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

Sherry Y. Wu, Xianbin Yang, Kshipra M. Gharpure, Hiroto Hatakeyama, Martin Egli, Michael H. McGuire, Archana S. Nagaraja, Takahito M. Miyake, Rajesha Rupaimoole, Chad V. Pecot, Morgan Taylor, Sunila Pradeep, Malgorzata Sierant, Cristian Rodriguez-Aguayo, Hyun J. Choi, Rebecca A. Previs, Guillermo N. Armaiz-Pena, Li Huang, Carlos Martinez, Tom HassellCristina Ivan, Vasudha Sehgal, Richa Singhania, Hee Dong Han, Chang Su, Ji Hoon Kim, Heather J. Dalton, Chandra Kovvali, Khandan Keyomarsi, Nigel A.J. McMillan, Willem W. Overwijk, Jinsong Liu, Ju Seog Lee, Keith A. Baggerly, Gabriel Lopez-Berestein, Prahlad T. Ram, Barbara Nawrot, Anil K. Sood

Research output: Contribution to journalArticle

65 Citations (Scopus)

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.

Original languageEnglish
Article number3459
JournalNature communications
Volume5
DOIs
Publication statusPublished - 2014 Mar 12

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Wu, S. Y., Yang, X., Gharpure, K. M., Hatakeyama, H., Egli, M., McGuire, M. H., Nagaraja, A. S., Miyake, T. M., Rupaimoole, R., Pecot, C. V., Taylor, M., Pradeep, S., Sierant, M., Rodriguez-Aguayo, C., Choi, H. J., Previs, R. A., Armaiz-Pena, G. N., Huang, L., Martinez, C., ... Sood, A. K. (2014). 2′-OMe-phosphorodithioate-modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity. Nature communications, 5, [3459]. https://doi.org/10.1038/ncomms4459