Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Georg Thieme Verlag KG  

Psoralen-conjugated triplex-forming oligonucleotides (Ps-TFOs) have been used to induce DNA mutations or suppress gene expression via the formation of crosslinked products with DNA in a sequence-specific manner. Psoralen can crosslink with DNA at its furan ring and/or pyrone ring side, yielding either a monoadduct or diadduct (interstrand crosslinking) product. The differences in the crosslinked structures of Ps-TFOs with the target DNAs are closely related to the changes in the biological outcomes induced by the Ps-TFOs. However, only few reports have discussed the photo-crosslinking properties of Ps-TFOs. The photo-crosslinking properties of Ps-TFOs with structurally diverse psoralen derivatives remain elusive. Herein, we report the modular synthesis of methyl-substituted novel psoralen N-hydroxysuccinimide (NHS) esters. Using these esters, the effect of the methyl substituent of psoralen on the photo-crosslinking of the corresponding Ps-TFOs was examined. Results revealed that the amount of the diadduct product was significantly reduced in the presence of the methyl substituents at C-3 and C-4 position while maintaining the total amount of photo-crosslinking product. This work demonstrates the possibility to control the crosslinked product of Ps-TFOs by introducing methyl groups into psoralen—this ability to manipulate the product is an important factor in the biological applications of Ps-TFOs.

DOI： 10.1055/a-2229-7441

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Language：English   Publishing type：Research paper (scientific journal)  

Off-target interactions between antisense oligonucleotides (ASOs) with state-of-the-art modifications and biological components still pose clinical safety liabilities. To mitigate a broad spectrum of off-target interactions and enhance the safety profile of ASO drugs, we here devise a nanoarchitecture named BRace On a THERapeutic aSo (BROTHERS or BRO), which is composed of a standard gapmer ASO paired with a partially complementary peptide nucleic acid (PNA) strand. We show that these non-canonical ASO/PNA hybrids have reduced non-specific protein-binding capacity. The optimization of the structural and thermodynamic characteristics of this duplex system enables the operation of an in vivo toehold-mediated strand displacement (TMSD) reaction, effectively reducing hybridization with RNA off-targets. The optimized BROs dramatically mitigate hepatotoxicity while maintaining the on-target knockdown activity of their parent ASOs in vivo. This technique not only introduces a BRO class of drugs that could have a transformative impact on the extrahepatic delivery of ASOs, but can also help uncover the toxicity mechanism of ASOs.

DOI： 10.1038/s41467-023-43714-0

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Recent developments in artificial nucleic acid and drug delivery systems present possibilities for the symbiotic engineering of therapeutic oligonucleotides, such as antisense oligonucleotides (ASOs) and small interfering ribonucleic acids (siRNAs). Employing these technologies, triplex-forming oligonucleotides (TFOs) or peptide nucleic acids (PNAs) can be applied to the development of symbiotic genome-targeting tools as well as a new class of oligonucleotide drugs, which offer conceptual advantages over antisense as the antigene target generally comprises two gene copies per cell rather than multiple copies of mRNA that are being continually transcribed. Further, genome editing by TFOs or PNAs induces permanent changes in the pathological genes, thus facilitating the complete cure of diseases. Nuclease-based gene-editing tools, such as zinc fingers, CRISPR-Cas9, and TALENs, are being explored for therapeutic applications, although their potential off-target, cytotoxic, and/or immunogenic effects may hinder their in vivo applications. Therefore, this review is aimed at describing the ongoing progress in TFO and PNA technologies, which can be symbiotic genome-targeting tools that will cause a near-future paradigm shift in drug development.

