{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T10:06:23Z","timestamp":1791972383007,"version":"4.3.4"},"reference-count":26,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2015,12,22]],"date-time":"2015-12-22T00:00:00Z","timestamp":1450742400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2015,12,22]],"date-time":"2015-12-22T00:00:00Z","timestamp":1450742400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>We present a remodeling method for high-affinity unnatural-base DNA aptamers to augment their thermal stability and nuclease resistance, for use as drug candidates targeting specific proteins. Introducing a unique mini-hairpin DNA provides robust stability to unnatural-base DNA aptamers generated by SELEX using genetic alphabet expansion, without reducing their high affinity. By this method, &gt;80% of the remodeled DNA aptamer targeting interferon-\u03b3 (<jats:italic>K<\/jats:italic><jats:sub>D<\/jats:sub> of 33\u2009pM) survived in human serum at 37\u2009\u00b0C after 3 days under our experimental conditions and sustainably inhibited the biological activity of interferon-\u03b3.<\/jats:p>","DOI":"10.1038\/srep18478","type":"journal-article","created":{"date-parts":[[2015,12,22]],"date-time":"2015-12-22T09:55:46Z","timestamp":1450778146000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":72,"title":["Architecture of high-affinity unnatural-base DNA aptamers toward pharmaceutical applications"],"prefix":"10.1038","volume":"5","author":[{"given":"Ken-ichiro","family":"Matsunaga","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michiko","family":"Kimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Hanson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Sanford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Howard A.","family":"Young","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ichiro","family":"Hirao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,12,22]]},"reference":[{"key":"BFsrep18478_CR1","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1038\/518027a","volume":"518","author":"A Bradbury","year":"2015","unstructured":"Bradbury, A. & Pluckthun, A. Reproducibility: Standardize antibodies used in research. Nature 518, 27\u201329 (2015).","journal-title":"Nature"},{"key":"BFsrep18478_CR2","doi-asserted-by":"publisher","first-page":"2235","DOI":"10.1021\/nn507494p","volume":"9","author":"YH Lao","year":"2015","unstructured":"Lao, Y. H., Phua, K. K. & Leong, K. W. Aptamer nanomedicine for cancer therapeutics: barriers and potential for translation. ACS Nano 9, 2235\u20132254 (2015).","journal-title":"ACS Nano"},{"key":"BFsrep18478_CR3","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1016\/j.imlet.2014.10.001","volume":"162","author":"R Nezlin","year":"2014","unstructured":"Nezlin, R. Aptamers in immunological research. Immunol. Lett. 162, 252\u2013255 (2014).","journal-title":"Immunol. Lett."},{"key":"BFsrep18478_CR4","doi-asserted-by":"publisher","first-page":"423","DOI":"10.4062\/biomolther.2013.085","volume":"21","author":"HY Kong","year":"2013","unstructured":"Kong, H. Y. & Byun, J. Nucleic Acid aptamers: new methods for selection, stabilization and application in biomedical science. Biomol. Ther. 21, 423\u2013434 (2013).","journal-title":"Biomol. Ther."},{"key":"BFsrep18478_CR5","doi-asserted-by":"publisher","first-page":"818","DOI":"10.1038\/346818a0","volume":"346","author":"AD Ellington","year":"1990","unstructured":"Ellington, A. D. & Szostak, J. W. In vitro selection of RNA molecules that bind specific ligands. Nature 346, 818\u2013822 (1990).","journal-title":"Nature"},{"key":"BFsrep18478_CR6","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1126\/science.2200121","volume":"249","author":"C Tuerk","year":"1990","unstructured":"Tuerk, C. & Gold, L. Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase. Science 249, 505\u2013510 (1990).","journal-title":"Science"},{"key":"BFsrep18478_CR7","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1038\/nrd1955","volume":"5","author":"EW Ng","year":"2006","unstructured":"Ng, E. W. et al. Pegaptanib, a targeted anti-VEGF aptamer for ocular vascular disease. Nat. Rev. Drug Discov. 