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G-Quadruplex DNA Motifs in the Malaria Parasite Plasmodium falciparum and Their Potential as Novel Antimalarial Drug Targets
G-quadruplexes are DNA or RNA secondary structures that can be formed from guanine-rich nucleic acids. These four-stranded structures, composed of stacked quartets of guanine bases, can be highly stable and have been demonstrated to occur in the DNA of human cells and other systems, where they play...
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| Published in: | Antimicrobial agents and chemotherapy 2018-03, Vol.62 (3) |
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| container_issue | 3 |
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| container_title | Antimicrobial agents and chemotherapy |
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| creator | Harris, Lynne M Monsell, Katelyn R Noulin, Florian Famodimu, M Toyin Smargiasso, Nicolas Damblon, Christian Horrocks, Paul Merrick, Catherine J |
| description | G-quadruplexes are DNA or RNA secondary structures that can be formed from guanine-rich nucleic acids. These four-stranded structures, composed of stacked quartets of guanine bases, can be highly stable and have been demonstrated to occur
in the DNA of human cells and other systems, where they play important biological roles, influencing processes such as telomere maintenance, DNA replication and transcription, or, in the case of RNA G-quadruplexes, RNA translation and processing. We report for the first time that DNA G-quadruplexes can be detected in the nuclei of the malaria parasite
, which has one of the most A/T-biased genomes sequenced and therefore possesses few guanine-rich sequences with the potential to form G-quadruplexes. We show that despite this paucity of putative G-quadruplex-forming sequences,
parasites are sensitive to several G-quadruplex-stabilizing drugs, including quarfloxin, which previously reached phase 2 clinical trials as an anticancer drug. Quarfloxin has a rapid initial rate of kill and is active against ring stages as well as replicative stages of intraerythrocytic development. We show that several G-quadruplex-stabilizing drugs, including quarfloxin, can suppress the transcription of a G-quadruplex-containing reporter gene in
but that quarfloxin does not appear to disrupt the transcription of rRNAs, which was proposed as its mode of action in both human cells and trypanosomes. These data suggest that quarfloxin has potential for repositioning as an antimalarial with a novel mode of action. Furthermore, G-quadruplex biology in
may present a target for development of other new antimalarial drugs. |
| doi_str_mv | 10.1128/AAC.01828-17 |
| format | article |
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in the DNA of human cells and other systems, where they play important biological roles, influencing processes such as telomere maintenance, DNA replication and transcription, or, in the case of RNA G-quadruplexes, RNA translation and processing. We report for the first time that DNA G-quadruplexes can be detected in the nuclei of the malaria parasite
, which has one of the most A/T-biased genomes sequenced and therefore possesses few guanine-rich sequences with the potential to form G-quadruplexes. We show that despite this paucity of putative G-quadruplex-forming sequences,
parasites are sensitive to several G-quadruplex-stabilizing drugs, including quarfloxin, which previously reached phase 2 clinical trials as an anticancer drug. Quarfloxin has a rapid initial rate of kill and is active against ring stages as well as replicative stages of intraerythrocytic development. We show that several G-quadruplex-stabilizing drugs, including quarfloxin, can suppress the transcription of a G-quadruplex-containing reporter gene in
but that quarfloxin does not appear to disrupt the transcription of rRNAs, which was proposed as its mode of action in both human cells and trypanosomes. These data suggest that quarfloxin has potential for repositioning as an antimalarial with a novel mode of action. Furthermore, G-quadruplex biology in
