Short interfering RNA guide strand modifiers from computational screening

Kazumitsu Onizuka, Jason G. Harrison, Alexi A. Ball-Jones, José M. Ibarra-Soza, Yuxuan Zheng, Diana Ly, Walter Lam, Stephanie Mac, Dean J. Tantillo, Peter A. Beal

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Short interfering RNAs (siRNAs) are promising drug candidates for a wide range of targets including those previously considered "undruggable". However, properties associated with the native RNA structure limit drug development, and chemical modifications are necessary. Here we describe the structure-guided discovery of functional modifications for the guide strand 5′-end using computational screening with the high-resolution structure of human Ago2, the key nuclease on the RNA interference pathway. Our results indicate the guide strand 5′-end nucleotide need not engage in Watson-Crick (W/C) H-bonding but must fit the general shape of the 5′-end binding site in MID/PIWI domains of hAgo2 for efficient knockdown. 1,2,3-Triazol-4-yl bases formed from the CuAAC reaction of azides and 1-ethynylribose, which is readily incorporated into RNA via the phosphoramidite, perform well at the guide strand 5′-end. In contrast, purine derivatives with modified Hoogsteen faces or N2 substituents are poor choices for 5′-end modifications. Finally, we identified a 1,2,3-triazol-4-yl base incapable of W/C H-bonding that performs well at guide strand position 12, where base pairing to target was expected to be important. This work expands the repertoire of functional nucleotide analogues for siRNAs.

Original languageEnglish (US)
Pages (from-to)17069-17077
Number of pages9
JournalJournal of the American Chemical Society
Volume135
Issue number45
DOIs
StatePublished - Nov 13 2013

Fingerprint

RNA
Small Interfering RNA
Screening
Nucleotides
Azides
RNA Interference
Base Pairing
Pharmaceutical Preparations
Binding Sites
Chemical modification
Derivatives
Binding sites
phosphoramidite
purine

ASJC Scopus subject areas

  • Chemistry(all)
  • Catalysis
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Onizuka, K., Harrison, J. G., Ball-Jones, A. A., Ibarra-Soza, J. M., Zheng, Y., Ly, D., ... Beal, P. A. (2013). Short interfering RNA guide strand modifiers from computational screening. Journal of the American Chemical Society, 135(45), 17069-17077. https://doi.org/10.1021/ja4079754

Short interfering RNA guide strand modifiers from computational screening. / Onizuka, Kazumitsu; Harrison, Jason G.; Ball-Jones, Alexi A.; Ibarra-Soza, José M.; Zheng, Yuxuan; Ly, Diana; Lam, Walter; Mac, Stephanie; Tantillo, Dean J.; Beal, Peter A.

In: Journal of the American Chemical Society, Vol. 135, No. 45, 13.11.2013, p. 17069-17077.

Research output: Contribution to journalArticle

Onizuka, K, Harrison, JG, Ball-Jones, AA, Ibarra-Soza, JM, Zheng, Y, Ly, D, Lam, W, Mac, S, Tantillo, DJ & Beal, PA 2013, 'Short interfering RNA guide strand modifiers from computational screening', Journal of the American Chemical Society, vol. 135, no. 45, pp. 17069-17077. https://doi.org/10.1021/ja4079754
Onizuka K, Harrison JG, Ball-Jones AA, Ibarra-Soza JM, Zheng Y, Ly D et al. Short interfering RNA guide strand modifiers from computational screening. Journal of the American Chemical Society. 2013 Nov 13;135(45):17069-17077. https://doi.org/10.1021/ja4079754
Onizuka, Kazumitsu ; Harrison, Jason G. ; Ball-Jones, Alexi A. ; Ibarra-Soza, José M. ; Zheng, Yuxuan ; Ly, Diana ; Lam, Walter ; Mac, Stephanie ; Tantillo, Dean J. ; Beal, Peter A. / Short interfering RNA guide strand modifiers from computational screening. In: Journal of the American Chemical Society. 2013 ; Vol. 135, No. 45. pp. 17069-17077.
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