Functional features defining the efficacy of cholesterol-conjugated, self-deliverable, chemically modified siRNAs

Nucleic Acids Research
Taisia ShmushkovichAlexey D Wolfson

Abstract

Progress in oligonucleotide chemistry has produced a shift in the nature of siRNA used, from formulated, minimally modified siRNAs, to unformulated, heavily modified siRNA conjugates. The introduction of extensive chemical modifications is essential for conjugate-mediated delivery. Modifications have a significant impact on siRNA efficacy through interference with recognition and processing by RNAi enzymatic machinery, severely restricting the sequence space available for siRNA design. Many algorithms available publicly can successfully predict the activity of non-modified siRNAs, but the efficiency of the algorithms for designing heavily modified siRNAs has never been systematically evaluated experimentally. Here we screened 356 cholesterol-conjugated siRNAs with extensive modifications and developed a linear regression-based algorithm that effectively predicts siRNA activity using two independent datasets. We further demonstrate that predictive determinants for modified and non-modified siRNAs differ substantially. The algorithm developed from the non-modified siRNAs dataset has no predictive power for modified siRNAs and vice versa. In the context of heavily modified siRNAs, the introduction of chemical asymmetry fully elimi...Continue Reading

References

Jan 11, 1977·Biochemistry·J C MatthewsM J Cormier
Jan 16, 2003·Nucleic Acids Research·Mohammed AmarzguiouiHans Prydz
May 29, 2003·Nucleic Acids Research·Frank CzaudernaJörg Kaufmann
Aug 19, 2003·RNA·Ya-Lin Chiu, Tariq M Rana
Oct 22, 2003·Cell·Anastasia KhvorovaSumedha D Jayasena
Feb 6, 2004·Nature Biotechnology·Angela ReynoldsAnastasia Khvorova
Apr 22, 2004·RNA·Juliana M LayzerBruce A Sullenger
Sep 3, 2004·Bioorganic & Medicinal Chemistry Letters·Christina LorenzCarlo Unverzagt
Jun 25, 2005·Journal of Medicinal Chemistry·Thazha P PrakashBalkrishen Bhat
Jul 19, 2005·Nature Biotechnology·Dieter HueskenJonathan Hall
Dec 14, 2005·Molecular Therapy : the Journal of the American Society of Gene Therapy·Adam D JudgeIan MacLachlan
Feb 14, 2006·BMC Bioinformatics·Svetlana A ShabalinaAleksey Y Ogurtsov
Apr 7, 2006·Biochemical and Biophysical Research Communications·Sorim ChoungYoung-Chul Choi
Sep 2, 2006·Nucleic Acids Research·Erich KollerNicholas M Dean
Dec 2, 2006·BMC Bioinformatics·Jean-Philippe VertYves Vandenbrouck
Feb 29, 2008·Biotechnology and Bioengineering·Joseph A GredellS Patrick Walton
Apr 29, 2008·Nature Biotechnology·Hakim TaferIvo L Hofacker
Jul 22, 2008·Oligonucleotides·Michael A CollingwoodMark A Behlke
Jan 12, 2010·Journal of Internal Medicine·A SchroederD G Anderson
Aug 20, 2011·PloS One·Firoz Ahmed, Gajendra P S Raghava
Jul 31, 2013·Genomics·Li LiuYong-Chun Zuo
Nov 5, 2013·Journal of Ocular Pharmacology and Therapeutics : the Official Journal of the Association for Ocular Pharmacology and Therapeutics·Michael ByrnePamela Pavco
Nov 28, 2013·Nucleic Acids Research·Ana Kozomara, Sam Griffiths-Jones
Dec 18, 2013·Journal of Translational Medicine·Abid QureshiManoj Kumar
Dec 2, 2015·Molecular Therapy. Nucleic Acids·Julia F AltermanAnastasia Khvorova
Jan 29, 2016·Scientific Reports·Showkat Ahmad DarManoj Kumar
Dec 3, 2016·Nucleic Acids Research·Socheata LyAnastasia Khvorova
Mar 1, 2017·Nature Biotechnology·Anastasia Khvorova, Jonathan K Watts
Mar 1, 2017·Nature Biotechnology·Steven F Dowdy
Jun 29, 2017·Genome Medicine·James C KaczmarekDaniel G Anderson
Feb 13, 2018·Nucleic Acids Research·Matthew R HasslerAnastasia Khvorova
Feb 20, 2018·Molecular Therapy : the Journal of the American Society of Gene Therapy·Donald J FosterStuart Milstein
May 8, 2018·Molecular Therapy : the Journal of the American Society of Gene Therapy·Maarten A LigtenbergRolf Kiessling

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Citations

Jul 17, 2019·Clinical and Translational Science·Rachel Chevalier
Jun 16, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Wanyi Tai
Mar 9, 2019·Nature Reviews. Drug Discovery·Ryan L SettenSi-Ping Han
Dec 24, 2019·Cellular & Molecular Biology Letters·Rafal Bartoszewski, Aleksander F Sikorski
Jul 24, 2020·International Journal of Molecular Sciences·Olga A KrashenininaAlya G Venyaminova
Feb 13, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Tatiana S GolubevaKonstantin E Orishchenko
Mar 2, 2021·Biochemical Pharmacology·Christopher L BarkauKeith T Gagnon
Mar 14, 2021·Life Sciences·Md Abdus SubhanVladimir P Torchilin
Jun 26, 2021·Biotechnology and Bioengineering·Shahin AghamiriHossein Ghanbarian
Mar 2, 2019·Bioconjugate Chemistry·William L WhitehouseStefan Howorka
Dec 20, 2019·Molecular Therapy. Nucleic Acids·Meirav SegalFrank J Slack

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Methods Mentioned

BETA
chemical modification
transfections
transfection
Assay

Software Mentioned

sdRNA
TriLink
QuantiGene
NumPy
R

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