Stereochemical bias introduced during RNA synthesis modulates the activity of phosphorothioate siRNAs

Nature Communications
Hartmut JahnsJonathan Hall

Abstract

An established means of improving the pharmacokinetics properties of oligoribonucleotides (ORNs) is to exchange their phosphodiester linkages for phosphorothioates (PSs). However, this strategy has not been pursued for small interfering RNAs (siRNAs), possibly because of sporadic reports that PS siRNAs show reduced inhibitory activity. The PS group is chiral at phosphorous (Rp/Sp centres), and conventional solid-phase synthesis of PS ORNs produces a population of diastereoisomers. Here we show that the choice of the activating agent for the synthesis of a PS ORN influences the Rp/Sp ratio of PS linkages throughout the strand. Furthermore, PS siRNAs composed of ORNs with a higher fraction of Rp centres show greater resistance to nucleases in serum and are more effective inhibitors in cells than their Sp counterparts. The finding that a stereochemically biased population of ORN diastereoisomers can be synthesized and exploited pharmacologically is important because uniform PS modification of siRNAs may provide a useful compromise of their pharmacokinetics and pharmacodynamics properties in RNAi therapeutics.

References

Jan 1, 1985·Annual Review of Biochemistry·F Eckstein
Jan 5, 2000·Genes & Development·T TuschlP A Sharp
Jan 16, 2003·Nucleic Acids Research·Mohammed AmarzguiouiHans Prydz
Jul 2, 2003·Biochemistry·Dwaine A BraaschDavid R Corey
Oct 21, 2003·Nucleosides, Nucleotides & Nucleic Acids·Vasulinga T Ravikumar, Douglas L Cole
Oct 22, 2003·Cell·Dianne S SchwarzPhillip D Zamore
Oct 22, 2003·Cell·Anastasia KhvorovaSumedha D Jayasena
Mar 18, 2004·Oligonucleotides·Arthur M KriegWojciech Stec
Mar 18, 2004·Nucleic Acids Research·Gabriele DornJonathan Hall
Nov 13, 2004·Nature·Jürgen SoutschekHans-Peter Vornlocher
Jun 25, 2005·Journal of Medicinal Chemistry·Thazha P PrakashBalkrishen Bhat
Jul 19, 2005·Nature Biotechnology·Dieter HueskenJonathan Hall
Jul 26, 2005·Nature Biotechnology·David V MorrisseyBarry Polisky
Jan 28, 2006·EMBO Reports·Philipp J F LeuschnerJavier Martinez
Feb 17, 2006·Molecular Therapy : the Journal of the American Society of Gene Therapy·Mark A Behlke
Apr 23, 2008·Current Protocols in Nucleic Acid Chemistry·Stefan Pitsch, Patrick A Weiss
Jul 25, 2009·The Journal of Biological Chemistry·Walt F LimaStanley T Crooke
Jun 15, 2010·ChemMedChem·Johannes WinklerChristian R Noe
Jul 9, 2010·Nucleic Acids Research·Haripriya AddepalliMartin A Maier
Nov 11, 2010·Nucleic Acids Research·Jochen ImigFriedrich A Grässer
Mar 25, 2011·Methods in Molecular Biology·Michaela Beitzinger, Gunter Meister
Sep 10, 2011·Nucleosides, Nucleotides & Nucleic Acids·Joshua A Mukhlall, William H Hersh
Sep 17, 2011·Chemistry & Biodiversity·Piotr Guga, Maria Koziołkiewicz
Apr 28, 2012·Science·Nicole T Schirle, Ian J MacRae
Jun 12, 2012·Cell·Elad ElkayamLeemor Joshua-Tor
Sep 20, 2012·Nucleic Acids Research·Helen L Lightfoot, Jonathan Hall
Dec 23, 2014·Nature Chemical Biology·Jochen ImigJonathan Hall

❮ Previous
Next ❯

Citations

Apr 3, 2016·Methods : a Companion to Methods in Enzymology·Sara Flür, Ronald Micura
Sep 16, 2015·Molecular Therapy. Nucleic Acids·Jenny K W LamSusan W S Leung
Sep 21, 2016·Molecular Therapy. Nucleic Acids·Elena MorozJean-Christophe Leroux
Apr 6, 2017·Chemical Biology & Drug Design·Chelliah SelvamRamasamy Thilagavathi
May 5, 2018·Expert Opinion on Drug Delivery·Kevin CraigMansoor Amiji
Dec 22, 2019·Chembiochem : a European Journal of Chemical Biology·Sukumar SakamuriCurt W Bradshaw
Apr 14, 2020·Nucleic Acids Research·Maryam HabibianMasad J Damha
Nov 29, 2016·Drug Discoveries & Therapeutics·Md Ariful IslamSatoshi Obika
Apr 27, 2017·Topics in Current Chemistry·Amit K DuttaHenning Jacob Jessen
May 11, 2018·Nucleic Acid Therapeutics·Maire F Osborn, Anastasia Khvorova
May 2, 2020·Nucleic Acids Research·Stanley T CrookeXue-Hai Liang
Apr 26, 2019·Analytical and Bioanalytical Chemistry·Martin EnmarkTorgny Fornstedt
Dec 12, 2020·Nucleic Acid Therapeutics· Meena, Marc M Lemaitre
Mar 2, 2021·Chemical Society Reviews·Luke K McKenzieMarcel Hollenstein
Feb 19, 2021·The Journal of Biological Chemistry·Stanley T CrookeRosanne M Crooke
Mar 25, 2019·Methods : a Companion to Methods in Enzymology·Marie FlammeMarcel Hollenstein
May 4, 2021·Frontiers in Cardiovascular Medicine·Isabel N SchellingerPhilip S Tsao
Aug 18, 2020·Biochemical Pharmacology·Stanley T CrookeRichard S Geary
May 26, 2021·Advanced Drug Delivery Reviews·Elias Fattal, François Fay
Jun 26, 2021·Biotechnology and Bioengineering·Shahin AghamiriHossein Ghanbarian
Jan 10, 2018·The Journal of Organic Chemistry·Xinghua ZhangLixian Wang
Aug 31, 2021·RSC Chemical Biology·Guillaume ClavéMichael Smietana

❮ Previous
Next ❯

Methods Mentioned

BETA
AsA
column chromatography
electrophoresis
transfection
transfections
Assay
immunoprecipitation
PCR

Software Mentioned

imageJ
ChemGenes
ImageQuantTL

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.