7589 233 |
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10.1038/nature16936 doi PQ20160307 (DE-627)OLC1971894575 (DE-599)GBVOLC1971894575 (PRQ)g1990-16376b6a17142b84c4c2c38814c3d1d64e83fb92d09f3ecdc67baa79fba438700 (KEY)0072945020160000530758900233structureandfunctionbaseddesignofplasmodiumselecti DE-627 ger DE-627 rakwb eng 070 500 DNB 500 AVZ BIODIV fid Stanley C Xie verfasserin aut Structure- and function-based design of Plasmodium-selective proteasome inhibitors 2016 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier The proteasome is a multi-component protease complex responsible for regulating key processes such as the cell cycle and antigen presentation. Compounds that target the proteasome are potentially valuable tools for the treatment of pathogens that depend on proteasome function for survival and replication. In particular, proteasome inhibitors have been shown to be toxic for the malaria parasite Plasmodium falciparum at all stages of its life cycle. Most compounds that have been tested against the parasite also inhibit the mammalian proteasome, resulting in toxicity that precludes their use as therapeutic agents. Therefore, better definition of the substrate specificity and structural properties of the Plasmodium proteasome could enable the development of compounds with sufficient selectivity to allow their use as anti-malarial agents. To accomplish this goal, here we use a substrate profiling method to uncover differences in the specificities of the human and P. falciparum proteasome. We design inhibitors based on amino-acid preferences specific to the parasite proteasome, and find that they preferentially inhibit the β2-subunit. We determine the structure of the P. falciparum 20S proteasome bound to the inhibitor using cryo-electron microscopy and single-particle analysis, to a resolution of 3.6 Å. These data reveal the unusually open P. falciparum β2 active site and provide valuable information about active-site architecture that can be used to further refine inhibitor design. Furthermore, consistent with the recent finding that the proteasome is important for stress pathways associated with resistance of artemisinin family anti-malarials, we observe growth inhibition synergism with low doses of this β2-selective inhibitor in artemisinin-sensitive and -resistant parasites. Finally, we demonstrate that a parasite-selective inhibitor could be used to attenuate parasite growth in vivo without appreciable toxicity to the host. Thus, the Plasmodium proteasome is a chemically tractable target that could be exploited by next-generation anti-malarial agents. Parasites Protease inhibitors Drug dosages Erythrocytes Proteins Malaria Proteases Ligands Plasmodium falciparum - drug effects Plasmodium - enzymology Plasmodium chabaudi - physiology Plasmodium chabaudi - enzymology Plasmodium falciparum - growth & development Artemisinins - pharmacology Antimalarials - pharmacology Substrate Specificity - drug effects Proteasome Inhibitors - adverse effects Plasmodium chabaudi - drug effects Antimalarials - adverse effects Proteasome Inhibitors - toxicity Proteasome Endopeptidase Complex - ultrastructure Proteasome Inhibitors - chemistry Plasmodium - drug effects Antimalarials - toxicity Protein Subunits - antagonists & inhibitors Proteasome Inhibitors - pharmacology Plasmodium falciparum - enzymology Protein Subunits - metabolism Proteasome Endopeptidase Complex - metabolism Antimalarials - chemistry Protein Subunits - chemistry Proteasome Endopeptidase Complex - chemistry Plasmodium - growth & development Ubiquitin-proteasome system Health aspects Plasmodium Euna Yoo oth Charles S Craik oth Paula C A da Fonseca oth Wouter A van der Linden oth Hao Li oth Anthony J O'Donoghue oth Matthew Bogyo oth Ian T Foe oth Leann Tilley oth Enthalten in Nature London : Macmillan Publishers Limited, part of Springer Nature, 1869 530(2016), 7589, Seite 233 (DE-627)129292834 (DE-600)120714-3 (DE-576)014473941 0028-0836 nnns volume:530 year:2016 number:7589 pages:233 http://dx.doi.org/10.1038/nature16936 Volltext http://www.ncbi.nlm.nih.gov/pubmed/26863983 http://search.proquest.com/docview/1765089218 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-SPO SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-FOR GBV_ILN_11 GBV_ILN_22 GBV_ILN_30 GBV_ILN_40 GBV_ILN_47 GBV_ILN_55 GBV_ILN_59 GBV_ILN_60 GBV_ILN_62 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_101 GBV_ILN_110 GBV_ILN_120 GBV_ILN_154 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_290 GBV_ILN_294 GBV_ILN_601 GBV_ILN_647 GBV_ILN_754 GBV_ILN_2001 GBV_ILN_2002 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2015 GBV_ILN_2016 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2026 GBV_ILN_2095 GBV_ILN_2116 GBV_ILN_2120 GBV_ILN_2121 GBV_ILN_2219 GBV_ILN_2221 GBV_ILN_2279 GBV_ILN_2286 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4125 GBV_ILN_4219 GBV_ILN_4251 GBV_ILN_4277 GBV_ILN_4302 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4317 GBV_ILN_4320 GBV_ILN_4324 GBV_ILN_4700 AR 530 2016 7589 233 |