DOI： 10.3390/pharmaceutics15102515

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Psoralen-conjugated triplex-forming oligonucleotides (Ps-TFOs) have been utilized for genome editing and anti-gene experiments for over thirty years. However, the research on Ps-TFOs employing artificial nucleotides is still limited, and their photo-crosslinking properties have not been thoroughly investigated in relation to biological activities. In this study, we extensively examined the photo-crosslinking properties of Ps-TFOs to provide fundamental insights for future Ps-TFO design. We developed novel Ps-TFOs containing 2'-O,4'-C-methylene-bridged nucleic acids (Ps-LNA-mixmer) and investigated their photo-crosslinking properties using stable cell lines that express firefly luciferase constitutively to evaluate the anti-gene activities of Ps-LNA-mixmer. As a result, Ps-LNA-mixmer successfully demonstrated suppression activity, and we presented the first-ever correlation between photo-crosslinking properties and their activities. However, our findings indicate that the photo-crosslinking process is insufficient under cell irradiation conditions (365 nm, 2 mW/cm2, 60 min). Therefore, our results highlight the need to develop new psoralen derivatives that are more reactive under cell irradiation conditions.

DOI： 10.1002/cmdc.202300348

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Psoralens and their derivatives, such as trioxsalen, have unique crosslinking features to DNA. However, psoralen monomers do not have sequence-specific crosslinking ability with the target DNA. With the development of psoralen-conjugated oligonucleotides (Ps-Oligos), sequence-specific crosslinking with target DNA has become achievable, thereby expanding the application of psoralen-conjugated molecules in gene transcription inhibition, gene knockout, and targeted recombination by genome editing. In this study, we developed two novel psoralen N-hydroxysuccinimide (NHS) esters that allow the introduction of psoralens into any amino-modified oligonucleotides.  Quantitative evaluation of the photo-crosslinking efficiencies of the Ps-Oligos to target single-stranded DNAs revealed that the crosslinking selectivity to 5-mC is the unique feature of trioxsalen. We found that the introduction of an oligonucleotide via a linker at the C-5 position of psoralen can promote favorable crosslinking to target double-stranded DNA. We believe our findings are essential information for the development of Ps-Oligos as novel gene regulation tools.

DOI： 10.1002/cbic.202200789

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Language：English   Publishing type：Research paper (scientific journal)  

Functionalized drug delivery systems have been investigated to improve the targetability and intracellular translocation of therapeutic drugs. We developed high functionality and quality lipids that met unique requirements, focusing on the quality of functional lipids for the preparation of targeted nanoparticles using microfluidic devices. While searching for a lipid with high solubility and dispersibility in solvents, which is one of the requirements, we noted that KK-(EK)4-lipid imparts nonspecific cellular association to polyethylene glycol (PEG)-modified (PEGylated) liposomes, such as cell-penetrating peptides (CPPs). We investigated whether KK-(EK)4-lipid, which has a near-neutral charge, is a novel CPP-modified lipid that enhances the intracellular translocation of nanoparticles. However, the cellular association mechanism of KK-(EK)4-lipid is unknown. Therefore, we synthesized (EK)n-lipid derivatives based on the sequence of KK-(EK)4-lipid and determined the sequence sites involved in cellular association. In addition, KK-(EK)4-lipid was applied to extracellular vesicles (EVs) and mRNA encapsulated lipid nanoparticles (mRNA-LNPs). KK-(EK)4-lipid-modified EVs and mRNA-LNPs showed higher cellular association and in vitro protein expression, respectively, compared to unmodified ones. We elucidated KK-(EK)4-lipid to have potential for applicability in the intracellular delivery of liposomes, EVs, and mRNA-LNPs.

DOI： 10.1080/10717544.2023.2191891

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Publishing type：Research paper (scientific journal)   Publisher：Informa UK Limited  

DOI： 10.2147/ijn.s390866

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Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Oligonucleotide therapeutics that can modulate gene expression have been gradually developed for clinical applications over several decades. However, rapid advances have been made in recent years. Artificial nucleic acid technology has overcome many challenges, such as (1) poor target affinity and selectivity, (2) low in vivo stability, and (3) classical side effects, such as immune responses; thus, its application in a wide range of disorders has been extensively examined. However, even highly optimized oligonucleotides exhibit side effects, which limits the general use of this class of agents. In this review, we discuss the physicochemical characteristics that aid interactions between drugs and molecules that belong to living organisms. By systematically organizing the related data, we hope to explore avenues for symbiotic engineering of oligonucleotide therapeutics that will result in more effective and safer drugs.

