Targeting protein translation, RNA splicing, and degradation by morpholino-based conjugates in Plasmodium falciparum
Identification and genetic validation of new targets from available genome sequences are critical steps toward the development of new potent and selective antimalarials. However, no methods are currently available for large-scale functional analysis of the Plasmodium falciparum genome. Here we prese...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Donna Wesolowski [verfasserIn] |
|---|
| Format: |
Artikel |
|---|---|
| Sprache: |
Englisch |
| Erschienen: |
2015 |
|---|
| Rechteinformationen: |
Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences |
|---|
| Übergeordnetes Werk: |
Enthalten in: Proceedings of the National Academy of Sciences of the United States of America - Washington, DC : NAS, 1877, 112(2015), 38, Seite 11935 |
|---|---|
| Übergeordnetes Werk: |
volume:112 ; year:2015 ; number:38 ; pages:11935 |
| Links: |
|---|
| DOI / URN: |
10.1073/pnas.1515864112 |
|---|
| Katalog-ID: |
OLC1970284242 |
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| 520 | |a Identification and genetic validation of new targets from available genome sequences are critical steps toward the development of new potent and selective antimalarials. However, no methods are currently available for large-scale functional analysis of the Plasmodium falciparum genome. Here we present evidence for successful use of morpholino oligomers (MO) to mediate degradation of target mRNAs or to inhibit RNA splicing or translation of several genes of P. falciparum involved in chloroquine transport, apicoplast biogenesis, and phospholipid biosynthesis. Consistent with their role in the parasite life cycle, down-regulation of these essential genes resulted in inhibition of parasite development. We show that a MO conjugate that targets the chloroquine-resistant transporter PfCRT is effective against chloroquine-sensitive and -resistant parasites, causes enlarged digestive vacuoles, and renders chloroquine-resistant strains more sensitive to chloroquine. Similarly, we show that a MO conjugate that targets the PfDXR involved in apicoplast biogenesis inhibits parasite growth and that this defect can be rescued by addition of isopentenyl pyrophosphate. MO-based gene regulation is a viable alternative approach to functional analysis of the P. falciparum genome. | ||
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| 650 | 4 | |a RNA Splicing - drug effects | |
| 650 | 4 | |a Hemiterpenes - metabolism | |
| 650 | 4 | |a Plasmodium falciparum - drug effects | |
| 650 | 4 | |a Parasites - growth & development | |
| 650 | 4 | |a Parasites - genetics | |
| 650 | 4 | |a Drug Resistance - drug effects | |
| 650 | 4 | |a Chloroquine - pharmacology | |
| 650 | 4 | |a Morpholinos - pharmacology | |
| 650 | 4 | |a Down-Regulation - drug effects | |
| 650 | 4 | |a Organophosphorus Compounds - metabolism | |
| 650 | 4 | |a Proteolysis - drug effects | |
| 650 | 4 | |a Plasmodium falciparum - growth & development | |
| 650 | 4 | |a Artemisinins - pharmacology | |
| 650 | 4 | |a Parasites - drug effects | |
| 650 | 4 | |a Protein Biosynthesis - drug effects | |
| 650 | 4 | |a Antimalarials - pharmacology | |
| 650 | 4 | |a RNA, Messenger - metabolism | |
| 650 | 4 | |a Peptides - pharmacology | |
| 650 | 4 | |a RNA, Messenger - genetics | |
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| 650 | 4 | |a Plasmodium falciparum - genetics | |
| 650 | 4 | |a Physiology, Pathological | |
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| 650 | 4 | |a Knots and splices | |
| 650 | 4 | |a Plasmodium falciparum | |
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10.1073/pnas.1515864112 doi PQ20160211 (DE-627)OLC1970284242 (DE-599)GBVOLC1970284242 (PRQ)g2111-adecc525e37d908bdfc76c2824cd8c8168909faad788adf6252a8586a56ed39a0 (KEY)0583363920150000112003811935targetingproteintranslationrnasplicinganddegradati DE-627 ger DE-627 rakwb eng 500 DNB 570 AVZ LING fid BIODIV fid Donna Wesolowski verfasserin aut Targeting protein translation, RNA splicing, and degradation by morpholino-based conjugates in Plasmodium falciparum 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Identification and genetic validation of new targets from available genome sequences are critical steps toward the development of new potent and selective antimalarials. However, no methods are currently available for large-scale functional analysis of the Plasmodium falciparum genome. Here we present evidence for successful use of morpholino oligomers (MO) to mediate degradation of target mRNAs or to inhibit RNA splicing or translation of several genes of P. falciparum involved in chloroquine transport, apicoplast biogenesis, and phospholipid biosynthesis. Consistent with their role in the parasite life cycle, down-regulation of these essential genes resulted in inhibition of parasite development. We show that a MO conjugate that targets the chloroquine-resistant transporter PfCRT is effective against chloroquine-sensitive and -resistant parasites, causes enlarged digestive vacuoles, and renders chloroquine-resistant strains more sensitive to chloroquine. Similarly, we show that a MO conjugate that targets the PfDXR involved in apicoplast biogenesis inhibits parasite growth and that this defect can be rescued by addition of isopentenyl pyrophosphate. MO-based gene regulation is a viable alternative approach to functional analysis of the P. falciparum genome. Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences RNA Splicing - drug effects Hemiterpenes - metabolism Plasmodium falciparum - drug effects Parasites - growth & development Parasites - genetics Drug Resistance - drug effects Chloroquine - pharmacology Morpholinos - pharmacology Down-Regulation - drug effects Organophosphorus Compounds - metabolism Proteolysis - drug effects Plasmodium falciparum - growth & development Artemisinins - pharmacology Parasites - drug effects Protein Biosynthesis - drug effects Antimalarials - pharmacology RNA, Messenger - metabolism Peptides - pharmacology RNA, Messenger - genetics Luciferases - metabolism Plasmodium falciparum - genetics Physiology, Pathological Genetic engineering Analysis Knots and splices Plasmodium falciparum Research Genetic aspects Usage Genomes Proteins Ribonucleic acid--RNA Parasites Biosynthesis Genes Aprajita Garg oth Choukri Ben Mamoun oth Sidney Altman oth Dulce Alonso oth Kirk W. Deitsch oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 112(2015), 38, Seite 11935 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:112 year:2015 number:38 pages:11935 http://dx.doi.org/10.1073/pnas.1515864112 Volltext http://www.pnas.org/content/112/38/11935.abstract http://www.ncbi.nlm.nih.gov/pubmed/26351679 http://search.proquest.com/docview/1717557413 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 112 2015 38 11935 |
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10.1073/pnas.1515864112 doi PQ20160211 (DE-627)OLC1970284242 (DE-599)GBVOLC1970284242 (PRQ)g2111-adecc525e37d908bdfc76c2824cd8c8168909faad788adf6252a8586a56ed39a0 (KEY)0583363920150000112003811935targetingproteintranslationrnasplicinganddegradati DE-627 ger DE-627 rakwb eng 500 DNB 570 AVZ LING fid BIODIV fid Donna Wesolowski verfasserin aut Targeting protein translation, RNA splicing, and degradation by morpholino-based conjugates in Plasmodium falciparum 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Identification and genetic validation of new targets from available genome sequences are critical steps toward the development of new potent and selective antimalarials. However, no methods are currently available for large-scale functional analysis of the Plasmodium falciparum genome. Here we present evidence for successful use of morpholino oligomers (MO) to mediate degradation of target mRNAs or to inhibit RNA splicing or translation of several genes of P. falciparum involved in chloroquine transport, apicoplast biogenesis, and phospholipid biosynthesis. Consistent with their role in the parasite life cycle, down-regulation of these essential genes resulted in inhibition of parasite development. We show that a MO conjugate that targets the chloroquine-resistant transporter PfCRT is effective against chloroquine-sensitive and -resistant parasites, causes enlarged digestive vacuoles, and renders chloroquine-resistant strains more sensitive to chloroquine. Similarly, we show that a MO conjugate that targets the PfDXR involved in apicoplast biogenesis inhibits parasite growth and that this defect can be rescued by addition of isopentenyl pyrophosphate. MO-based gene regulation is a viable alternative approach to functional analysis of the P. falciparum genome. Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences RNA Splicing - drug effects Hemiterpenes - metabolism Plasmodium falciparum - drug effects Parasites - growth & development Parasites - genetics Drug Resistance - drug effects Chloroquine - pharmacology Morpholinos - pharmacology Down-Regulation - drug effects Organophosphorus Compounds - metabolism Proteolysis - drug effects Plasmodium falciparum - growth & development Artemisinins - pharmacology Parasites - drug effects Protein Biosynthesis - drug effects Antimalarials - pharmacology RNA, Messenger - metabolism Peptides - pharmacology RNA, Messenger - genetics Luciferases - metabolism Plasmodium falciparum - genetics Physiology, Pathological Genetic engineering Analysis Knots and splices Plasmodium falciparum Research Genetic aspects Usage Genomes Proteins Ribonucleic acid--RNA Parasites Biosynthesis Genes Aprajita Garg oth Choukri Ben Mamoun oth Sidney Altman oth Dulce Alonso oth Kirk W. Deitsch oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 112(2015), 38, Seite 11935 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:112 year:2015 number:38 pages:11935 http://dx.doi.org/10.1073/pnas.1515864112 Volltext http://www.pnas.org/content/112/38/11935.abstract http://www.ncbi.nlm.nih.gov/pubmed/26351679 http://search.proquest.com/docview/1717557413 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 112 2015 38 11935 |