5, 123\u2013132 (2006).","journal-title":"Nat. Rev. Drug Discov."},{"key":"BFsrep18478_CR8","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1016\/1074-5521(95)90032-2","volume":"2","author":"LS Green","year":"1995","unstructured":"Green, L. S. et al. Nuclease-resistant nucleic acid ligands to vascular permeability factor\/vascular endothelial growth factor. Chem. Biol. 2, 683\u2013695 (1995).","journal-title":"Chem. Biol."},{"key":"BFsrep18478_CR9","doi-asserted-by":"publisher","first-page":"7639","DOI":"10.1021\/bi0521442","volume":"45","author":"M Bozza","year":"2006","unstructured":"Bozza, M., Sheardy, R. D., Dilone, E., Scypinski, S. & Galazka, M. Characterization of the secondary structure and stability of an RNA aptamer that binds vascular endothelial growth factor. Biochemistry 45, 7639\u20137643 (2006).","journal-title":"Biochemistry"},{"key":"BFsrep18478_CR10","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1016\/j.cbpa.2008.06.028","volume":"12","author":"AD Keefe","year":"2008","unstructured":"Keefe, A. D. & Cload, S. T. SELEX with modified nucleotides. Curr. Opin. Chem. Biol. 12, 448\u2013456 (2008).","journal-title":"Curr. Opin. Chem. Biol."},{"key":"BFsrep18478_CR11","doi-asserted-by":"publisher","first-page":"4159","DOI":"10.2174\/092986711797189646","volume":"18","author":"Y Yang","year":"2011","unstructured":"Yang, Y., Ren, X., Schluesener, H. J. & Zhang, Z. Aptamers: selection, modification and application to nervous system diseases. Curr. Med. Chem. 18, 4159\u20134168 (2011).","journal-title":"Curr. Med. Chem."},{"key":"BFsrep18478_CR12","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1016\/S0969-8051(99)00103-1","volume":"27","author":"H Dougan","year":"2000","unstructured":"Dougan, H. et al. Extending the lifetime of anticoagulant oligodeoxynucleotide aptamers in blood. Nucl. Med. Biol. 27, 289\u2013297 (2000).","journal-title":"Nucl. Med. Biol."},{"key":"BFsrep18478_CR13","doi-asserted-by":"publisher","first-page":"1112","DOI":"10.1038\/nbt0996-1112","volume":"14","author":"S Klussmann","year":"1996","unstructured":"Klussmann, S., Nolte, A., Bald, R., Erdmann, V. A. & Furste, J. P. Mirror-image RNA that binds D-adenosine. Nat. Biotechnol. 14, 1112\u20131115 (1996).","journal-title":"Nat. Biotechnol."},{"key":"BFsrep18478_CR14","doi-asserted-by":"publisher","first-page":"e15004","DOI":"10.1371\/journal.pone.0015004","volume":"5","author":"L Gold","year":"2010","unstructured":"Gold, L. et al. Aptamer-based multiplexed proteomic technology for biomarker discovery. PLoS One 5, e15004 (2010).","journal-title":"PLoS One"},{"key":"BFsrep18478_CR15","doi-asserted-by":"publisher","first-page":"8321","DOI":"10.1021\/bi300471d","volume":"51","author":"W He","year":"2012","unstructured":"He, W. et al. X-aptamers: a bead-based selection method for random incorporation of druglike moieties onto next-generation aptamers for enhanced binding. Biochemistry 51, 8321\u20138323 (2012).","journal-title":"Biochemistry"},{"key":"BFsrep18478_CR16","doi-asserted-by":"publisher","first-page":"1449","DOI":"10.1073\/pnas.1311778111","volume":"111","author":"K Sefah","year":"2014","unstructured":"Sefah, K. et al. In vitro selection with artificial expanded genetic information systems. Proc. Natl. Acad. Sci. USA 111, 1449\u20131454 (2014).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"BFsrep18478_CR17","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1038\/nature13314","volume":"509","author":"DA Malyshev","year":"2014","unstructured":"Malyshev, D. A. et al. A semi-synthetic organism with an expanded genetic alphabet. Nature 509, 385\u2013388 (2014).","journal-title":"Nature"},{"key":"BFsrep18478_CR18","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1038\/nbt.2556","volume":"31","author":"M Kimoto","year":"2013","unstructured":"Kimoto, M., Yamashige, R., Matsunaga, K., Yokoyama, S. & Hirao, I. Generation of high-affinity DNA aptamers using an expanded genetic alphabet. Nat. Biotechnol. 31, 453\u2013457 (2013).","journal-title":"Nat. Biotechnol."},{"key":"BFsrep18478_CR19","doi-asserted-by":"publisher","first-page":"1152","DOI":"10.1002\/eji.200322875","volume":"33","author":"R Gonsky","year":"2003","unstructured":"Gonsky, R., Deem, R. L., Young, H. A. & Targan, S. R. CD2 mediates activation of the IFN-gamma intronic STAT binding region in mucosal T cells. Eur. J. Immunol. 