DOI： 10.3390/pharmaceutics14122647

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Pharmaceutical Society of Japan  

DOI： 10.1248/cpb.c22-00333

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

In the process of cell development and differentiation, C-5-methylation of cytosine (5-methylcytosine: 5-mC) in genome DNA is an important transcriptional regulator that switches between differentiated and undifferentiated states. Further, abnormal DNA methylations are often present in tumor suppressor genes and are associated with many diseases. Therefore, 5-mC detection technology is an important tool in the most exciting fields of molecular biology and diagnosing diseases such as cancers. In this study, we found a novel photo-crosslinking property of psoralen-conjugated oligonucleotide (Ps-Oligo) to the double-stranded DNA (ds-DNA) containing 5-mC in the presence of a cationic comb-type copolymer, poly(allylamine)-graft-dextran (PAA-g-Dex). Photo-crosslinking efficiency of Ps-Oligo to 5-mC in ds-DNA was markedly enhanced in the presence of PAA-g-Dex, permitting 5-mC-targeted crosslinking. We believe that the combination of PAA-g-Dex and Ps-Oligo will be an effective tool for detecting 5-mC in genomic DNA.

DOI： 10.1021/acsbiomaterials.2c00048

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Nucleic acid medicines have been developed as new therapeutic agents against various diseases; however, targeted delivery of these reagents into cancer cells, particularly hematologic cancer cells, via systemic administration is limited by the lack of efficient and cell-specific delivery systems. We previously demonstrated that monoclonal antibody (mAb)-oligonucleotide complexes targeting exosomal microRNAs with linear oligo-D-arginine (Arg) linkers were transferred into solid cancer cells and inhibited exosomal miRNA functions. In this study, we developed exosome-capturing anti-CD63 mAb-conjugated small interfering RNAs (siRNAs) with branched Arg linkers and investigated their effects on multiple myeloma (MM) cells. Anti-CD63 mAb-conjugated siRNAs were successfully incorporated into MM cells. The incorporation of exosomes was inhibited by endocytosis inhibitors. We also conducted a functional analysis of anti-CD63 mAb-conjugated siRNAs. Ab-conjugated luciferase+ (luc+) siRNAs significantly decreased the luminescence intensity in OPM-2-luc+ cells. Moreover, treatment with anti-CD63 mAb-conjugated with MYC and CTNNB1 siRNAs decreased the mRNA transcript levels of MYC and CTNNB1 to 52.5% and 55.3%, respectively, in OPM-2 cells. In conclusion, exosome-capturing Ab-conjugated siRNAs with branched Arg linkers can be effectively delivered into MM cells via uptake of exosomes by parental cells. This technology has the potential to lead to a breakthrough in drug delivery systems for hematologic cancers.

DOI： 10.3390/cancers14030566

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Language：English   Publishing type：Research paper (scientific journal)  

Antisense oligonucleotides (ASOs) containing bridged nucleic acids (BNAs) have been proven to be very powerful. However, ensuring a reliable discovery and translational development scheme for this class of ASOs with wider therapeutic windows remains a fundamental challenge. We here demonstrate the robustness of our scheme in the context of the selection of ASOs having two different BNA chemistries (2,'4'-BNA/locked nucleic acid [LNA] and amido-bridged nucleic acid [AmNA]) targeting human proprotein convertase subtilisin/kexin type 9 (PCSK9). The scheme features a two-step process, including (1) a unique and sensitive in vitro screening approach, called Ca2+ enrichment of medium (CEM) transfection, and (2) a ligand-targeted drug delivery approach to better reach target tissues, averting unintended accumulation of ASOs. Using CEM screening, we identified a candidate ASO that shows >70% cholesterol-lowering action in monkeys. An N-acetylgalactosamine (GalNAc) ligand then was appended to the candidate ASO to further broaden the therapeutic margin by altering the molecule's pharmacokinetics. The GalNAc conjugate, HsPCSK9-1811-LNA, was found to be at least ten times more potent in non-human primates (compared with the unconjugated counterpart), with reduced nephrotoxicity in rats. Overall, we successfully showed that our drug development scheme is better suited for selecting clinically relevant BNA-based ASOs, especially for the treatment of liver-associated diseases.

