2′,4′-BNANC: A Novel Bridged Nucleic Acid Analogue with Excellent Hybridizing and Nuclease Resistance Profiles

Rahman, Sharif; Seki, Sayori; Utsuki, Kazushige; Obika, Satoshi; Miyashita, Kazuyuki; Imanishi, Takeshi

doi:10.1080/15257770701548980

Cited by 19 publications

(7 citation statements)

References 8 publications

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“…BNA is a third generation nucleic acid analog with excellent mismatch discriminating power and is considered more potent in blocking. Its strong nuclease resistant properties coupled with a 3′ phosphate also prevents amplification of the wild-type DNA and selectively amplifies mutant DNA [11, 12]. The resulting WTB-PCR product can then be sequenced by traditional Sanger sequencing methods.…”

Section: Introductionmentioning

confidence: 99%

Using high-sensitivity sequencing for the detection of mutations in BTK and PLCγ2 genes in cellular and cell-free DNA and correlation with progression in patients treated with BTK inhibitors

Albitar

DeDios

et al. 2017

Oncotarget

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Patients with chronic lymphocytic leukemia (CLL) that develop resistance to Bruton tyrosine kinase (BTK) inhibitors are typically positive for mutations in BTK or phospholipase c gamma 2 (PLCγ2). We developed a high sensitivity (HS) assay utilizing wild-type blocking polymerase chain reaction achieved via bridged and locked nucleic acids. We used this high sensitivity assay in combination with Sanger sequencing and next generation sequencing (NGS) and tested cellular DNA and cell-free DNA (cfDNA) from patients with CLL treated with the BTK inhibitor, ibrutinib. We also tested ibrutinib-naïve patients with CLL. HS testing achieved 100x greater sensitivity than Sanger. HS Sanger sequencing was capable of detecting < 1 mutant allele in background of 1000 wild-type alleles (1:1000). Similar sensitivity was achieved with HS NGS. No BTK or PLCγ2 mutations were detected in any of the 44 ibrutinib-naïve CLL patients. We demonstrate that without the HS testing 56% of positive samples would have been missed for BTK and 85% of PLCγ2 would have been missed. With the use of HS, we were able to detect multiple mutant clones in the same sample in 37.5% of patients; most would have been missed without HS testing. We also demonstrate that with HS sequencing, plasma cfDNA is more reliable than cellular DNA in detecting mutations. Our studies indicate that wild-type blocking and HS sequencing is necessary for proper and early detection of BTK or PLCγ2 mutations in monitoring patients treated with BTK inhibitors. Furthermore, cfDNA from plasma is very reliable sample-type for testing.

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Section: Introductionmentioning

confidence: 99%

Using high-sensitivity sequencing for the detection of mutations in BTK and PLCγ2 genes in cellular and cell-free DNA and correlation with progression in patients treated with BTK inhibitors

Albitar

DeDios

et al. 2017

Oncotarget

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“…The purpose of this work was to inhibit production of this enzyme in the A. baumannii A155 clinical strain using antisense BNA NC -DNA co-oligomers complementary to the region of initiation of translation. We selected BNA NC -DNA molecules as antisense molecules because of their high affinity of binding to the sense molecule, their specificity, which may lead to a highly efficient and selective inhibitory effect, and their low toxicity (24,25).…”

Section: Resultsmentioning

confidence: 99%

“…New analogs related to LNAs, the 2=,4=-bridged nucleic acid-NC (BNA NC ) analogs ( Fig. 1), that exhibit advantages such as higher binding affinity to a cRNA and excellent single-mismatch discriminating ability, have been recently introduced (24). Furthermore, tests carried out in mice showed that BNA NC -based antisense molecules have minimal toxicity (25).…”

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confidence: 99%

Inhibition of AAC(6′)-Ib-Mediated Resistance to Amikacin in Acinetobacter baumannii by an Antisense Peptide-Conjugated 2′,4′-Bridged Nucleic Acid-NC-DNA Hybrid Oligomer

