4′-Guanidinium-modified siRNA: a molecular tool to control RNAi activity through RISC priming and selective antisense strand loading

Nawale, Ganesh N.; Bahadorikhalili, Saeed; Sengupta, Pallabi; Kadekar, Sandeep; Chatterjee, Subhrangsu; Varghese, Oommen P.

doi:10.1039/c9cc04141a

Cited by 8 publications

(9 citation statements)

References 26 publications

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“…The incorporation of 8 nucleosides into an siRNA passenger strand showed RNAi activity identical to the unmodified siRNA, with 50% of the siRNA strands remaining intact after 48 h in 20% BSA [ 214 ]. Recent work on the synthesis of novel 4'- C -guanidinocarbohydrazidomethyl-5-methyluridine (GMU) ( Figure 9K ) has shown that functionalizing the C4' position with guanidinium leads to siRNAs with increased thermal stability (1–3 °C/mod) and improved stability in human serum [ 215 ]. These guanidinium-modified siRNAs also lead to sustained gene silencing with only picomolar concentrations after 96 h of transfection [ 215 ].…”

Section: Reviewmentioning

confidence: 99%

“…Recent work on the synthesis of novel 4'- C -guanidinocarbohydrazidomethyl-5-methyluridine (GMU) ( Figure 9K ) has shown that functionalizing the C4' position with guanidinium leads to siRNAs with increased thermal stability (1–3 °C/mod) and improved stability in human serum [ 215 ]. These guanidinium-modified siRNAs also lead to sustained gene silencing with only picomolar concentrations after 96 h of transfection [ 215 ]. Their qPCR experiments show that the cause of this sustained gene silencing activity is due to enhanced guide strand recruitment within the RISC complex [ 215 ].…”

Section: Reviewmentioning

confidence: 99%

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Beyond ribose and phosphate: Selected nucleic acid modifications for structure–function investigations and therapeutic applications

Liczner¹,

Duke²,

Juneau³

et al. 2021

Beilstein J. Org. Chem.

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Over the past 25 years, the acceleration of achievements in the development of oligonucleotide-based therapeutics has resulted in numerous new drugs making it to the market for the treatment of various diseases. Oligonucleotides with alterations to their scaffold, prepared with modified nucleosides and solid-phase synthesis, have yielded molecules with interesting biophysical properties that bind to their targets and are tolerated by the cellular machinery to elicit a therapeutic outcome. Structural techniques, such as crystallography, have provided insights to rationalize numerous properties including binding affinity, nuclease stability, and trends observed in the gene silencing. In this review, we discuss the chemistry, biophysical, and structural properties of a number of chemically modified oligonucleotides that have been explored for gene silencing.

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Section: Reviewmentioning

confidence: 99%

Section: Reviewmentioning

confidence: 99%

Beyond ribose and phosphate: Selected nucleic acid modifications for structure–function investigations and therapeutic applications

Liczner¹,

Duke²,

Juneau³

et al. 2021

Beilstein J. Org. Chem.

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“…The effect of 4′‐ C ‐aminomethyl‐2′‐ O ‐ethyl (4′‐AM‐2′‐OEt) and 4′‐ C ‐azidomethyl‐2′‐ O ‐ethyl‐uridine (4′‐AzM‐2′‐OEt) chemical modifications on RNA duplex were studied using molecular dynamics (MD) simulations. Comparisons of MD results for these modifications executed using results from the MD simulations of 2′‐OH‐uridine unmodified and 2′‐ O ‐ethyl‐uridine (2′‐OEt) modified RNAs [33,49,50] (Figure 4). The C2′‐ endo conformers of 4′‐AM‐2′‐OEt and of 4′‐AzM‐2′‐OEt as seen in the stereoelectronic study was used to calculate the RESP charges using the RED tools package.…”

Section: Resultsmentioning

confidence: 99%

“…We also report a new route for synthesizing 2′‐ O ‐ethyl‐uridine nucleoside C (2′‐OEt−U) in just 3 steps (Figure 1). The synthesis of 2′‐ O ‐methyl and 2′‐ O ‐ethyl uridine ribonucleoside phosphoramidites and their incorporation into oligoribonucleotides were reported previously in the literature [31–33] . To the best of our knowledge, the influence of 2′‐ O ‐ethyl modification on sugar conformation has not been studied so far.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Structural, and Conformational Analysis of 4′‐C‐Alkyl‐2′‐O‐Ethyl‐Uridine Modified Nucleosides