DOI： 10.1016/j.omtn.2021.10.008

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

Genome editing has been expected to widely increase the available treatment options for various diseases and permit pharmaceutical interventions in previously untreatable conditions. The availability of genome editing tools was dramatically increased by the development of the CRISPR-Cas9 system. However, a number of issues limit the use of the CRISPR-Cas9 system and other gene-editing tools in the clinical treatment of diseases. This review summarized the history and types of genome editing tools and limitations of their use. In addition, the study addressed several next-generation technologies aiming to overcome the limitations of current gene therapy protocols in an effort to accelerate the clinical development of potential treatment options. This review has provided an extensive foundation of the current state of genome editing technology and its clinical development. This review also indicate that the study additionally highlighted the need for multidisciplinary approaches to overcome current bottlenecks in the development of genome editing.

DOI： 10.1016/j.dmpk.2021.100427

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Mary Ann Liebert Inc  

Ligand-targeted drug delivery (LTDD) has gained more attention in the field of nucleic acid therapeutics. To further elicit the potential of therapeutic oligonucleotides by means of LTDD, we newly developed (R)- and (S)-3-amino-1,2-propanediol (APD) manifold for ligand conjugation. N-acetylgalactosamine (GalNAc)/asialoglycoprotein receptor (ASGPr) system has been shown to be a powerful and robust paradigm of LTDD. Our novel APD-based GalNAc (GalNAcAPD) was shown to have intrinsic chemical instability that could play a role in better manipulation of active drug release. The APD manifold also enables facile production of conjugates through an on-support ligand cluster synthesis. We showed in a series of in vivo studies that while the knockdown activity of antisense oligonucleotides (ASOs) bearing 5'-GalNAcAPD was comparable to the conventional hydroxy-L-prolinol-linked GalNAc (GalNAcHP), 3'-GalNAcAPD elicited ASO activity by more than twice as much as the conventional 3'-GalNAcHP. This was ascribed partly to the GalNAcAPD's ideal susceptibility to nucleolytic digestion, which is expected to facilitate cytosolic internalization of ASO drugs. Moreover, an in vivo/ex vivo imaging study visualized the enhancement effect of monoantennary GalNAcAPD on liver localization of ASOs. This versatile manifold with chemical and biological instability would benefit therapeutic oligonucleotides that target both the liver and extrahepatic tissues.

DOI： 10.1089/nat.2021.0036

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Other Link： https://www.liebertpub.com/doi/pdf/10.1089/nat.2021.0036

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Pharmaceutical Society of Japan  

A facile and reliable fluorescence method for the quantification of urinary uracil concentration is proposed herein. The assay utilizes a specific fluorescence (FL) derivatization reaction for uracil using 3-methylbenzamidoxime as a fluorogenic reagent. Although the presence of urine inhibited the FL reaction, 10 µL of urine was sufficient for the detection of urinary uracil. The uracil derivative was successfully separated from other fluorescent impurities using simple reversed-phase LC with FL detection. Urinary uracil concentrations from 16 people were compared with the concentrations obtained by the traditional column-switching liquid chromatographic analysis with UV detection. The FL derivative of uracil appeared as a single peak in the chromatograms of all samples. However, several samples showed an additional peak overlapping the uracil peak when using the column-switching method because of UV-active impurities. These results indicated that that the present method is not affected by interfering substances in urine and affords a precise determination of urinary uracil. We expect the proposed method to be applicable for diagnosing dihydropyrimidine dehydrogenase deficiency in 5-fluorouracil chemotherapy.