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10.1073/pnas.1515864112 doi PQ20160211 (DE-627)OLC1970284242 (DE-599)GBVOLC1970284242 (PRQ)g2111-adecc525e37d908bdfc76c2824cd8c8168909faad788adf6252a8586a56ed39a0 (KEY)0583363920150000112003811935targetingproteintranslationrnasplicinganddegradati DE-627 ger DE-627 rakwb eng 500 DNB 570 AVZ LING fid BIODIV fid Donna Wesolowski verfasserin aut Targeting protein translation, RNA splicing, and degradation by morpholino-based conjugates in Plasmodium falciparum 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Identification and genetic validation of new targets from available genome sequences are critical steps toward the development of new potent and selective antimalarials. However, no methods are currently available for large-scale functional analysis of the Plasmodium falciparum genome. Here we present evidence for successful use of morpholino oligomers (MO) to mediate degradation of target mRNAs or to inhibit RNA splicing or translation of several genes of P. falciparum involved in chloroquine transport, apicoplast biogenesis, and phospholipid biosynthesis. Consistent with their role in the parasite life cycle, down-regulation of these essential genes resulted in inhibition of parasite development. We show that a MO conjugate that targets the chloroquine-resistant transporter PfCRT is effective against chloroquine-sensitive and -resistant parasites, causes enlarged digestive vacuoles, and renders chloroquine-resistant strains more sensitive to chloroquine. Similarly, we show that a MO conjugate that targets the PfDXR involved in apicoplast biogenesis inhibits parasite growth and that this defect can be rescued by addition of isopentenyl pyrophosphate. MO-based gene regulation is a viable alternative approach to functional analysis of the P. falciparum genome. Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences RNA Splicing - drug effects Hemiterpenes - metabolism Plasmodium falciparum - drug effects Parasites - growth & development Parasites - genetics Drug Resistance - drug effects Chloroquine - pharmacology Morpholinos - pharmacology Down-Regulation - drug effects Organophosphorus Compounds - metabolism Proteolysis - drug effects Plasmodium falciparum - growth & development Artemisinins - pharmacology Parasites - drug effects Protein Biosynthesis - drug effects Antimalarials - pharmacology RNA, Messenger - metabolism Peptides - pharmacology RNA, Messenger - genetics Luciferases - metabolism Plasmodium falciparum - genetics Physiology, Pathological Genetic engineering Analysis Knots and splices Plasmodium falciparum Research Genetic aspects Usage Genomes Proteins Ribonucleic acid--RNA Parasites Biosynthesis Genes Aprajita Garg oth Choukri Ben Mamoun oth Sidney Altman oth Dulce Alonso oth Kirk W. Deitsch oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 112(2015), 38, Seite 11935 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:112 year:2015 number:38 pages:11935 http://dx.doi.org/10.1073/pnas.1515864112 Volltext http://www.pnas.org/content/112/38/11935.abstract http://www.ncbi.nlm.nih.gov/pubmed/26351679 http://search.proquest.com/docview/1717557413 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 112 2015 38 11935 |
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10.1073/pnas.1515864112 doi PQ20160211 (DE-627)OLC1970284242 (DE-599)GBVOLC1970284242 (PRQ)g2111-adecc525e37d908bdfc76c2824cd8c8168909faad788adf6252a8586a56ed39a0 (KEY)0583363920150000112003811935targetingproteintranslationrnasplicinganddegradati DE-627 ger DE-627 rakwb eng 500 DNB 570 AVZ LING fid BIODIV fid Donna Wesolowski verfasserin aut Targeting protein translation, RNA splicing, and degradation by morpholino-based conjugates in Plasmodium falciparum 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Identification and genetic validation of new targets from available genome sequences are critical steps toward the development of new potent and selective antimalarials. However, no methods are currently available for large-scale functional analysis of the Plasmodium falciparum genome. Here we present evidence for successful use of morpholino oligomers (MO) to mediate degradation of target mRNAs or to inhibit RNA splicing or translation of several genes of P. falciparum involved in chloroquine transport, apicoplast biogenesis, and phospholipid biosynthesis. Consistent with their role in the parasite life cycle, down-regulation of these essential genes resulted in inhibition of parasite development. We show that a MO conjugate that targets the chloroquine-resistant transporter PfCRT is effective against chloroquine-sensitive and -resistant parasites, causes enlarged digestive vacuoles, and renders chloroquine-resistant strains more sensitive to chloroquine. Similarly, we show that a MO conjugate that targets the PfDXR involved in apicoplast biogenesis inhibits parasite growth and that this defect can be rescued by addition of isopentenyl pyrophosphate. MO-based gene regulation is a viable alternative approach to functional analysis of the P. falciparum genome. Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences RNA Splicing - drug effects Hemiterpenes - metabolism Plasmodium falciparum - drug effects Parasites - growth & development Parasites - genetics Drug Resistance - drug effects Chloroquine - pharmacology Morpholinos - pharmacology Down-Regulation - drug effects Organophosphorus Compounds - metabolism Proteolysis - drug effects Plasmodium falciparum - growth & development Artemisinins - pharmacology Parasites - drug effects Protein Biosynthesis - drug effects Antimalarials - pharmacology RNA, Messenger - metabolism Peptides - pharmacology RNA, Messenger - genetics Luciferases - metabolism Plasmodium falciparum - genetics Physiology, Pathological Genetic engineering Analysis Knots and splices Plasmodium falciparum Research Genetic aspects Usage Genomes Proteins Ribonucleic acid--RNA Parasites Biosynthesis Genes Aprajita Garg oth Choukri Ben Mamoun oth Sidney Altman oth Dulce Alonso oth Kirk W. Deitsch oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 112(2015), 38, Seite 11935 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:112 year:2015 number:38 pages:11935 http://dx.doi.org/10.1073/pnas.1515864112 Volltext http://www.pnas.org/content/112/38/11935.abstract http://www.ncbi.nlm.nih.gov/pubmed/26351679 http://search.proquest.com/docview/1717557413 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 112 2015 38 11935 |
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10.1073/pnas.1515864112 doi PQ20160211 (DE-627)OLC1970284242 (DE-599)GBVOLC1970284242 (PRQ)g2111-adecc525e37d908bdfc76c2824cd8c8168909faad788adf6252a8586a56ed39a0 (KEY)0583363920150000112003811935targetingproteintranslationrnasplicinganddegradati DE-627 ger DE-627 rakwb eng 500 DNB 570 AVZ LING fid BIODIV fid Donna Wesolowski verfasserin aut Targeting protein translation, RNA splicing, and degradation by morpholino-based conjugates in Plasmodium falciparum 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Identification and genetic validation of new targets from available genome sequences are critical steps toward the development of new potent and selective antimalarials. However, no methods are currently available for large-scale functional analysis of the Plasmodium falciparum genome. Here we present evidence for successful use of morpholino oligomers (MO) to mediate degradation of target mRNAs or to inhibit RNA splicing or translation of several genes of P. falciparum involved in chloroquine transport, apicoplast biogenesis, and phospholipid biosynthesis. Consistent with their role in the parasite life cycle, down-regulation of these essential genes resulted in inhibition of parasite development. We show that a MO conjugate that targets the chloroquine-resistant transporter PfCRT is effective against chloroquine-sensitive and -resistant parasites, causes enlarged digestive vacuoles, and renders chloroquine-resistant strains more sensitive to chloroquine. Similarly, we show that a MO conjugate that targets the PfDXR involved in apicoplast biogenesis inhibits parasite growth and that this defect can be rescued by addition of isopentenyl pyrophosphate. MO-based gene regulation is a viable alternative approach to functional analysis of the P. falciparum genome. Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences RNA Splicing - drug effects Hemiterpenes - metabolism Plasmodium falciparum - drug effects Parasites - growth & development Parasites - genetics Drug Resistance - drug effects Chloroquine - pharmacology Morpholinos - pharmacology Down-Regulation - drug effects Organophosphorus Compounds - metabolism Proteolysis - drug effects Plasmodium falciparum - growth & development Artemisinins - pharmacology Parasites - drug effects Protein Biosynthesis - drug effects Antimalarials - pharmacology RNA, Messenger - metabolism Peptides - pharmacology RNA, Messenger - genetics Luciferases - metabolism Plasmodium falciparum - genetics Physiology, Pathological Genetic engineering Analysis Knots and splices Plasmodium falciparum Research Genetic aspects Usage Genomes Proteins Ribonucleic acid--RNA Parasites Biosynthesis Genes Aprajita Garg oth Choukri Ben Mamoun oth Sidney Altman oth Dulce Alonso oth Kirk W. Deitsch oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 112(2015), 38, Seite 11935 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:112 year:2015 number:38 pages:11935 http://dx.doi.org/10.1073/pnas.1515864112 Volltext http://www.pnas.org/content/112/38/11935.abstract http://www.ncbi.nlm.nih.gov/pubmed/26351679 http://search.proquest.com/docview/1717557413 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 112 2015 38 11935 |
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targeting protein translation, rna splicing, and degradation by morpholino-based conjugates in plasmodium falciparum |
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Targeting protein translation, RNA splicing, and degradation by morpholino-based conjugates in Plasmodium falciparum |
| abstract |