33, 1152\u20131162 (2003).","journal-title":"Eur. J. Immunol."},{"key":"BFsrep18478_CR20","doi-asserted-by":"publisher","first-page":"1851","DOI":"10.1021\/ac9025237","volume":"82","author":"N Tuleuova","year":"2010","unstructured":"Tuleuova, N. et al. Development of an aptamer beacon for detection of interferon-gamma. Anal. Chem. 82, 1851\u20131857 (2010).","journal-title":"Anal. Chem."},{"key":"BFsrep18478_CR21","doi-asserted-by":"publisher","first-page":"2223","DOI":"10.1093\/nar\/17.6.2223","volume":"17","author":"I Hirao","year":"1989","unstructured":"Hirao, I. et al. Extraordinary stable structure of short single-stranded DNA fragments containing a specific base sequence: d(GCGAAAGC). Nucleic Acids Res. 17, 2223\u20132231 (1989).","journal-title":"Nucleic Acids Res."},{"key":"BFsrep18478_CR22","doi-asserted-by":"publisher","first-page":"576","DOI":"10.1093\/nar\/22.4.576","volume":"22","author":"I Hirao","year":"1994","unstructured":"Hirao, I. et al. Most compact hairpin-turn structure exerted by a short DNA fragment, d(GCGAAGC) in solution: an extraordinarily stable structure resistant to nucleases and heat. Nucleic Acids Res. 22, 576\u2013582 (1994).","journal-title":"Nucleic Acids Res."},{"key":"BFsrep18478_CR23","doi-asserted-by":"publisher","first-page":"4761","DOI":"10.1021\/bi961738p","volume":"36","author":"S Yoshizawa","year":"1997","unstructured":"Yoshizawa, S., Kawai, G., Watanabe, K., Miura, K. & Hirao, I. GNA trinucleotide loop sequences producing extraordinarily stable DNA minihairpins. Biochemistry 36, 4761\u20134767 (1997).","journal-title":"Biochemistry"},{"key":"BFsrep18478_CR24","doi-asserted-by":"publisher","first-page":"2217","DOI":"10.1093\/nar\/22.12.2217","volume":"22","author":"S Yoshizawa","year":"1994","unstructured":"Yoshizawa, S. et al. Nuclease resistance of an extraordinarily thermostable mini-hairpin DNA fragment, d(GCGAAGC) and its application to in vitro protein synthesis. Nucleic Acids Res. 22, 2217\u20132221 (1994).","journal-title":"Nucleic Acids Res."},{"key":"BFsrep18478_CR25","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1186\/s13075-015-0582-9","volume":"17","author":"F Bian","year":"2015","unstructured":"Bian, F. et al. Altered balance of interleukin-13\/interferon-gamma contributes to lacrimal gland destruction and secretory dysfunction in CD25 knockout model of Sjogren\u2019s syndrome. Arthritis Res. Ther. 17, 53 (2015).","journal-title":"Arthritis Res. Ther."},{"key":"BFsrep18478_CR26","doi-asserted-by":"publisher","first-page":"5582","DOI":"10.1016\/j.bmcl.2007.07.088","volume":"17","author":"M Kimoto","year":"2007","unstructured":"Kimoto, M., Moriyama, K., Yokoyama, S. & Hirao, I. Cytostatic evaluations of nucleoside analogs related to unnatural base pairs for a genetic expansion system. Bioorg. Med. Chem. Lett. 17, 5582\u20135585 (2007).","journal-title":"Bioorg. Med. Chem. Lett."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep18478","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep18478.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep18478.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,6]],"date-time":"2023-01-06T01:03:15Z","timestamp":1672966995000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep18478"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,12,22]]},"references-count":26,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,11,22]]}},"alternative-id":["BFsrep18478"],"URL":"https:\/\/doi.org\/10.1038\/srep18478","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,12,22]]},"assertion":[{"value":"2 July 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 November 2015","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 December 2015","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"There is potential competing interest. A patent application describing ideas presented in this article has been filed by TagCyx Biotechnologies and RIKEN. M.K. and I.H. own stock in TagCyx Biotechnologies.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"18478"}}