DOI： 10.1248/cpb.c21-00221

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

With the development of new anticancer medicines, novel modalities are being explored for cancer treatment. For many years, conventional modalities, such as small chemical drugs and antibody drugs, have worked by “inhibiting the function” of target proteins. In recent years, however, nucleic acid drugs, such as ASOs and siRNAs, have attracted attention as a new modality for cancer treatment because nucleic acid drugs can directly promote the “loss of function” of target genes. Recently, nucleic acid drugs for use in cancer therapy have been extensively developed and some of them have currently been under investigation in clinical trials. To develop novel nucleic acid drugs for cancer treatment, it is imperative that cancer researchers, including ourselves, cover and understand those latest findings. In this review, we introduce and provide an overview of various DDSs and ligand modification technologies that are being employed to improve the success and development of nucleic acid drugs, then we also discuss the future of nucleic acid drug developments for cancer therapy. It is our belief this review will increase the awareness of nucleic acid drugs worldwide and build momentum for the future development of new cancer-targeted versions of these drugs.

DOI： 10.3390/cancers13153881

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

The 332-nucleotides small nuclear RNA (snRNA) 7SK is a highly conserved non-coding RNA that regulates transcriptional elongation. By binding with positive transcriptional elongation factor b (P-TEFb) via HEXIM1, 7SK snRNA reduces the kinase activity of P-TEFb and inhibits transcriptional elongation. Additionally, it is reported that 7SK inhibition results in the stimulation of human immunodeficiency virus (HIV)-specific transcription. These reports suggest that the 7SK is a naturally occurring functional molecule as negative regulator of P-TEFb and HIV transcription. In this study, we developed functional oligonucleotides that mimic the function of 7SK (7SK-mimics) as novel inhibitors of HIV-replication. We defined the essential region of 7SK regarding its suppressive effects on transcriptional downregulation using an antisense strategy. Based on the results, we designed 7SK-mimics containing the defined region. The inhibitory effects of 7SK mimics on HIV-1 long terminal repeat promoter specific transcription was drastic compared with those of the control-mimic molecule. Notably, these effects were more enhanced by co-transfection with Tat-expressing plasmids. From these results, it is indicated that the 7SK mimics may have great therapeutic potential for HIV/AIDS treatment.

DOI： 10.1002/cmdc.202100422

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3390/pharmaceutics13060817

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Nucleic acid and genetic medicines are increasingly being developed, owing to their potential to treat a variety of intractable diseases. A comprehensive understanding of the in vivo fate of these agents is vital for the rational design, discovery, and fast and straightforward development of the drugs. In case of intravascular administration of nucleic acids and genetic medicines, interaction with blood components, especially plasma proteins, is unavoidable. However, on the flip side, such interaction can be utilized wisely to manipulate the pharmacokinetics of the agents. In other words, plasma protein binding can help in suppressing the elimination of nucleic acids from the blood stream and deliver naked oligonucleotides and gene carriers into target cells. To control the distribution of these agents in the body, the ligand conjugation method is widely applied. It is also important to understand intracellular localization. In this context, endocytosis pathway, endosomal escape, and nuclear transport should be considered and discussed. Encapsulated nucleic acids and genes must be dissociated from the carriers to exert their activity. In this review, we summarize the in vivo fate of nucleic acid and gene medicines and provide guidelines for the rational design of drugs.

DOI： 10.3390/pharmaceutics13020159

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

MicroRNAs in exosomes (exosomal miRNAs) are considered as significant targets for cancer therapy. Anti-miR oligonucleotides are often used for the functional inhibition of miRNAs; however, there are no studies regarding the regulation of exosomal miRNA functions. In this study, we attempted to develop a novel drug delivery system using anti-exosome antibody–anti-miR oligonucleotide complexes (ExomiR-Tracker) to hijack exosomes to carry anti-miR oligonucleotides inside exosome-recipient cells. We found that ExomiR-Tracker bound to the exosomes, and then the complexes were introduced into the recipient cells. We also found that anti-miR oligonucleotides introduced into the recipient cells can exhibit inhibitory effects on exosomal miRNA functions in vitro and in vivo. We believe that our strategy would be a promising one for targeting exosomal miRNAs.