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10.1038/nature16936 doi PQ20160307 (DE-627)OLC1971894575 (DE-599)GBVOLC1971894575 (PRQ)g1990-16376b6a17142b84c4c2c38814c3d1d64e83fb92d09f3ecdc67baa79fba438700 (KEY)0072945020160000530758900233structureandfunctionbaseddesignofplasmodiumselecti DE-627 ger DE-627 rakwb eng 070 500 DNB 500 AVZ BIODIV fid Stanley C Xie verfasserin aut Structure- and function-based design of Plasmodium-selective proteasome inhibitors 2016 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier The proteasome is a multi-component protease complex responsible for regulating key processes such as the cell cycle and antigen presentation. Compounds that target the proteasome are potentially valuable tools for the treatment of pathogens that depend on proteasome function for survival and replication. In particular, proteasome inhibitors have been shown to be toxic for the malaria parasite Plasmodium falciparum at all stages of its life cycle. Most compounds that have been tested against the parasite also inhibit the mammalian proteasome, resulting in toxicity that precludes their use as therapeutic agents. Therefore, better definition of the substrate specificity and structural properties of the Plasmodium proteasome could enable the development of compounds with sufficient selectivity to allow their use as anti-malarial agents. To accomplish this goal, here we use a substrate profiling method to uncover differences in the specificities of the human and P. falciparum proteasome. We design inhibitors based on amino-acid preferences specific to the parasite proteasome, and find that they preferentially inhibit the β2-subunit. We determine the structure of the P. falciparum 20S proteasome bound to the inhibitor using cryo-electron microscopy and single-particle analysis, to a resolution of 3.6 Å. These data reveal the unusually open P. falciparum β2 active site and provide valuable information about active-site architecture that can be used to further refine inhibitor design. Furthermore, consistent with the recent finding that the proteasome is important for stress pathways associated with resistance of artemisinin family anti-malarials, we observe growth inhibition synergism with low doses of this β2-selective inhibitor in artemisinin-sensitive and -resistant parasites. Finally, we demonstrate that a parasite-selective inhibitor could be used to attenuate parasite growth in vivo without appreciable toxicity to the host. Thus, the Plasmodium proteasome is a chemically tractable target that could be exploited by next-generation anti-malarial agents. Parasites Protease inhibitors Drug dosages Erythrocytes Proteins Malaria Proteases Ligands Plasmodium falciparum - drug effects Plasmodium - enzymology Plasmodium chabaudi - physiology Plasmodium chabaudi - enzymology Plasmodium falciparum - growth & development Artemisinins - pharmacology Antimalarials - pharmacology Substrate Specificity - drug effects Proteasome Inhibitors - adverse effects Plasmodium chabaudi - drug effects Antimalarials - adverse effects Proteasome Inhibitors - toxicity Proteasome Endopeptidase Complex - ultrastructure Proteasome Inhibitors - chemistry Plasmodium - drug effects Antimalarials - toxicity Protein Subunits - antagonists & inhibitors Proteasome Inhibitors - pharmacology Plasmodium falciparum - enzymology Protein Subunits - metabolism Proteasome Endopeptidase Complex - metabolism Antimalarials - chemistry Protein Subunits - chemistry Proteasome Endopeptidase Complex - chemistry Plasmodium - growth & development Ubiquitin-proteasome system Health aspects Plasmodium Euna Yoo oth Charles S Craik oth Paula C A da Fonseca oth Wouter A van der Linden oth Hao Li oth Anthony J O'Donoghue oth Matthew Bogyo oth Ian T Foe oth Leann Tilley oth Enthalten in Nature London : Macmillan Publishers Limited, part of Springer Nature, 1869 530(2016), 7589, Seite 233 (DE-627)129292834 (DE-600)120714-3 (DE-576)014473941 0028-0836 nnns volume:530 year:2016 number:7589 pages:233 http://dx.doi.org/10.1038/nature16936 Volltext http://www.ncbi.nlm.nih.gov/pubmed/26863983 http://search.proquest.com/docview/1765089218 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-SPO SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-FOR GBV_ILN_11 GBV_ILN_22 GBV_ILN_30 GBV_ILN_40 GBV_ILN_47 GBV_ILN_55 GBV_ILN_59 GBV_ILN_60 GBV_ILN_62 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_101 GBV_ILN_110 GBV_ILN_120 GBV_ILN_154 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_290 GBV_ILN_294 GBV_ILN_601 GBV_ILN_647 GBV_ILN_754 GBV_ILN_2001 GBV_ILN_2002 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2015 GBV_ILN_2016 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2026 GBV_ILN_2095 GBV_ILN_2116 GBV_ILN_2120 GBV_ILN_2121 GBV_ILN_2219 GBV_ILN_2221 GBV_ILN_2279 GBV_ILN_2286 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4125 GBV_ILN_4219 GBV_ILN_4251 GBV_ILN_4277 GBV_ILN_4302 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4317 GBV_ILN_4320 GBV_ILN_4324 GBV_ILN_4700 AR 530 2016 7589 233 |
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Parasites Protease inhibitors Drug dosages Erythrocytes Proteins Malaria Proteases Ligands Plasmodium falciparum - drug effects Plasmodium - enzymology Plasmodium chabaudi - physiology Plasmodium chabaudi - enzymology Plasmodium falciparum - growth & development Artemisinins - pharmacology Antimalarials - pharmacology Substrate Specificity - drug effects Proteasome Inhibitors - adverse effects Plasmodium chabaudi - drug effects Antimalarials - adverse effects Proteasome Inhibitors - toxicity Proteasome Endopeptidase Complex - ultrastructure Proteasome Inhibitors - chemistry Plasmodium - drug effects Antimalarials - toxicity Protein Subunits - antagonists & inhibitors Proteasome Inhibitors - pharmacology Plasmodium falciparum - enzymology Protein Subunits - metabolism Proteasome Endopeptidase Complex - metabolism Antimalarials - chemistry Protein Subunits - chemistry Proteasome Endopeptidase Complex - chemistry Plasmodium - growth & development Ubiquitin-proteasome system Health aspects Plasmodium |
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Stanley C Xie @@aut@@ Euna Yoo @@oth@@ Charles S Craik @@oth@@ Paula C A da Fonseca @@oth@@ Wouter A van der Linden @@oth@@ Hao Li @@oth@@ Anthony J O'Donoghue @@oth@@ Matthew Bogyo @@oth@@ Ian T Foe @@oth@@ Leann Tilley @@oth@@ |
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070 500 DNB 500 AVZ BIODIV fid Structure- and function-based design of Plasmodium-selective proteasome inhibitors Parasites Protease inhibitors Drug dosages Erythrocytes Proteins Malaria Proteases Ligands Plasmodium falciparum - drug effects Plasmodium - enzymology Plasmodium chabaudi - physiology Plasmodium chabaudi - enzymology Plasmodium falciparum - growth & development Artemisinins - pharmacology Antimalarials - pharmacology Substrate Specificity - drug effects Proteasome Inhibitors - adverse effects Plasmodium chabaudi - drug effects Antimalarials - adverse effects Proteasome Inhibitors - toxicity Proteasome Endopeptidase Complex - ultrastructure Proteasome Inhibitors - chemistry Plasmodium - drug effects Antimalarials - toxicity Protein Subunits - antagonists & inhibitors Proteasome Inhibitors - pharmacology Plasmodium falciparum - enzymology Protein Subunits - metabolism Proteasome Endopeptidase Complex - metabolism Antimalarials - chemistry Protein Subunits - chemistry Proteasome Endopeptidase Complex - chemistry Plasmodium - growth & development Ubiquitin-proteasome system Health aspects Plasmodium |
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structure- and function-based design of plasmodium-selective proteasome inhibitors |
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Structure- and function-based design of Plasmodium-selective proteasome inhibitors |
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The proteasome is a multi-component protease complex responsible for regulating key processes such as the cell cycle and antigen presentation. Compounds that target the proteasome are potentially valuable tools for the treatment of pathogens that depend on proteasome function for survival and replication. In particular, proteasome inhibitors have been shown to be toxic for the malaria parasite Plasmodium falciparum at all stages of its life cycle. Most compounds that have been tested against the parasite also inhibit the mammalian proteasome, resulting in toxicity that precludes their use as therapeutic agents. Therefore, better definition of the substrate specificity and structural properties of the Plasmodium proteasome could enable the development of compounds with sufficient selectivity to allow their use as anti-malarial agents. To accomplish this goal, here we use a substrate profiling method to uncover differences in the specificities