Delivery of Antisense Peptide Nucleic Acids to Cells by Conjugation with Small Arginine-Rich Cell-Penetrating Peptide (R/W)9
Identifieur interne : 000F94 ( Main/Exploration ); précédent : 000F93; suivant : 000F95Delivery of Antisense Peptide Nucleic Acids to Cells by Conjugation with Small Arginine-Rich Cell-Penetrating Peptide (R/W)9
Auteurs : Céline Cordier [France] ; Fatima Boutimah [France] ; Mathilde Bourdeloux [France] ; Florian Dupuy [France] ; Elisabeth Met [France] ; Patrizia Alberti [France] ; François Loll [France] ; Gérard Chassaing [France] ; Fabienne Burlina [France] ; Tula Ester Saison-Behmoaras [France]Source :
- PLoS ONE [ 1932-6203 ] ; 2014-08-15.
Abstract
Peptide nucleic acids (PNAs) are very attractive antisense and antigene agents, but these molecules are not passively taken into cells. Here, using a functional cell assay and fluorescent-based methods, we investigated cell uptake and antisense activity of a tridecamer PNA that targets the HIV-1 polypurine tract sequence delivered using the arginine-rich (R/W)9 peptide (RRWWRRWRR). At micromolar concentrations, without use of any transfection agents, almost 80% inhibition of the target gene expression was obtained with the conjugate in the presence of the endosomolytic agent chloroquine. We show that chloroquine not only induced escape from endosomes but also enhanced the cellular uptake of the conjugate. Mechanistic studies revealed that (R/W)9-PNA conjugates were internalized via pinocytosis. Replacement of arginines with lysines reduced the uptake of the conjugate by six-fold, resulting in the abolition of intracellular target inhibition. Our results show that the arginines play a crucial role in the conjugate uptake and antisense activity. To determine whether specificity of the interactions of arginines with cell surface proteoglycans result in the internalization, we used flow cytometry to examine uptake of arginine-and lysine-rich conjugates in wild-type CHO-K1 and proteoglycan-deficient A745 cells. The uptake of both conjugates was decreased by four fold in CHO-745 cells; therefore proteoglycans promote internalization of cationic peptides, irrespective of the chemical nature of their positive charges. Our results show that arginine-rich cell-penetrating peptides, especially (R/W)9, are a promising tool for PNA internalization.
Url:
DOI: 10.1371/journal.pone.0104999
Affiliations:
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Le document en format XML
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<sourceDesc><biblStruct><analytic><title xml:lang="en">Delivery of Antisense Peptide Nucleic Acids to Cells by Conjugation with Small Arginine-Rich Cell-Penetrating Peptide (R/W)9</title>
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<tutelle active="#struct-93591" type="direct"><org type="institution" xml:id="struct-93591" status="OLD"> <orgName>Université Pierre et Marie Curie - Paris 6</orgName>
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<desc> <address> <addrLine>4 place Jussieu - 75005 Paris</addrLine>
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<tutelle name="U1154" active="#struct-303623" type="direct"><org type="institution" xml:id="struct-303623" status="VALID"> <idno type="IdRef">026388278</idno>
<orgName>Institut National de la Santé et de la Recherche Médicale</orgName>
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<country>France</country>
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<author><name sortKey="Chassaing, Gerard" sort="Chassaing, Gerard" uniqKey="Chassaing G" first="Gérard" last="Chassaing">Gérard Chassaing</name>
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<orgName type="acronym">UPMC</orgName>
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<country>France</country>
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<author><name sortKey="Burlina, Fabienne" sort="Burlina, Fabienne" uniqKey="Burlina F" first="Fabienne" last="Burlina">Fabienne Burlina</name>
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<orgName type="acronym">UPMC</orgName>
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<country>France</country>
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</author>
<author><name sortKey="Saison Behmoaras, Tula Ester" sort="Saison Behmoaras, Tula Ester" uniqKey="Saison Behmoaras T" first="Tula Ester" last="Saison-Behmoaras">Tula Ester Saison-Behmoaras</name>
<affiliation wicri:level="1"><hal:affiliation type="laboratory" xml:id="struct-245694" status="OLD"> <idno type="IdRef">184513758</idno>
<orgName>Structure et Instabilité des Génomes</orgName>