DOI： 10.3390/pharmaceutics12060545

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Language：English   Publishing type：Research paper (scientific journal)  

The asialoglycoprotein receptor (ASGPr) and N-acetylgalactosamine (GalNAc) is one of the most reliable receptor-ligand combinations for delivering antisense oligonucleotides (ASOs) to the liver. Here, we show that a modular GalNAc conjugation strategy allows us to reinforce the activity of the parent, naked 2',4'-BNA/LNA gapmer targeting apolipoprotein B. The conjugation partly reduced a possible hepatotoxicity of the parent ASO. The structure-activity study revealed the significance of the metabolic susceptibility of the GalNAc moiety to nucleolytic cleavage that results in exposure of the parent gapmer. The broad usefulness of our delivery strategy of ASOs to the liver has been demonstrated.

DOI： 10.1080/15257770.2019.1677911

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Recently, mRNAs and microRNAs (miRNAs) have been identified in exosomes, which can be taken up by neighboring or distant cells. These exosomal-miRNAs may regulate gene expression in recipient cells. miRNAs are a type of non-coding RNA that induce post-transcriptional gene silencing of their target genes and regulate a wide range of biological processes, including apoptosis, differentiation, metabolism, and cell proliferation. According to recent reports, aberrant expression of miRNAs is associated with most pathological disease processes, including carcinogenesis. Therefore circulating onco-miRs are considered as significant therapeutic targets for cancer therapy. However, there is no report to regulate the function of miRNAs in exosomes. In this study, we developed novel drug delivery system using anti-exosome antibody-oligonucleotide conjugates (ExomiR-Tracker) for functional inhibition of circulating miRNAs. The "ExomiR-Tracker" is the world's first innovative molecule that has targeting property for exosome-recipient cells and specifically delivers nucleic acid medicines to the target cells. We found that ExomiR-Tracker can bind to the surface of exosomes and that the complexes are introduced into exosome-recipient cells then inhibit the activity of miRNA. We showed that ExomiR-Tracker can accumulate in cancerous tumors after intravenous administration. Existing technologies have difficulties for introducing anti-miR into exosomes and extremely low possibility to deliver anti-miR to exosome-recipient cells after intravenous administration. However, we successfully developed useful inhibition technology against exosomal-miRNA.

DOI： 10.1248/yakushi.19-00218-3

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Point mutations are well characterized activators of oncogenes but are often indistinguishable using common gene technologies. In general, the precise sites of point-mutated oncogenes are difficult to distinguish under physiological conditions primarily because single nucleotide mismatch do not affect the annealing temperatures of DNA probes sufficiently. To address this limitation, we developed photo-responsive oligodeoxyribonucleotides containing 2'-O-[N-(4,5',8-trimethylpsoralen-4'-ylmethylcarbamoyl)]adenosine (Ps-amd-Oligo), which can be used to selectively manipulate and identify genes with point mutations. Here we present time course analyses of the photo-cross-linking efficiency of Ps-amd-Oligo with DNA and RNA and show promising selectivity for the oncogene H-ras.

DOI： 10.1080/15257770.2019.1677912

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Ligand-targeted drug delivery (LTDD) has emerged as an attractive option in the field of oligonucleotide drugs following the great success of N-acetylgalactosamine (GalNAc)-conjugated siRNA and antisense oligonucleotides. GalNAc is a well-known ligand of the asialoglycoprotein receptor (ASGPR), and is classified as a C-type lectin associated with the metabolism of desialylated glycoproteins. This article describes the synthesis of a non-nucleosidic monovalent GalNAc phosphoramidite-a useful reagent for facilitating the conjugation of GalNAc epitopes into oligonucleotides using DNA synthesizers-together with some important caveats. The monomeric GalNAc consists of three parts: (1) a GalNAc moiety, (2) a linker moiety, and (3) a trans-4-hydroxyprolinol (tHP) branch point. The GalNAc moiety and the tHP moiety are coupled via a condensation reaction to prepare the monovalent GalNAc phosphoramidite. © 2019 by John Wiley & Sons, Inc. Basic Protocol 1: Synthesis of N-acetylgalactosamine ligand Basic Protocol 2: Preparation of trans-4-hydroxyprolinol building block Basic Protocol 3: Preparation of GalNAc phosphoramidite.