Identification and genetic validation of new targets from available genome sequences are critical steps toward the development of new potent and selective antimalarials. However, no methods are currently available for large-scale functional analysis of the Plasmodium falciparum genome. Here we present evidence for successful use of morpholino oligomers (MO) to mediate degradation of target mRNAs or to inhibit RNA splicing or translation of several genes of P. falciparum involved in chloroquine transport, apicoplast biogenesis, and phospholipid biosynthesis. Consistent with their role in the parasite life cycle, down-regulation of these essential genes resulted in inhibition of parasite development. We show that a MO conjugate that targets the chloroquine-resistant transporter PfCRT is effective against chloroquine-sensitive and -resistant parasites, causes enlarged digestive vacuoles, and renders chloroquine-resistant strains more sensitive to chloroquine. Similarly, we show that a MO conjugate that targets the PfDXR involved in apicoplast biogenesis inhibits parasite growth and that this defect can be rescued by addition of isopentenyl pyrophosphate. MO-based gene regulation is a viable alternative approach to functional analysis of the P. falciparum genome. |
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Identification and genetic validation of new targets from available genome sequences are critical steps toward the development of new potent and selective antimalarials. However, no methods are currently available for large-scale functional analysis of the Plasmodium falciparum genome. Here we present evidence for successful use of morpholino oligomers (MO) to mediate degradation of target mRNAs or to inhibit RNA splicing or translation of several genes of P. falciparum involved in chloroquine transport, apicoplast biogenesis, and phospholipid biosynthesis. Consistent with their role in the parasite life cycle, down-regulation of these essential genes resulted in inhibition of parasite development. We show that a MO conjugate that targets the chloroquine-resistant transporter PfCRT is effective against chloroquine-sensitive and -resistant parasites, causes enlarged digestive vacuoles, and renders chloroquine-resistant strains more sensitive to chloroquine. Similarly, we show that a MO conjugate that targets the PfDXR involved in apicoplast biogenesis inhibits parasite growth and that this defect can be rescued by addition of isopentenyl pyrophosphate. MO-based gene regulation is a viable alternative approach to functional analysis of the P. falciparum genome. |
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Identification and genetic validation of new targets from available genome sequences are critical steps toward the development of new potent and selective antimalarials. However, no methods are currently available for large-scale functional analysis of the Plasmodium falciparum genome. Here we present evidence for successful use of morpholino oligomers (MO) to mediate degradation of target mRNAs or to inhibit RNA splicing or translation of several genes of P. falciparum involved in chloroquine transport, apicoplast biogenesis, and phospholipid biosynthesis. Consistent with their role in the parasite life cycle, down-regulation of these essential genes resulted in inhibition of parasite development. We show that a MO conjugate that targets the chloroquine-resistant transporter PfCRT is effective against chloroquine-sensitive and -resistant parasites, causes enlarged digestive vacuoles, and renders chloroquine-resistant strains more sensitive to chloroquine. Similarly, we show that a MO conjugate that targets the PfDXR involved in apicoplast biogenesis inhibits parasite growth and that this defect can be rescued by addition of isopentenyl pyrophosphate. MO-based gene regulation is a viable alternative approach to functional analysis of the P. falciparum genome. |
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Targeting protein translation, RNA splicing, and degradation by morpholino-based conjugates in Plasmodium falciparum |
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However, no methods are currently available for large-scale functional analysis of the Plasmodium falciparum genome. Here we present evidence for successful use of morpholino oligomers (MO) to mediate degradation of target mRNAs or to inhibit RNA splicing or translation of several genes of P. falciparum involved in chloroquine transport, apicoplast biogenesis, and phospholipid biosynthesis. Consistent with their role in the parasite life cycle, down-regulation of these essential genes resulted in inhibition of parasite development. We show that a MO conjugate that targets the chloroquine-resistant transporter PfCRT is effective against chloroquine-sensitive and -resistant parasites, causes enlarged digestive vacuoles, and renders chloroquine-resistant strains more sensitive to chloroquine. Similarly, we show that a MO conjugate that targets the PfDXR involved in apicoplast biogenesis inhibits parasite growth and that this defect can be rescued by addition of isopentenyl pyrophosphate. MO-based gene regulation is a viable alternative approach to functional analysis of the P. falciparum genome.