may present a target for development of other new antimalarial drugs.</description><identifier>ISSN: 0066-4804</identifier><identifier>ISSN: 1098-6596</identifier><identifier>EISSN: 1098-6596</identifier><identifier>DOI: 10.1128/AAC.01828-17</identifier><identifier>PMID: 29311059</identifier><language>eng</language><publisher>United States: American Society for Microbiology</publisher><subject>Antimalarials ; Antimalarials - pharmacology ; Biochemistry, biophysics & molecular biology ; Biochimie, biophysique & biologie moléculaire ; DNA content ; DNA replication ; DNA structure ; DNA transcription ; EC50 ; Experimental Therapeutics ; G-quadruplex ; G-Quadruplexes ; G-Quadruplexes - drug effects ; Humans ; Life sciences ; Malaria ; Malaria, Falciparum - microbiology ; Plasmodium falciparum ; Plasmodium falciparum - drug effects ; Plasmodium falciparum - genetics ; Quarfloxin ; RNA 18S ; RNA processing ; RNA translation ; Sciences du vivant ; Trypanosoma</subject><ispartof>Antimicrobial agents and chemotherapy, 2018-03, Vol.62 (3)</ispartof><rights>Copyright © 2018 American Society for Microbiology.</rights><rights>Copyright © 2018 American Society for Microbiology. 2018 American Society for Microbiology</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a505t-14bc20c3587cc15fb0528e7793cb72efd25d9f9fc3b6323208f4155d9b91af673</citedby><cites>FETCH-LOGICAL-a505t-14bc20c3587cc15fb0528e7793cb72efd25d9f9fc3b6323208f4155d9b91af673</cites><orcidid>0000-0001-7583-2176</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://journals.asm.org/doi/pdf/10.1128/AAC.01828-17$$EPDF$$P50$$Gasm2$$H</linktopdf><linktohtml>$$Uhttps://journals.asm.org/doi/full/10.1128/AAC.01828-17$$EHTML$$P50$$Gasm2$$H</linktohtml><link.rule.ids>230,315,730,783,787,888,3196,27937,27938,52764,52765,52766,53805,53807</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29311059$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Harris, Lynne M</creatorcontrib><creatorcontrib>Monsell, Katelyn R</creatorcontrib><creatorcontrib>Noulin, Florian</creatorcontrib><creatorcontrib>Famodimu, M Toyin</creatorcontrib><creatorcontrib>Smargiasso, Nicolas</creatorcontrib><creatorcontrib>Damblon, Christian</creatorcontrib><creatorcontrib>Horrocks, Paul</creatorcontrib><creatorcontrib>Merrick, Catherine J</creatorcontrib><title>G-Quadruplex DNA Motifs in the Malaria Parasite Plasmodium falciparum and Their Potential as Novel Antimalarial Drug Targets</title><title>Antimicrobial agents and chemotherapy</title><addtitle>Antimicrob Agents Chemother</addtitle><addtitle>Antimicrob Agents Chemother</addtitle><description>G-quadruplexes are DNA or RNA secondary structures that can be formed from guanine-rich nucleic acids. These four-stranded structures, composed of stacked quartets of guanine bases, can be highly stable and have been demonstrated to occur
in the DNA of human cells and other systems, where they play important biological roles, influencing processes such as telomere maintenance, DNA replication and transcription, or, in the case of RNA G-quadruplexes, RNA translation and processing. We report for the first time that DNA G-quadruplexes can be detected in the nuclei of the malaria parasite
, which has one of the most A/T-biased genomes sequenced and therefore possesses few guanine-rich sequences with the potential to form G-quadruplexes. We show that despite this paucity of putative G-quadruplex-forming sequences,
parasites are sensitive to several G-quadruplex-stabilizing drugs, including quarfloxin, which previously reached phase 2 clinical trials as an anticancer drug. Quarfloxin has a rapid initial rate of kill and is active against ring stages as well as replicative stages of intraerythrocytic development. We show that several G-quadruplex-stabilizing drugs, including quarfloxin, can suppress the transcription of a G-quadruplex-containing reporter gene in