DOI： 10.1002/cpnc.99

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DOI： 10.1248/cpb.c19-00126

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DOI： 10.1016/j.tetlet.2018.08.064

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DOI： 10.1246/cl.171186

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DOI： 10.1089/nat.2017.0663

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DOI： 10.1021/acs.jpcb.7b01926

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DOI： 10.1246/cl.160895

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Chemical Society of Japan  

DOI： 10.1246/cl.170298

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DOI： 10.1111/php.12232

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DOI： 10.1016/j.bmc.2013.12.044

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DOI： 10.1002/0471142700.nc0515s58

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DOI： 10.1016/j.bmcl.2013.08.100

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DOI： 10.1246/cl.2012.1684

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DOI： 10.2174/157341311798220600

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Other Link： http://orcid.org/0000-0002-7495-2974

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DOI： 10.1246/cl.2011.1247

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DOI： 10.1089/oli.2010.0277

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Recently, various microRNAs (miRNAs) and endogenous small interfering RNAs (siRNAs) have been identified and play important roles in gene regulatory networks. However it is a little known about their biological functions. These small RNAs exhibit their function to form a ribonucleoprotein complex, the RISC (RNA-induced silencing complex), which modulates gene expression by translational repression. In this study, we developed a novel peptide antagonist to inhibit the RISC function. The peptide was conjugated to 2'-O-methyl oligoribonucleotides, which have a complementary sequence to the guide strand of siRNA, and regulatory effects of the peptide on RISC activity were examined. It was revealed that the peptide drastically enhanced inhibitory effects of the oligonucleotide on RISC activity. Here we demonstrate our peptide-oligonucleotide conjugate that can provide a powerful and specific way to regulate the small RNA function.

DOI： 10.1093/nass/nrp027

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Language：English   Publishing type：Research paper (international conference proceedings)  

In our previous study, we reported that bispyrene-modified RNA probes (OMUpy2) were useful for RNA detection in homogeneous physiological media(1-2). The aim of this study is to establish in situ monitoring system to detect mRNAs in living cells by OMUpy2. We chose c-fos mRNA as a target RNA which is known as one of the immediate-early genes. The real-time moni- toring of mRNAs was carried out in living C4II cells. After transfection of OMUpy2 into the cells which had been incubated with serum-free medium, cells were stimulated by media with serum and the resulting expression of mRNA was monitored by a fluorescence microscope. In the case of OMUpy2-CF3S, which was complementary to c-fos mRNA, fluorescence emission around 480 nm was observed obviously. These results suggest that mRNA expressed by the serum stimulation was successfully visualized in a real-time manner.

DOI： 10.1093/nass/nrp077

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Language：English   Publishing type：Research paper (international conference proceedings)  

Nucleic acid-based drugs, such as antisense oligonucleotide, ribozyme, and small interfering RNA, are specific compounds that inhibit gene expression at the post-transcriptional level. To develop more effective nucleic acid-based drugs, we focused on photo-reactive antisense oligonucleotides. We have optimized the structure of psoralen-conjugated oligonucleotide to improve their sequence selectivity and photo-crosslinking efficiency. Previously, we reported that photo reactive oligonucleotides containing 2'-O-psoralenyl-methoxyethyl adenosine (2'-Ps-eom) showed drastic photo-reactivity with a strictly sequence specific manner in vitro. In this report, we evaluated the binding ability toward intracellular target mRNA. The 2'-Ps-eom selectively photo-cross-linked to the target mRNA extracted from cells. The 2'-Ps-eom also cross-linked to target mRNA in cells. Furthermore, 2'-Ps-eom did not cross-link to mRNA having a mismatch base. These results suggest that 2'-Ps-eom is a powerful antisense molecule to inhibit the expression of mRNA having a point mutation.

