Gene selective mRNA cleavage inhibits the development of Plasmodium falciparum
Unique peptide-morpholino oligomer (PMO) conjugates have been designed to bind and promote the cleavage of specific mRNA as a tool to inhibit gene function and parasite growth. The new conjugates were validated using the P. falciparum gyrase mRNA as a target (PfGyrA). Assays in vitro demonstrated a...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2012-04, Vol.109 (16), p.6235-6240 |
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| creator | Augagneur, Yoann Wesolowski, Donna Tae, Hyun Seop Altman, Sidney Ben Mamoun, Choukri |
| description | Unique peptide-morpholino oligomer (PMO) conjugates have been designed to bind and promote the cleavage of specific mRNA as a tool to inhibit gene function and parasite growth. The new conjugates were validated using the P. falciparum gyrase mRNA as a target (PfGyrA). Assays in vitro demonstrated a selective degradation of the PfGyrA mRNA directed by the external guide sequences, which are morpholino oligomers in the conjugates. Fluorescence microscopy revealed that labeled conjugates are delivered into Plasmodium-infected erythrocytes during all intraerythrocytic stages of parasite development. Consistent with the expression of PfGyrA in all stages of parasite development, proliferation assays showed that these conjugates have potent antimalarial activity, blocking early development, maturation, and replication of the parasite. The conjugates were equally effective against drug sensitive and resistant P. falciparum strains. The potency, selectivity, and predicted safety of PMO conjugates make this approach attractive for the development of a unique class of target-specific antimalarials and for large-scale functional analysis of the malarial genome. |
| doi_str_mv | 10.1073/pnas.1203516109 |
| format | Article |
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The new conjugates were validated using the P. falciparum gyrase mRNA as a target (PfGyrA). Assays in vitro demonstrated a selective degradation of the PfGyrA mRNA directed by the external guide sequences, which are morpholino oligomers in the conjugates. Fluorescence microscopy revealed that labeled conjugates are delivered into Plasmodium-infected erythrocytes during all intraerythrocytic stages of parasite development. Consistent with the expression of PfGyrA in all stages of parasite development, proliferation assays showed that these conjugates have potent antimalarial activity, blocking early development, maturation, and replication of the parasite. The conjugates were equally effective against drug sensitive and resistant P. falciparum strains. The potency, selectivity, and predicted safety of PMO conjugates make this approach attractive for the development of a unique class of target-specific antimalarials and for large-scale functional analysis of the malarial genome.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1203516109</identifier><identifier>PMID: 22474358</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Amino Acid Sequence ; Antimalarials ; Base Sequence ; Biological Sciences ; chemistry ; Developmental biology ; DNA Gyrase ; DNA Gyrase - genetics ; DNA Gyrase - metabolism ; early development ; Enzymes ; Erythrocytes ; Erythrocytes - parasitology ; Fluorescein ; Fluorescein - chemistry ; Fluorescence ; fluorescence microscopy ; Gene Expression Regulation, Developmental ; Gene Expression Regulation, Developmental - genetics ; genes ; genetics ; growth & development ; HeLa Cells ; Humans ; Malaria ; Messenger RNA ; metabolism ; Microscopy, Fluorescence ; Morpholinos ; Morpholinos - chemistry ; Morpholinos - genetics ; Morpholinos - metabolism ; Parasites ; parasitology ; Peptides ; Peptides - chemistry ; Plasmodium falciparum ; Plasmodium falciparum - genetics ; Plasmodium falciparum - growth & development ; Plasmodium falciparum - metabolism ; Protozoan Proteins ; Protozoan Proteins - genetics ; Protozoan Proteins - metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; RNA ; RNA Cleavage ; RNA, Messenger ; RNA, Messenger - genetics ; RNA, Messenger - metabolism ; Schizonts</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2012-04, Vol.109 (16), p.6235-6240</ispartof><rights>copyright © 1993-2008 National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Apr 17, 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c557t-df7b2a34108131152f34ec31ac5a2794eb4c4716ea56c52d9316a3ad327e08753</citedby><cites>FETCH-LOGICAL-c557t-df7b2a34108131152f34ec31ac5a2794eb4c4716ea56c52d9316a3ad327e08753</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/109/16.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/41588503$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/41588503$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22474358$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Augagneur, Yoann</creatorcontrib><creatorcontrib>Wesolowski, Donna</creatorcontrib><creatorcontrib>Tae, Hyun Seop</creatorcontrib><creatorcontrib>Altman, Sidney</creatorcontrib><creatorcontrib>Ben Mamoun, Choukri</creatorcontrib><title>Gene selective mRNA cleavage inhibits the development of Plasmodium falciparum</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Unique peptide-morpholino oligomer (PMO) conjugates have been designed to bind and promote the cleavage of specific mRNA as a tool to inhibit gene function and parasite growth. The new conjugates were validated using the P. falciparum gyrase mRNA as a target (PfGyrA). Assays in vitro demonstrated a selective degradation of the PfGyrA mRNA directed by the external guide sequences, which are morpholino oligomers in the conjugates. Fluorescence microscopy revealed that labeled conjugates are delivered into Plasmodium-infected erythrocytes during all intraerythrocytic stages of parasite development. Consistent with the expression of PfGyrA in all stages of parasite development, proliferation assays showed that these conjugates have potent antimalarial activity, blocking early development, maturation, and replication of the parasite. The conjugates were equally effective against drug sensitive and resistant P. falciparum strains. 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The new conjugates were validated using the P. falciparum gyrase mRNA as a target (PfGyrA). Assays in vitro demonstrated a selective degradation of the PfGyrA mRNA directed by the external guide sequences, which are morpholino oligomers in the conjugates. Fluorescence microscopy revealed that labeled conjugates are delivered into Plasmodium-infected erythrocytes during all intraerythrocytic stages of parasite development. Consistent with the expression of PfGyrA in all stages of parasite development, proliferation assays showed that these conjugates have potent antimalarial activity, blocking early development, maturation, and replication of the parasite. The conjugates were equally effective against drug sensitive and resistant P. falciparum strains. 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| subjects | Amino Acid Sequence Antimalarials Base Sequence Biological Sciences chemistry Developmental biology DNA Gyrase DNA Gyrase - genetics DNA Gyrase - metabolism early development Enzymes Erythrocytes Erythrocytes - parasitology Fluorescein Fluorescein - chemistry Fluorescence fluorescence microscopy Gene Expression Regulation, Developmental Gene Expression Regulation, Developmental - genetics genes genetics growth & development HeLa Cells Humans Malaria Messenger RNA metabolism Microscopy, Fluorescence Morpholinos Morpholinos - chemistry Morpholinos - genetics Morpholinos - metabolism Parasites parasitology Peptides Peptides - chemistry Plasmodium falciparum Plasmodium falciparum - genetics Plasmodium falciparum - growth & development Plasmodium falciparum - metabolism Protozoan Proteins Protozoan Proteins - genetics Protozoan Proteins - metabolism Reverse Transcriptase Polymerase Chain Reaction RNA RNA Cleavage RNA, Messenger RNA, Messenger - genetics RNA, Messenger - metabolism Schizonts |
| title | Gene selective mRNA cleavage inhibits the development of Plasmodium falciparum |
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