2′-OMe-phosphorodithioate-modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity

Wu, Sherry Y., Yang, Xianbin, Gharpure, Kshipra M., Hatakeyama, Hiroto, Egli, Martin, McGuire, Michael H., Nagaraja, Archana S., Miyake, Takahito M., Rupaimoole, Rajesha, Pecot, Chad V., Taylor, Morgan, Pradeep, Sunila, Sierant, Malgorzata, Rodriguez-Aguayo, Cristian, Choi, Hyun J., Previs, Rebecca A., Armaiz-Pena, Guillermo N., Huang Li, Martinez, Carlos, Hassell Tom, Ivan, Cristina, Sehgal, Vasudha, Singhania, Richa, Han, Hee-Dong, Su, Chang, Kim, Ji Hoon, Dalton, Heather J., Kovvali, Chandra, Keyomarsi, Khandan, McMillan, Nigel A. J., Overwijk, Willem W., Liu, Jinsong, Lee, Ju-Seog, Baggerly, Keith A., Lopez-Berestein, Gabriel, Ram, Prahlad T., Nawrot, Barbara and Sood, Anil K. (2014) 2′-OMe-phosphorodithioate-modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity. Nature Communications, 5 . doi:10.1038/ncomms4459

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Author Wu, Sherry Y.
Yang, Xianbin
Gharpure, Kshipra M.
Hatakeyama, Hiroto
Egli, Martin
McGuire, Michael H.
Nagaraja, Archana S.
Miyake, Takahito M.
Rupaimoole, Rajesha
Pecot, Chad V.
Taylor, Morgan
Pradeep, Sunila
Sierant, Malgorzata
Rodriguez-Aguayo, Cristian
Choi, Hyun J.
Previs, Rebecca A.
Armaiz-Pena, Guillermo N.
Huang Li
Martinez, Carlos
Hassell Tom
Ivan, Cristina
Sehgal, Vasudha
Singhania, Richa
Han, Hee-Dong
Su, Chang
Kim, Ji Hoon
Dalton, Heather J.
Kovvali, Chandra
Keyomarsi, Khandan
McMillan, Nigel A. J.
Overwijk, Willem W.
Liu, Jinsong
Lee, Ju-Seog
Baggerly, Keith A.
Lopez-Berestein, Gabriel
Ram, Prahlad T.
Nawrot, Barbara
Sood, Anil K.
Title 2′-OMe-phosphorodithioate-modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity
Journal name Nature Communications   Check publisher's open access policy
ISSN 2041-1723
Publication date 2014-03-12
Year available 2014
Sub-type Article (original research)
DOI 10.1038/ncomms4459
Open Access Status File (Publisher version)
Volume 5
Total pages 21
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Collection year 2015
Language eng
Formatted abstract
Improving small interfering RNA (siRNA) efficacy in target cell populations remains a challenge to its clinical implementation.
Here, we report a chemical modification, consisting of phosphorodithioate (PS2) and 2′-O-Methyl (2′-OMe) MePS2 on one
nucleotide that significantly enhances potency and resistance to degradation for various siRNAs. We find enhanced potency
stems from an unforeseen increase in siRNA loading to the RNA-induced silencing complex, likely due to the unique interaction mediated by 2′-OMe and PS2. We demonstrate the therapeutic utility of MePS2 siRNAs in chemoresistant ovarian cancer mouse models via targeting GRAM domain containing 1B (GRAMD1B), a protein involved in chemoresistance. GRAMD1B silencing is achieved in tumours following MePS2-modified siRNA treatment, leading to a synergistic anti-tumour effect in combination with paclitaxel. Given the previously limited success in enhancing siRNA potency with chemically modified siRNAs, our findings represent an important advance in siRNA design with the potential for application in numerous cancer types.
Keyword Biological sciences
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Article number: 3459

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
UQ Diamantina Institute Publications
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Citation counts: TR Web of Science Citation Count  Cited 21 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 26 times in Scopus Article | Citations
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