but that quarfloxin does not appear to disrupt the transcription of rRNAs, which was proposed as its mode of action in both human cells and trypanosomes. These data suggest that quarfloxin has potential for repositioning as an antimalarial with a novel mode of action. Furthermore, G-quadruplex biology in
may present a target for development of other new antimalarial drugs.</description><subject>Antimalarials</subject><subject>Antimalarials - pharmacology</subject><subject>Biochemistry, biophysics & molecular biology</subject><subject>Biochimie, biophysique & biologie moléculaire</subject><subject>DNA content</subject><subject>DNA replication</subject><subject>DNA structure</subject><subject>DNA transcription</subject><subject>EC50</subject><subject>Experimental Therapeutics</subject><subject>G-quadruplex</subject><subject>G-Quadruplexes</subject><subject>G-Quadruplexes - drug effects</subject><subject>Humans</subject><subject>Life sciences</subject><subject>Malaria</subject><subject>Malaria, Falciparum - microbiology</subject><subject>Plasmodium falciparum</subject><subject>Plasmodium falciparum - drug effects</subject><subject>Plasmodium falciparum - genetics</subject><subject>Quarfloxin</subject><subject>RNA 18S</subject><subject>RNA processing</subject><subject>RNA translation</subject><subject>Sciences du vivant</subject><subject>Trypanosoma</subject><issn>0066-4804</issn><issn>1098-6596</issn><issn>1098-6596</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNp1kU1v1DAQhi0Eokvhxhn5itQUf8SOfUGKth8gtWWRlrPlOE7WlTde2ckKpP74ejdQ0UNPnrFnnnk9LwAfMTrHmIgvdb08R1gQUeDqFVhgJEXBmeSvwQIhzotSoPIEvEvpHuWcSfQWnBBJMUZMLsDDdfFz0m2cdt7-hhd3NbwNo-sSdAMcNxbeaq-j03Clo05utHDlddqG1k1b2Glv3E7HHOqhheuNdRGuwmiH0WkPdYJ3YW89rHO-nTkeXsSph2sdezum9-BNZiT74e95Cn5dXa6X34qbH9ffl_VNoRliY4HLxhBkKBOVMZh1DWJE2KqS1DQVsV1LWCs72RnacEooQaIrMct3jcS64xU9BV9n7m5qtrY1WWDUXu1ilhX_qKCdev4yuI3qw14xQThmZQbQGeCd7a0KsXFqT46Nx3jyvdJGNVYRwoUiZcX5oets7jIxpBRt9zQRI3XwTmXv1NE7hQ8qP8_lecFE3YcpDnkpL9V--v9HT-B_xtJHvqSimQ</recordid><startdate>20180301</startdate><enddate>20180301</enddate><creator>Harris, Lynne M</creator><creator>Monsell, Katelyn R</creator><creator>Noulin, Florian</creator><creator>Famodimu, M Toyin</creator><creator>Smargiasso, Nicolas</creator><creator>Damblon, Christian</creator><creator>Horrocks, Paul</creator><creator>Merrick, Catherine J</creator><general>American Society for Microbiology</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>Q33</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-7583-2176</orcidid></search><sort><creationdate>20180301</creationdate><title>G-Quadruplex DNA Motifs in the Malaria Parasite Plasmodium falciparum and Their Potential as Novel Antimalarial Drug Targets</title><author>Harris, Lynne M ; Monsell, Katelyn R ; Noulin, Florian ; Famodimu, M Toyin ; Smargiasso, Nicolas ; Damblon, Christian ; Horrocks, Paul ; Merrick, Catherine J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a505t-14bc20c3587cc15fb0528e7793cb72efd25d9f9fc3b6323208f4155d9b91af673</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Antimalarials</topic><topic>Antimalarials - pharmacology</topic><topic>Biochemistry, biophysics & molecular biology</topic><topic>Biochimie, biophysique & biologie moléculaire</topic><topic>DNA content</topic><topic>DNA replication</topic><topic>DNA structure</topic><topic>DNA transcription</topic><topic>EC50</topic><topic>Experimental Therapeutics</topic><topic>G-quadruplex</topic><topic>G-Quadruplexes</topic><topic>G-Quadruplexes - drug effects</topic><topic>Humans</topic><topic>Life sciences</topic><topic>Malaria</topic><topic>Malaria, Falciparum - microbiology</topic><topic>Plasmodium falciparum</topic><topic>Plasmodium falciparum - drug effects</topic><topic>Plasmodium falciparum - genetics</topic><topic>Quarfloxin</topic><topic>RNA 18S</topic><topic>RNA processing</topic><topic>RNA translation</topic><topic>Sciences du vivant</topic><topic>Trypanosoma</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Harris, Lynne M</creatorcontrib><creatorcontrib>Monsell, Katelyn R</creatorcontrib><creatorcontrib>Noulin, Florian</creatorcontrib><creatorcontrib>Famodimu, M