Expanding the binding space of argonaute-2: incorporation of either <i>E</i> or <i>Z</i> isomers of 6′-vinylphosphonate at the 5′ end of the antisense strand improves RNAi activity
A phosphate or a phosphate mimic at the 5' terminus of the antisense strand of a small interfering RNA (siRNA) is required for efficient loading into the RISC complex through the MID domain binding pocket of Ago2. Introduction of 5'-<i>E</i>-vinylphosphonate improves this binding and siRNA potency, but the <i>Z</i> isomer does not. Here, we demonstrate that both the <i>E</i> and <i>Z</i> isomers of 6'-vinylphosphonate at the 5' ends of antisense strands of siRNAs have equivalent potencies.
Authors
- Sarah LeBlanc
- June Qin
- Dhrubajyoti Datta (ORCID: https://orcid.org/0000-0003-2077-1294)
- Christopher S. Theile
- Juan C. Salinas (ORCID: https://orcid.org/0000-0001-6280-4512)
- Muthiah A. Manoharan (ORCID: https://orcid.org/0000-0002-7931-1172)
- Tuyen Nguyen (ORCID: https://orcid.org/0000-0001-8068-9538)
- Haiyan Peng (ORCID: https://orcid.org/0000-0002-0083-8589)
- Martin Egli (ORCID: https://orcid.org/0000-0003-4145-356X)
- Patrick J. Miller (ORCID: https://orcid.org/0000-0002-8418-127X)
- M.S.N. Khan
- Jayanta Kundu (ORCID: https://orcid.org/0000-0003-2669-8112)
Institutions
- Alnylam Pharmaceuticals (United States) (US)
- Vanderbilt University (US)
Publication Details
- Journal
- Chemical Communications
- Published
- 2025-01-01
- DOI
- https://doi.org/10.1039/d5cc00348b
- Citations
- 4
- Primary Topic
- DNA and Nucleic Acid Chemistry
- Type
- article
- Field-Weighted Citation Impact
- 3.22