Synthesis and Antisense Properties of 2′β-F-Arabinouridine Modified Oligonucleotides with 4′-C-OMe Substituent

He, Xiaoyang; Wang, Jing; Lu, Dandan; Wang, Shengqi

doi:10.3390/molecules23092374

Cited by 5 publications

(4 citation statements)

References 20 publications

(28 reference statements)

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“…As previously found with 2′-F, 4′-OMe uridine, this new library of uridines exhibited primarily a C3′- endo (“North”) sugar conformation [5] and their incorporation into siRNAs led to virtually no change in duplex melting temperature [4,6]. This property, together with the observation that C2′/C4′ modifications impart much desirable resistance toward endo/exo nuclease degradation [3,7,8], prompted us to evaluate whether these analogues are compatible with the RNA-induced silencing complex (RISC) and able to regulate gene expression through the RNAi pathway. Herein we report studies that assess the gene silencing efficiency of C2′/C4′ modified siRNA duplexes (Fig.…”

Section: Introductionmentioning

confidence: 68%

Effect of Sugar 2′,4′-Modifications on Gene Silencing Activity of siRNA Duplexes

Malek-Adamian

Fakhoury

Arnold

et al. 2019

Nucleic Acid Therapeutics

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In this study, we explore the effect of a library of 2¢-, 4¢-, and 2¢,4¢-modified uridine nucleosides and their impact on silencing firefly luciferase and on down-regulated in renal cell carcinoma (DRR) gene targets. The modifications studied were 2¢-F-ribose, 2¢-F-arabinose, 2¢-OMe-ribose, 2¢-F,4¢-OMe-ribose, 2¢-F,4¢-OMe-arabinose, and 2¢-OMe,4¢-F-ribose. We found that 2¢,4¢-modifications are well tolerated within A-form RNA duplexes, leading to virtually no change in melting temperature as assessed by UV thermal melting. The impact of the dual (2¢,4¢) modification was assessed by comparing gene silencing ability to 2¢-or 4¢-(singly) modified siRNA counterparts. siRNAs with (2¢,4¢)-modified overhangs generally outperformed the native siRNA as well as siRNAs with a 2¢-or 4¢-modified overhang, suggesting that 2¢,4¢-modified nucleotides interact favorably with Argonaute protein's PAZ domain. Among the most active siRNAs were those with 2¢-F,4¢-OMe-ribose or 2¢-F,4¢-OMe-arabinose at the overhangs. When modifications were placed at both overhangs and internal positions, a duplex with the 2¢-F (internal) and 2¢-F,4¢-OMe (overhang) combination was found to be the most potent, followed by the duplex with 2¢-OMe (internal) and 2¢,4¢-diOMe (overhang) modifications. Given the nuclease resistance exhibited by 2¢,4¢-modified siRNAs, particularly when the modification is placed at or near the overhangs, these findings may allow the creation of superior siRNAs for therapy.

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Section: Introductionmentioning

confidence: 68%

Effect of Sugar 2′,4′-Modifications on Gene Silencing Activity of siRNA Duplexes

Malek-Adamian

Fakhoury

Arnold

et al. 2019

Nucleic Acid Therapeutics

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“…For example, a non-gapmer ASO agents consisting of amido-bridged nucleic acid (AmNA, Figure 2 F) were found to demonstrate a lower risk of hepatotoxicity 37 . To enable RNAse H dependent cleavage, fluorine and 4'methoxy nucleotides were proposed (araN, Figure 2 F) 38 , 39 . Uracil and cytosine derivatives of 2'3'-dideoxy-2'-fluoro-3'-C-hydroxymethyl-β-D-lyxonucleotides (Figure 2 F) incorporations are responsible for obtaining ASO agents molecules with reduced toxicities and OTE 39 .…”