of the human and P. falciparum proteasome. We design inhibitors based on amino-acid preferences specific to the parasite proteasome, and find that they preferentially inhibit the β2-subunit. We determine the structure of the P. falciparum 20S proteasome bound to the inhibitor using cryo-electron microscopy and single-particle analysis, to a resolution of 3.6 Å. These data reveal the unusually open P. falciparum β2 active site and provide valuable information about active-site architecture that can be used to further refine inhibitor design. Furthermore, consistent with the recent finding that the proteasome is important for stress pathways associated with resistance of artemisinin family anti-malarials, we observe growth inhibition synergism with low doses of this β2-selective inhibitor in artemisinin-sensitive and -resistant parasites. Finally, we demonstrate that a parasite-selective inhibitor could be used to attenuate parasite growth in vivo without appreciable toxicity to the host. Thus, the Plasmodium proteasome is a chemically tractable target that could be exploited by next-generation anti-malarial agents. |
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The proteasome is a multi-component protease complex responsible for regulating key processes such as the cell cycle and antigen presentation. Compounds that target the proteasome are potentially valuable tools for the treatment of pathogens that depend on proteasome function for survival and replication. In particular, proteasome inhibitors have been shown to be toxic for the malaria parasite Plasmodium falciparum at all stages of its life cycle. Most compounds that have been tested against the parasite also inhibit the mammalian proteasome, resulting in toxicity that precludes their use as therapeutic agents. Therefore, better definition of the substrate specificity and structural properties of the Plasmodium proteasome could enable the development of compounds with sufficient selectivity to allow their use as anti-malarial agents. To accomplish this goal, here we use a substrate profiling method to uncover differences in the specificities of the human and P. falciparum proteasome. We design inhibitors based on amino-acid preferences specific to the parasite proteasome, and find that they preferentially inhibit the β2-subunit. We determine the structure of the P. falciparum 20S proteasome bound to the inhibitor using cryo-electron microscopy and single-particle analysis, to a resolution of 3.6 Å. These data reveal the unusually open P. falciparum β2 active site and provide valuable information about active-site architecture that can be used to further refine inhibitor design. Furthermore, consistent with the recent finding that the proteasome is important for stress pathways associated with resistance of artemisinin family anti-malarials, we observe growth inhibition synergism with low doses of this β2-selective inhibitor in artemisinin-sensitive and -resistant parasites. Finally, we demonstrate that a parasite-selective inhibitor could be used to attenuate parasite growth in vivo without appreciable toxicity to the host. Thus, the Plasmodium proteasome is a chemically tractable target that could be exploited by next-generation anti-malarial agents. |
| abstract_unstemmed |
The proteasome is a multi-component protease complex responsible for regulating key processes such as the cell cycle and antigen presentation. Compounds that target the proteasome are potentially valuable tools for the treatment of pathogens that depend on proteasome function for survival and replication. In particular, proteasome inhibitors have been shown to be toxic for the malaria parasite Plasmodium falciparum at all stages of its life cycle. Most compounds that have been tested against the parasite also inhibit the mammalian proteasome, resulting in toxicity that precludes their use as therapeutic agents. Therefore, better definition of the substrate specificity and structural properties of the Plasmodium proteasome could enable the development of compounds with sufficient selectivity to allow their use as anti-malarial agents. To accomplish this goal, here we use a substrate profiling method to uncover differences in the specificities of the human and P. falciparum proteasome. We design inhibitors based on amino-acid preferences specific to the parasite proteasome, and find that they preferentially inhibit the β2-subunit. We determine the structure of the P. falciparum 20S proteasome bound to the inhibitor using cryo-electron microscopy and single-particle analysis, to a resolution of 3.6 Å. These data reveal the unusually