Toyin</creatorcontrib><creatorcontrib>Smargiasso, Nicolas</creatorcontrib><creatorcontrib>Damblon, Christian</creatorcontrib><creatorcontrib>Horrocks, Paul</creatorcontrib><creatorcontrib>Merrick, Catherine J</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Université de Liège - Open Repository and Bibliography (ORBI)</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Antimicrobial agents and chemotherapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Harris, Lynne M</au><au>Monsell, Katelyn R</au><au>Noulin, Florian</au><au>Famodimu, M Toyin</au><au>Smargiasso, Nicolas</au><au>Damblon, Christian</au><au>Horrocks, Paul</au><au>Merrick, Catherine J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>G-Quadruplex DNA Motifs in the Malaria Parasite Plasmodium falciparum and Their Potential as Novel Antimalarial Drug Targets</atitle><jtitle>Antimicrobial agents and chemotherapy</jtitle><stitle>Antimicrob Agents Chemother</stitle><addtitle>Antimicrob Agents Chemother</addtitle><date>2018-03-01</date><risdate>2018</risdate><volume>62</volume><issue>3</issue><issn>0066-4804</issn><issn>1098-6596</issn><eissn>1098-6596</eissn><abstract>G-quadruplexes are DNA or RNA secondary structures that can be formed from guanine-rich nucleic acids. These four-stranded structures, composed of stacked quartets of guanine bases, can be highly stable and have been demonstrated to occur
in the DNA of human cells and other systems, where they play important biological roles, influencing processes such as telomere maintenance, DNA replication and transcription, or, in the case of RNA G-quadruplexes, RNA translation and processing. We report for the first time that DNA G-quadruplexes can be detected in the nuclei of the malaria parasite
, which has one of the most A/T-biased genomes sequenced and therefore possesses few guanine-rich sequences with the potential to form G-quadruplexes. We show that despite this paucity of putative G-quadruplex-forming sequences,
parasites are sensitive to several G-quadruplex-stabilizing drugs, including quarfloxin, which previously reached phase 2 clinical trials as an anticancer drug. Quarfloxin has a rapid initial rate of kill and is active against ring stages as well as replicative stages of intraerythrocytic development. We show that several G-quadruplex-stabilizing drugs, including quarfloxin, can suppress the transcription of a G-quadruplex-containing reporter gene in
but that quarfloxin does not appear to disrupt the transcription of rRNAs, which was proposed as its mode of action in both human cells and trypanosomes. These data suggest that quarfloxin has potential for repositioning as an antimalarial with a novel mode of action. Furthermore, G-quadruplex biology in
may present a target for development of other new antimalarial drugs.</abstract><cop>United States</cop><pub>American Society for Microbiology</pub><pmid>29311059</pmid><doi>10.1128/AAC.01828-17</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0001-7583-2176</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Antimicrobial agents and chemotherapy, 2018-03, Vol.62 (3) |
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| language | eng |
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| source | American Society for Microbiology Journals; PubMed Central |
| subjects | Antimalarials Antimalarials - pharmacology Biochemistry, biophysics & molecular biology Biochimie, biophysique & biologie moléculaire DNA content DNA replication DNA structure DNA transcription EC50 Experimental Therapeutics G-quadruplex G-Quadruplexes G-Quadruplexes - drug effects Humans Life sciences Malaria Malaria, Falciparum - microbiology Plasmodium falciparum Plasmodium falciparum - drug effects Plasmodium falciparum - genetics Quarfloxin RNA 18S RNA processing RNA translation Sciences du vivant Trypanosoma |
| title | G-Quadruplex DNA Motifs in the Malaria Parasite Plasmodium falciparum and Their Potential as Novel Antimalarial Drug Targets |
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