Lopez

Arivett

Actis

et al. 2015

Antimicrob Agents Chemother

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bMultiresistant Acinetobacter baumannii, a common etiologic agent of severe nosocomial infections in compromised hosts, usually harbors aac(6=)-Ib. This gene specifies resistance to amikacin and other aminoglycosides, seriously limiting the effectiveness of these antibiotics. An antisense oligodeoxynucleotide (ODN4) that binds to a duplicated sequence on the aac(6=)-Ib mRNA, one of the copies overlapping the initiation codon, efficiently inhibited translation in vitro. An isosequential nuclease-resistant hybrid oligomer composed of 2=,4=-bridged nucleic acid-NC (BNA NC ) residues and deoxynucleotides (BNA NC -DNA) conjugated to the permeabilizing peptide (RXR) 4 XB ("X" and "B" stand for 6-aminohexanoic acid and ␤-alanine, respectively) (CPPBD4) inhibited translation in vitro at the same levels observed in testing ODN4. Furthermore, CPPBD4 in combination with amikacin inhibited growth of a clinical A. baumannii strain harboring aac(6=)-Ib in liquid cultures, and when both compounds were used as combination therapy to treat infected Galleria mellonella organisms, survival was comparable to that seen with uninfected controls.A cinetobacter baumannii is an opportunistic human pathogen, mainly nosocomial, that causes bacteremia, meningitis, urinary tract infections, pneumonia, and necrotizing fasciitis among other infections (1-4). Multidrug-resistant A. baumannii strains are increasingly found in hospitals, complicating treatment of the infections they cause (4). Antisense technologies could be a path for designing new therapeutic strategies to overcome this problem. Options include the silencing of one or more essential genes (5-12) or the silencing of one or more resistance genes to induce phenotypic conversion to susceptibility (13-16). In the latter case, the antisense compound would be administered in combination with the appropriate antibiotic. However, in spite of important advances, silencing of bacterial genes by antisense oligomers is far from reaching its full potential (10). The main antisense mechanisms of gene silencing include degradation of the target mRNA by double-stranded RNA (dsRNA)-specific RNase, RNase H, or RNase P and steric hindrance of translation (interference with assembly of the ribosome or translation arrest) (10, 17). Practical application of any of these strategies requires that the antisense compounds resist the action of the ubiquitous nucleases and reach the cytosol to exert their action.There are numerous nuclease-resistant nucleotide analogs available that are adequate for different antisense strategies (10,18,19). For example, hybrid molecules containing locked nucleic acid and deoxyribonucleotide residues (LNA-DNA) in different configurations have been successfully utilized in bacteria and eukaryotes (16,(20)(21)(22)(23). New analogs related to LNAs, the 2=,4=-bridged nucleic acid-NC (BNA NC ) analogs (Fig. 1), that exhibit advantages such as higher binding affinity to a cRNA and excellent single-mismatch discriminating ability, have been recently introduced (24). Furthermore,...

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“…Exhaustive listings and a description of oligonucleotide analogs and their applications can be found in recent reviews [3,6,16,23,25,26,27]. A derivative of LNA, 2′- O ,4′-aminoethylene bridged nucleic acid (BNA), also known as 2′,4′-BNA NC (BNA NC ) [28,29,30,31] (Figure 1) has been recently introduced and other derivatives have followed or are in development. As a consequence, LNA is considered the earliest generation of bridged nucleic acids (BNA).…”

Section: Oligonucleotides and Analogsmentioning

confidence: 99%

Bridged Nucleic Acids Reloaded

2019

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Oligonucleotides are key compounds widely used for research, diagnostics, and therapeutics. The rapid increase in oligonucleotide-based applications, together with the progress in nucleic acids research, has led to the design of nucleotide analogs that, when part of these oligomers, enhance their efficiency, bioavailability, or stability. One of the most useful nucleotide analogs is the first-generation bridged nucleic acids (BNA), also known as locked nucleic acids (LNA), which were used in combination with ribonucleotides, deoxyribonucleotides, or other analogs to construct oligomers with diverse applications. However, there is still room to improve their efficiency, bioavailability, stability, and, importantly, toxicity. A second-generation BNA, BNANC (2′-O,4′-aminoethylene bridged nucleic acid), has been recently made available. Oligomers containing these analogs not only showed less toxicity when compared to LNA-containing compounds but, in some cases, also exhibited higher specificity. Although there are still few applications where BNANC-containing compounds have been researched, the promising results warrant more effort in incorporating these analogs for other applications. Furthermore, newer BNA compounds will be introduced in the near future, offering great hope to oligonucleotide-based fields of research and applications.

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2′,4′-BNA^NC: A Novel Bridged Nucleic Acid Analogue with Excellent Hybridizing and Nuclease Resistance Profiles

Cited by 19 publications

References 8 publications

Using high-sensitivity sequencing for the detection of mutations in BTK and PLCγ2 genes in cellular and cell-free DNA and correlation with progression in patients treated with BTK inhibitors

Using high-sensitivity sequencing for the detection of mutations in BTK and PLCγ2 genes in cellular and cell-free DNA and correlation with progression in patients treated with BTK inhibitors

Inhibition of AAC(6′)-Ib-Mediated Resistance to Amikacin in Acinetobacter baumannii by an Antisense Peptide-Conjugated 2′,4′-Bridged Nucleic Acid-NC-DNA Hybrid Oligomer

Bridged Nucleic Acids Reloaded

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