</subfield></datafield><datafield tag="540" ind1=" " ind2=" "><subfield code="a">Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">RNA Splicing - drug effects</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Hemiterpenes - metabolism</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Plasmodium falciparum - drug effects</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Parasites - growth & development</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Parasites - genetics</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Drug Resistance - drug effects</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Chloroquine - pharmacology</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Morpholinos - pharmacology</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Down-Regulation - drug effects</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Organophosphorus Compounds - metabolism</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Proteolysis - drug effects</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Plasmodium falciparum - growth & development</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Artemisinins - pharmacology</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Parasites - drug effects</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Protein Biosynthesis - drug effects</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Antimalarials - pharmacology</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">RNA, Messenger - metabolism</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Peptides - pharmacology</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">RNA, Messenger - genetics</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Luciferases - metabolism</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Plasmodium falciparum - genetics</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Physiology, Pathological</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Genetic engineering</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Analysis</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Knots and splices</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Plasmodium falciparum</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Research</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Genetic aspects</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Usage</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Genomes</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Proteins</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Ribonucleic acid--RNA</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Parasites</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Biosynthesis</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Genes</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Aprajita Garg</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Choukri Ben Mamoun</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Sidney Altman</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Dulce Alonso</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Kirk W. Deitsch</subfield><subfield code="4">oth</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">Enthalten in</subfield><subfield code="t">Proceedings of the National Academy of Sciences of the United States of America</subfield><subfield code="d">Washington, DC : NAS, 1877</subfield><subfield code="g">112(2015), 38, Seite 11935</subfield><subfield code="w">(DE-627)129505269</subfield><subfield code="w">(DE-600)209104-5</subfield><subfield code="w">(DE-576)014909189</subfield><subfield code="x">0027-8424</subfield><subfield code="7">nnns</subfield></datafield><datafield tag="773" ind1="1" ind2="8"><subfield code="g">volume:112</subfield><subfield code="g">year:2015</subfield><subfield code="g">number:38</subfield><subfield code="g">pages:11935</subfield></datafield><datafield tag="856" ind1="4" ind2="1"><subfield code="u">http://dx.doi.org/10.1073/pnas.1515864112</subfield><subfield code="3">Volltext</subfield></datafield><datafield tag="856" ind1="4" ind2="2"><subfield code="u">http://www.pnas.org/content/112/38/11935.abstract</subfield></datafield><datafield tag="856" ind1="4" ind2="2"><subfield code="u">http://www.ncbi.nlm.nih.gov/pubmed/26351679</subfield></datafield><datafield tag="856" ind1="4" ind2="2"><subfield code="u">http://search.proquest.com/docview/1717557413</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_USEFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SYSFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_OLC</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">FID-LING</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">FID-BIODIV</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-PHY</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-CHE</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-MAT</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-FOR</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-PHA</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-DE-84</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OPC-MAT</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OPC-FOR</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_40</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_59</subfield></datafield><datafield tag="951" ind1=" " ind2=" "><subfield code="a">AR</subfield></datafield><datafield tag="952" ind1=" " ind2=" "><subfield code="d">112</subfield><subfield code="j">2015</subfield><subfield code="e">38</subfield><subfield code="h">11935</subfield></datafield></record></collection>
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