Rational Design of Dual-Functional Aptamers That Inhibit the Protease and Helicase Activities of HCV NS3
Identifieur interne : 002F96 ( Main/Merge ); précédent : 002F95; suivant : 002F97Rational Design of Dual-Functional Aptamers That Inhibit the Protease and Helicase Activities of HCV NS3
Auteurs : Takuya Umehara ; Kotaro Fukuda ; Fumiko Nishikawa ; Michinori Kohara ; Tsunemi Hasegawa ; Satoshi Nishikawa [Japon]Source :
- Journal of Biochemistry [ 0021-924X ] ; 2005.
Abstract
The hepatitis C virus (HCV) non-structural protein 3 (NS3) is a multifunctional enzyme with protease and helicase activities. It is essential for HCV proliferation and is therefore a target for anti-HCV drugs. Previously, we obtained RNA aptamers that inhibit either the protease or helicase activity of NS3. During the present study, these aptamers were used to create advanced dual-functional (ADD) aptamers that were potentially more effective inhibitors of NS3 activity. The structural domain of the helicase aptamer, #5Δ, was conjugated via an oligo(U) tract to the 3′-end of the dual functional aptamer NEO-III-14U or the protease aptamer G9-II. The spacer length was optimized to obtain two ADD aptamers, NEO-35-s41 and G925-s50; both were more effective inhibitors of NS3 protease/helicase activity in vitro, especially the helicase, with a four- to five-fold increase in inhibition compared with #5 and NEO-III-14U. Furthermore, G925-s50 effectively inhibited NS3 protease activity in living cells and HCV replication in vitro. Overall, we have demonstrated rational RNA aptamer design based on features of both aptamer and target molecules, as well as successfully combining aptamer function and increasing NS3 inhibition.
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DOI: 10.1093/jb/mvi042
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<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title xml:lang="en">Rational Design of Dual-Functional Aptamers That Inhibit the Protease and Helicase Activities of HCV NS3</title><author><name sortKey="Umehara, Takuya" sort="Umehara, Takuya" uniqKey="Umehara T" first="Takuya" last="Umehara">Takuya Umehara</name></author><author><name sortKey="Fukuda, Kotaro" sort="Fukuda, Kotaro" uniqKey="Fukuda K" first="Kotaro" last="Fukuda">Kotaro Fukuda</name></author><author><name sortKey="Nishikawa, Fumiko" sort="Nishikawa, Fumiko" uniqKey="Nishikawa F" first="Fumiko" last="Nishikawa">Fumiko Nishikawa</name></author><author><name sortKey="Kohara, Michinori" sort="Kohara, Michinori" uniqKey="Kohara M" first="Michinori" last="Kohara">Michinori Kohara</name></author><author><name sortKey="Hasegawa, Tsunemi" sort="Hasegawa, Tsunemi" uniqKey="Hasegawa T" first="Tsunemi" last="Hasegawa">Tsunemi Hasegawa</name></author><author><name sortKey="Nishikawa, Satoshi" sort="Nishikawa, Satoshi" uniqKey="Nishikawa S" first="Satoshi" last="Nishikawa">Satoshi Nishikawa</name></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:70528AE6124F359D8D24EBE10DCB172BC828CCD1</idno><date when="2005" year="2005">2005</date><idno type="doi">10.1093/jb/mvi042</idno><idno type="url">https://api.istex.fr/ark:/67375/HXZ-RBWR4510-W/fulltext.pdf</idno><idno type="wicri:Area/Istex/Corpus">001536</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">001536</idno><idno type="wicri:Area/Istex/Curation">001536</idno><idno type="wicri:Area/Istex/Checkpoint">000A78</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Checkpoint">000A78</idno><idno type="wicri:doubleKey">0021-924X:2005:Umehara T:rational:design:of</idno><idno type="wicri:Area/Main/Merge">002F96</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main">Rational Design of Dual-Functional Aptamers That Inhibit the Protease and Helicase Activities of HCV NS3</title><author><name sortKey="Umehara, Takuya" sort="Umehara, Takuya" uniqKey="Umehara T" first="Takuya" last="Umehara">Takuya Umehara</name><affiliation></affiliation><affiliation><wicri:noCountry code="subField">and</wicri:noCountry></affiliation></author><author><name sortKey="Fukuda, Kotaro" sort="Fukuda, Kotaro" uniqKey="Fukuda K" first="Kotaro" last="Fukuda">Kotaro Fukuda</name><affiliation></affiliation><affiliation><wicri:noCountry code="subField">and</wicri:noCountry></affiliation></author><author><name sortKey="Nishikawa, Fumiko" sort="Nishikawa, Fumiko" uniqKey="Nishikawa F" first="Fumiko" last="Nishikawa">Fumiko Nishikawa</name><affiliation><wicri:noCountry code="subField">305-8566;</wicri:noCountry></affiliation></author><author><name sortKey="Kohara, Michinori" sort="Kohara, Michinori" uniqKey="Kohara M" first="Michinori" last="Kohara">Michinori Kohara</name><affiliation><wicri:noCountry code="subField">113-8613</wicri:noCountry></affiliation></author><author><name sortKey="Hasegawa, Tsunemi" sort="Hasegawa, Tsunemi" uniqKey="Hasegawa T" first="Tsunemi" last="Hasegawa">Tsunemi Hasegawa</name><affiliation><wicri:noCountry code="subField">and</wicri:noCountry></affiliation></author><author><name sortKey="Nishikawa, Satoshi" sort="Nishikawa, Satoshi" uniqKey="Nishikawa S" first="Satoshi" last="Nishikawa">Satoshi Nishikawa</name><affiliation></affiliation><affiliation wicri:level="1"><country wicri:rule="url">Japon</country><wicri:regionArea>To whom correspondence should be addressed. Tel: +81-298-61-6085, Fax: +81-298-61-6159</wicri:regionArea><wicri:noRegion>Fax: +81-298-61-6159</wicri:noRegion></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Journal of Biochemistry</title><title level="j" type="abbrev">J Biochem</title><idno type="ISSN">0021-924X</idno><imprint><publisher>Oxford University Press</publisher><date type="published">2005</date><biblScope unit="vol">137</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="339">339</biblScope><biblScope unit="page" to="347">347</biblScope></imprint><idno type="ISSN">0021-924X</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0021-924X</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The hepatitis C virus (HCV) non-structural protein 3 (NS3) is a multifunctional enzyme with protease and helicase activities. It is essential for HCV proliferation and is therefore a target for anti-HCV drugs. Previously, we obtained RNA aptamers that inhibit either the protease or helicase activity of NS3. During the present study, these aptamers were used to create advanced dual-functional (ADD) aptamers that were potentially more effective inhibitors of NS3 activity. The structural domain of the helicase aptamer, #5Δ, was conjugated via an oligo(U) tract to the 3′-end of the dual functional aptamer NEO-III-14U or the protease aptamer G9-II. The spacer length was optimized to obtain two ADD aptamers, NEO-35-s41 and G925-s50; both were more effective inhibitors of NS3 protease/helicase activity in vitro, especially the helicase, with a four- to five-fold increase in inhibition compared with #5 and NEO-III-14U. Furthermore, G925-s50 effectively inhibited NS3 protease activity in living cells and HCV replication in vitro. Overall, we have demonstrated rational RNA aptamer design based on features of both aptamer and target molecules, as well as successfully combining aptamer function and increasing NS3 inhibition.</div></front></TEI></record>Pour manipuler ce document sous Unix (Dilib)
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