Section: Antisense Oligonucleotides (Aso Agents)mentioning

confidence: 99%

Specificity of oligonucleotide gene therapy (OGT) agents

Nedorezova¹,

Dubovichenko²,

Belyaeva³

et al. 2022

Theranostics

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Oligonucleotide gene therapy (OGT) agents (e. g. antisense, deoxyribozymes, siRNA and CRISPR/Cas) are promising therapeutic tools. Despite extensive efforts, only few OGT drugs have been approved for clinical use. Besides the problem of efficient delivery to targeted cells, hybridization specificity is a potential limitation of OGT agents. To ensure tight binding, a typical OGT agent hybridizes to the stretch of 15-25 nucleotides of a unique targeted sequence. However, hybrids of such lengths tolerate one or more mismatches under physiological conditions, the problem known as the affinity/specificity dilemma. Here, we assess the scale of this problem by analyzing OGT hybridization-dependent off-target effects (HD OTE) in vitro , in animal models and clinical studies. All OGT agents except deoxyribozymes exhibit HD OTE in vitro , with most thorough evidence of poor specificity reported for siRNA and CRISPR/Cas9. Notably, siRNA suppress non-targeted genes due to (1) the partial complementarity to mRNA 3'-untranslated regions (3'-UTR), and (2) the antisense activity of the sense strand. CRISPR/Cas9 system can cause hundreds of non-intended dsDNA breaks due to low specificity of the guide RNA, which can limit therapeutic applications of CRISPR/Cas9 by ex-vivo formats. Contribution of this effects to the observed in vivo toxicity of OGT agents is unclear and requires further investigation. Locked or peptide nucleic acids improve OGT nuclease resistance but not specificity. Approaches that use RNA marker dependent (conditional) activation of OGT agents may improve specificity but require additional validation in cell culture and in vivo .

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“…To an extent, chemical modification and the conjugation of oligonucleotides have addressed these chemical barriers. The modification increased the half-life of ASOs and reduced their degradation by exonucleases [ 10 , 63 , 64 ]. The in vivo delivery can be further improved by efficiently using nanotechnology and material science [ 10 ].…”

Section: Nanoparticles For Gene Regulation In Muscle Dystrophiesmentioning

confidence: 99%

Nanomedicine for Treating Muscle Dystrophies: Opportunities, Challenges, and Future Perspectives

Ahmed

Qaisar

2022

IJMS

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Muscular dystrophies are a group of genetic muscular diseases characterized by impaired muscle regeneration, which leads to pathological inflammation that drives muscle wasting and eventually results in weakness, functional dependency, and premature death. The most known causes of death include respiratory muscle failure due to diaphragm muscle decay. There is no definitive treatment for muscular dystrophies, and conventional therapies aim to ameliorate muscle wasting by promoting physiological muscle regeneration and growth. However, their effects on muscle function remain limited, illustrating the requirement for major advancements in novel approaches to treatments, such as nanomedicine. Nanomedicine is a rapidly evolving field that seeks to optimize drug delivery to target tissues by merging pharmaceutical and biomedical sciences. However, the therapeutic potential of nanomedicine in muscular dystrophies is poorly understood. This review highlights recent work in the application of nanomedicine in treating muscular dystrophies. First, we discuss the history and applications of nanomedicine from a broader perspective. Second, we address the use of nanoparticles for drug delivery, gene regulation, and editing to target Duchenne muscular dystrophy and myotonic dystrophy. Next, we highlight the potential hindrances and limitations of using nanomedicine in the context of cell culture and animal models. Finally, the future perspectives for using nanomedicine in clinics are summarized with relevance to muscular dystrophies.

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Synthesis and Antisense Properties of 2′β-F-Arabinouridine Modified Oligonucleotides with 4′-C-OMe Substituent

Cited by 5 publications

References 20 publications

Effect of Sugar 2′,4′-Modifications on Gene Silencing Activity of siRNA Duplexes

Effect of Sugar 2′,4′-Modifications on Gene Silencing Activity of siRNA Duplexes

Specificity of oligonucleotide gene therapy (OGT) agents

Nanomedicine for Treating Muscle Dystrophies: Opportunities, Challenges, and Future Perspectives

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