Harikrishna

Gore

2021

Eur J Org Chem

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Sugar modifications have attracted much attention due to their potential structural and functional influence on therapeutic nucleic acids. Herein, we report the synthesis of dual modified 4′‐C‐azidomethyl‐2′‐O‐ethyl‐uridine (4′‐AzM‐2′‐OEt−U) and 4′‐C‐aminomethyl‐2′‐O‐ethyl‐uridine (4′‐AM‐2′‐OEt−U) nucleosides using linear multi‐step synthesis (16 linear steps). Additionally, we report an alternative route for the synthesis of 2′‐O‐ethyl‐uridine nucleoside which has been achieved in three steps with an overall yield of 40 %. X‐ray structure of 4′‐AzM‐2′‐OEt−U illustrates that the nucleoside adopts C2′‐endo (South) conformation having a DNA‐type glycosidic bond (χ) angle of −116.01°. Computational studies revealed the C2′‐endo and C4′‐exo conformations for 4′‐AzM‐2′‐OEt−U and 4′‐AM‐2′‐OEt−U free nucleosides, respectively. The C4′‐exo conformation in 4′‐AM‐2′‐OEt−U free nucleoside is collectively stabilized by various non‐covalent interactions between positively charged aminomethyl and 2′,3′‐hydroxyl groups. Insights into the structural and conformational analysis of dual sugar modified nucleosides and oligonucleotides will be helpful in the rational design of modified nucleosides and therapeutic oligonucleotides.

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“…Sugar 2¢-modifications include 2¢-O-Me, 2¢-F, 2¢-MOE, locked nucleic acids (LNA), 2¢-O-allyl, 2¢-O-aminoethyl, 2¢-Oguanidinoethyl, and 2¢-O-cyanoethyl, of which 2¢-O-Me and 2¢-F are extensively studied at clinical trials and already being used in recently approved drugs, Patisiran and Givlaari [15][16][17]. Likewise, various 2¢,4¢-dual modifications have also been explored in ribose, including 4¢-AM-2¢-O-Me, 4¢-AMEt-2¢-O-Me, 4¢-AMPr-2¢-O-Me, 4¢-AMEt-2¢-F, 4¢-O-Me-2¢-F, 4¢-F-2¢-O-Me, and 2¢,4¢-di-O-Me [41][42][43][44][45][46].…”

Section: Introductionmentioning

confidence: 99%

Folate Receptor-Mediated siRNA Delivery: Recent Developments and Future Directions for RNAi Therapeutics

Gangopadhyay

Nikam

Gore

2021

Nucleic Acid Therapeutics

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RNA interference (RNAi), a gene regulatory process mediated by small interfering RNAs (siRNAs), has made remarkable progress as a potential therapeutic agent against various diseases. However, RNAi is associated with fundamental challenges such as poor systemic delivery and susceptibility to the nucleases. Targeting ligand-bound delivery vehicles has improved the accumulation of drug at the target site, which has resulted in high transfection efficiency and enhanced gene silencing. Recently, folate receptor (FR)-mediated targeted delivery of siRNAs has garnered attention due to their enhanced cellular uptake and high transfection efficiency toward tumor cells. Folic acid (FA), due to its small size, low immunogenicity, high in vivo stability, and high binding affinity toward FRs, has attracted much attention for targeted siRNA delivery. FRs are overexpressed in a large number of tumors, including ovarian, breast, kidney, and lung cancer cells. In this review, we discuss recent advances in FA-mediated siRNA delivery to treat cancers and inflammatory diseases. This review summarizes various FA-conjugated nanoparticle systems reported so far in the literature, including liposome, silica, metal, graphene, dendrimers, chitosan, organic copolymers, and RNA nanoparticles. This review will help in the design and development of potential delivery vehicles for siRNA drug targeting to tumor cells using an FR-mediated approach.

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4′-Guanidinium-modified siRNA: a molecular tool to control RNAi activity through RISC priming and selective antisense strand loading

Abstract: We present synthesis, biochemical, biophysical and computational evaluation of 4′ gunanidino modified siRNA.

Cited by 8 publications

References 26 publications

Beyond ribose and phosphate: Selected nucleic acid modifications for structure–function investigations and therapeutic applications

Beyond ribose and phosphate: Selected nucleic acid modifications for structure–function investigations and therapeutic applications

Synthesis, Structural, and Conformational Analysis of 4′‐C‐Alkyl‐2′‐O‐Ethyl‐Uridine Modified Nucleosides

Folate Receptor-Mediated siRNA Delivery: Recent Developments and Future Directions for RNAi Therapeutics

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