open P. falciparum β2 active site and provide valuable information about active-site architecture that can be used to further refine inhibitor design. Furthermore, consistent with the recent finding that the proteasome is important for stress pathways associated with resistance of artemisinin family anti-malarials, we observe growth inhibition synergism with low doses of this β2-selective inhibitor in artemisinin-sensitive and -resistant parasites. Finally, we demonstrate that a parasite-selective inhibitor could be used to attenuate parasite growth in vivo without appreciable toxicity to the host. Thus, the Plasmodium proteasome is a chemically tractable target that could be exploited by next-generation anti-malarial agents. |
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<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a2200265 4500</leader><controlfield tag="001">OLC1971894575</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230714182342.0</controlfield><controlfield tag="007">tu</controlfield><controlfield tag="008">160308s2016 xx ||||| 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1038/nature16936</subfield><subfield code="2">doi</subfield></datafield><datafield tag="028" ind1="5" ind2="2"><subfield code="a">PQ20160307</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)OLC1971894575</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-599)GBVOLC1971894575</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(PRQ)g1990-16376b6a17142b84c4c2c38814c3d1d64e83fb92d09f3ecdc67baa79fba438700</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(KEY)0072945020160000530758900233structureandfunctionbaseddesignofplasmodiumselecti</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="082" ind1="0" ind2="4"><subfield code="a">070</subfield><subfield code="a">500</subfield><subfield code="q">DNB</subfield></datafield><datafield tag="082" ind1="0" ind2="4"><subfield code="a">500</subfield><subfield code="q">AVZ</subfield></datafield><datafield tag="084" ind1=" " ind2=" "><subfield code="a">BIODIV</subfield><subfield code="2">fid</subfield></datafield><datafield tag="100" ind1="0" ind2=" "><subfield code="a">Stanley C Xie</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Structure- and function-based design of Plasmodium-selective proteasome inhibitors</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2016</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">ohne Hilfsmittel zu benutzen</subfield><subfield code="b">n</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Band</subfield><subfield code="b">nc</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">The proteasome is a multi-component protease complex responsible for regulating key processes such as the cell cycle and antigen presentation. Compounds that target the proteasome are potentially valuable tools for the treatment of pathogens that depend on proteasome function for survival and replication. In particular, proteasome inhibitors have been shown to be toxic for the malaria parasite Plasmodium falciparum at all stages of its life cycle. Most compounds that have been tested against the parasite also inhibit the mammalian proteasome, resulting in toxicity that precludes their use as therapeutic agents. Therefore, better definition of the substrate specificity and structural properties of the Plasmodium proteasome could enable the development of compounds with sufficient selectivity to allow their use as anti-malarial agents. To accomplish this goal, here we use a substrate profiling method to uncover differences in the specificities of the human and P. falciparum proteasome. We design inhibitors based on amino-acid preferences specific to the parasite proteasome, and find that they preferentially inhibit the β2-subunit. We determine the structure of the P. falciparum 20S proteasome bound to the inhibitor using cryo-electron microscopy and single-particle analysis, to a resolution of 3.6 Å. These data reveal the unusually open P. falciparum β2 active site and provide valuable information about active-site architecture that can be used to further refine inhibitor design. Furthermore, consistent with the recent finding that the proteasome is important for stress pathways associated with resistance of artemisinin family anti-malarials, we observe growth inhibition synergism with low doses of this β2-selective inhibitor in artemisinin-sensitive and -resistant parasites. Finally, we demonstrate that a parasite-selective inhibitor could be used to attenuate parasite growth in vivo without appreciable toxicity to the host. 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