<orgName type="acronym">STRING</orgName>
<desc> <address> <addrLine>43 rue Cuvier - Case postale 26 - 75231 Paris Cedex 05</addrLine>
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<tutelle active="#struct-93591" type="direct"><org type="institution" xml:id="struct-93591" status="OLD"> <orgName>Université Pierre et Marie Curie - Paris 6</orgName>
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<tutelle name="U1154" active="#struct-303623" type="direct"><org type="institution" xml:id="struct-303623" status="VALID"> <idno type="IdRef">026388278</idno>
<orgName>Institut National de la Santé et de la Recherche Médicale</orgName>
<orgName type="acronym">INSERM</orgName>
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<orgName>Centre National de la Recherche Scientifique</orgName>
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</hal:affiliation>
<country>France</country>
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<idno type="DOI">10.1371/journal.pone.0104999</idno>
<series><title level="j">PLoS ONE</title>
<idno type="ISSN">1932-6203</idno>
<imprint><date type="datePub">2014-08-15</date>
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<front><div type="abstract" xml:lang="en"> <p>Peptide nucleic acids (PNAs) are very attractive antisense and antigene agents, but these molecules are not passively taken into cells. Here, using a functional cell assay and fluorescent-based methods, we investigated cell uptake and antisense activity of a tridecamer PNA that targets the HIV-1 polypurine tract sequence delivered using the arginine-rich (R/W)9 peptide (RRWWRRWRR). At micromolar concentrations, without use of any transfection agents, almost 80% inhibition of the target gene expression was obtained with the conjugate in the presence of the endosomolytic agent chloroquine. We show that chloroquine not only induced escape from endosomes but also enhanced the cellular uptake of the conjugate. Mechanistic studies revealed that (R/W)9-PNA conjugates were internalized via pinocytosis. Replacement of arginines with lysines reduced the uptake of the conjugate by six-fold, resulting in the abolition of intracellular target inhibition. Our results show that the arginines play a crucial role in the conjugate uptake and antisense activity. To determine whether specificity of the interactions of arginines with cell surface proteoglycans result in the internalization, we used flow cytometry to examine uptake of arginine-and lysine-rich conjugates in wild-type CHO-K1 and proteoglycan-deficient A745 cells. The uptake of both conjugates was decreased by four fold in CHO-745 cells; therefore proteoglycans promote internalization of cationic peptides, irrespective of the chemical nature of their positive charges. Our results show that arginine-rich cell-penetrating peptides, especially (R/W)9, are a promising tool for PNA internalization.</p>
</div>
</front>
</TEI>
<affiliations><list><country><li>France</li>
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</list>
<tree><country name="France"><noRegion><name sortKey="Cordier, Celine" sort="Cordier, Celine" uniqKey="Cordier C" first="Céline" last="Cordier">Céline Cordier</name>
</noRegion>
<name sortKey="Alberti, Patrizia" sort="Alberti, Patrizia" uniqKey="Alberti P" first="Patrizia" last="Alberti">Patrizia Alberti</name>
<name sortKey="Bourdeloux, Mathilde" sort="Bourdeloux, Mathilde" uniqKey="Bourdeloux M" first="Mathilde" last="Bourdeloux">Mathilde Bourdeloux</name>
<name sortKey="Boutimah, Fatima" sort="Boutimah, Fatima" uniqKey="Boutimah F" first="Fatima" last="Boutimah">Fatima Boutimah</name>
<name sortKey="Burlina, Fabienne" sort="Burlina, Fabienne" uniqKey="Burlina F" first="Fabienne" last="Burlina">Fabienne Burlina</name>
<name sortKey="Chassaing, Gerard" sort="Chassaing, Gerard" uniqKey="Chassaing G" first="Gérard" last="Chassaing">Gérard Chassaing</name>
<name sortKey="Dupuy, Florian" sort="Dupuy, Florian" uniqKey="Dupuy F" first="Florian" last="Dupuy">Florian Dupuy</name>
<name sortKey="Loll, Francois" sort="Loll, Francois" uniqKey="Loll F" first="François" last="Loll">François Loll</name>
<name sortKey="Met, Elisabeth" sort="Met, Elisabeth" uniqKey="Met E" first="Elisabeth" last="Met">Elisabeth Met</name>
<name sortKey="Saison Behmoaras, Tula Ester" sort="Saison Behmoaras, Tula Ester" uniqKey="Saison Behmoaras T" first="Tula Ester" last="Saison-Behmoaras">Tula Ester Saison-Behmoaras</name>
</country>
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</record>
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