Circular Antisense Oligonucleotides for Specific RNase-H-Mediated microRNA Inhibition with Reduced Off-Target Effects and Nonspecific Immunostimulation

Gubu, Amu; Su, Wenbo; Zhao, Xiaoru; Zhang, Xueli; Fan, Xinli; Wang, Jing; Wang, Qian; Tang, Xinjing

doi:10.1021/acs.jmedchem.1c01421

Cited by 5 publications

(5 citation statements)

References 44 publications

(62 reference statements)

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“…37 Bis-azide linker 1 was synthesized according to the literature. 38 The ssRNA containing just the 1′-ethynyl-2′-deoxyribose modification (30 μM) was first clicked with an excess of 1 (5.5 mM) in 10:1 H 2 O/MeCN to afford an azide-functionalized product. A flat copper bar was added to the mixture, and then the reaction was stirred in the dark at room temperature for 1 h. The copper bar was then removed, and the reaction was allowed to continue at room temperature for 2 h. The oligonucleotides were passed through a 3 K M w cutoff filter, washed twice with water, and then dried under vacuum.…”

Section: ■ Introductionmentioning

confidence: 99%

Selective Inhibition of ADAR1 Using 8-Azanebularine-Modified RNA Duplexes

et al. 2023

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Adenosine deaminases acting on RNA (ADARs) are RNA editing enzymes that catalyze the hydrolytic deamination of adenosine (A) to inosine (I) in dsRNA. In humans, two catalytically active ADARs, ADAR1 and ADAR2, perform this A-to-I editing event. The growing field of nucleotide base editing has highlighted ADARs as promising therapeutic agents while multiple studies have also identified ADAR1’s role in cancer progression. However, the potential for site-directed RNA editing as well as the rational design of inhibitors is being hindered by the lack of detailed molecular understanding of RNA recognition by ADAR1. Here, we designed short RNA duplexes containing the nucleoside analog, 8-azanebularine (8-azaN), to gain insight into molecular recognition by the human ADAR1 catalytic domain. From gel shift and in vitro deamination experiments, we validate ADAR1 catalytic domain’s duplex secondary structure requirement and present a minimum duplex length for binding (14 bp, with 5 bp 5′ and 8 bp 3′ to editing site). These findings concur with predicted RNA-binding contacts from a previous structural model of the ADAR1 catalytic domain. Finally, we establish that neither 8-azaN as a free nucleoside nor a ssRNA bearing 8-azaN inhibits ADAR1 and demonstrate that the 8-azaN-modified RNA duplexes selectively inhibit ADAR1 and not the closely related ADAR2 enzyme.

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Section: ■ Introductionmentioning

confidence: 99%

Selective Inhibition of ADAR1 Using 8-Azanebularine-Modified RNA Duplexes

et al. 2023

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“…Nonspecific immunity is one of the key side effects of ASO therapy because of activation of Toll-like reporters. 39 , 40 , 41 , 42 , 43 Thus, nonspecific immunostimulation of cASO-CB was also investigated compared with its corresponding lASO in PC-3 cells. 100 nM cASO TCTP -CB and lASO TCTP were transfected into PC-3 cells, and four typical immune indicators, interleukin-6 (IL-6), interferon-β (IFN-β), Toll-like receptor 9 (TLR9), and IFN regulatory factor 7 (IRF7), were evaluated.…”

Section: Resultsmentioning

confidence: 99%

Cathepsin B-activatable cyclic antisense oligonucleotides for cell-specific target gene knockdown in vitro and in vivo

Wang¹,

Fan²,

Mu³

et al. 2023

Molecular Therapy - Nucleic Acids

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“…The linear M1.3 was produced through digestion of the M13mp18 with restriction enzymes, followed by circularization facilitated by a splint and T4 DNA ligase. Overall, these DNA dumbbells or C-ODNs could be prepared by similar methods, with a greater emphasis on innovative sequence design strategies to achieve specific objectives, such as encoding miRNAs, , binding microRNA to inhibit its functions, RCA central templates, , or aptamers …”

Section: Different Origins Of Cssdnamentioning

confidence: 99%

Circular Single-Stranded DNA: Discovery, Biological Effects, and Applications

Cao,

Tang,

Song

2024

ACS Synth. Biol.

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The field of nucleic acid therapeutics has witnessed a significant surge in recent times, as evidenced by the increasing number of approved genetic drugs. However, current platform technologies containing plasmids, lipid nanoparticle-mRNAs, and adeno-associated virus vectors encounter various limitations and challenges. Thus, we are devoted to finding a novel nucleic acid vector and have directed our efforts toward investigating circular single-stranded DNA (CssDNA), an ancient form of nucleic acid. CssDNAs are ubiquitous, but generally ignored. Accumulating evidence suggests that CssDNAs possess exceptional properties as nucleic acid vectors, exhibiting great potential for clinical applications in genetic disorders, gene editing, and immune cell therapy. Here, we comprehensively review the discovery and biological effects of CssDNAs as well as their applications in the field of biomedical research for the first time. Undoubtedly, as an ancient form of DNA, CssDNA holds immense potential and promises novel insights for biomedical research.

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Circular Antisense Oligonucleotides for Specific RNase-H-Mediated microRNA Inhibition with Reduced Off-Target Effects and Nonspecific Immunostimulation

Cited by 5 publications

References 44 publications

Selective Inhibition of ADAR1 Using 8-Azanebularine-Modified RNA Duplexes

Selective Inhibition of ADAR1 Using 8-Azanebularine-Modified RNA Duplexes

Cathepsin B-activatable cyclic antisense oligonucleotides for cell-specific target gene knockdown in vitro and in vivo

Circular Single-Stranded DNA: Discovery, Biological Effects, and Applications

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