DOI： 10.1093/nass/nrn261

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Language：English   Publishing type：Research paper (international conference proceedings)  

We developed a mutation diagnosis system using a 1,N'-ethenoadenosine forming reaction. Furan-derivatized oligodeoxyribonucleotides were synthesized and fluorescence properties were studied in the presence of complimentary strand under oxidative conditions. Strong emission at 430 nm was observed in the presence of A allele ODN.

DOI： 10.1093/nass/nrn119

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.jconrel.2007.04.018

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DOI： 10.1093/humrep/del514

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DOI： 10.1016/j.ygyno.2006.12.030

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DOI： 10.1021/nl0626232

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Language：English   Publishing type：Research paper (international conference proceedings)  

DOI： 10.1002/masy.200750352

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DOI： 10.1080/15257770701521508

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Language：English   Publishing type：Research paper (international conference proceedings)  

We have developed diaminonaphthyridine-conjugated DNA probes (DANP-ODNs), which contain diaminonaphtyridine (DANP) derivatives at 5' end of oligodeoxynucleotides. We here report the synthesis and fluorescence properties of aeDNAP-ODN, ahDANP-ODN, and baeDANP-ODN which contains N-amino ethyl-2,7-diamino-1,8-naphtyridine, N-aminohexyl-2,7-diamino1,8-naphthyridine, and N,N'-bisaminoethyl-2,7-diamino-1,8-naphtyridine, respectively. The emission spectra of DANP-ODNs were measured in the presence of their complementary strand having single nucleotide alteration. The fluorescence intensity at 420 nm of baeDANP-ODN is 12-fold higher in the presence of Callele ODN than that in the presence of A-allele ODN.

DOI： 10.1093/nass/nrm155

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Language：English   Publishing type：Research paper (international conference proceedings)  

It has been reported that point mutations in genes are responsible for various cancers and the selective regulation of the gene expression is an important issue to develop new types of anticancer drugs. In this report, we report new types of antisense molecules that photo-cross-link to target mRNA having a point mutation site in a sequence specific manner. We designed and synthesized photo-reactive antisense oligonucleotides containing a 2'-O-psoralen-conjugated adenosine (2'-Ps-oligo). They contain a psoralen via an ethoxymethylene linker (2'-Ps-eom), a propoxymethylene linker (2'-Ps-pom) and a buthoxymethylene linker (2'-Ps-bom), respectively. We evaluated the photo-cross-linking efficiency and the sequence specificity toward complementary RNA. 2'-Ps-eom showed the highest photo-cross-linking efficiency among 2'-Ps-oligos.

DOI： 10.1093/nass/nrm222

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Language：English   Publishing type：Research paper (international conference proceedings)  

We have developed a photo-cross-linked oligonucleotide (clip-ODN) for a novel type of gene regulator molecule. Here, we examined the ability of the clip-ODN as a decoy DNA on regulation of the transcriptional activity of estrogen receptor (ER). A photo-cross-linking reagent, 4,5',8-[4'-(aminoethyl-amino) methyl]-trimethylpsoralen (aeAMT) was conjugated with an ODN at the 5'-end, and the aeAMT was cross-linked with the thymine residue of the complementary oligonucleotide upon UVA irradiation (365nm). The clip-ODN drastically inhibited the proliferation of breast cancer cell line (MCF-7) than non-cliped one in a sequence specific manner. This finding revealed that photo-cross-linking of double stranded ODN improve the regulatory ability as a decoy DNA, and clip-ODN may be a valuable tool in gene therapy protocols for inhibiting breast cancer cells' proliferation.

DOI： 10.1093/nass/nrm046

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Language：English   Publishing type：Research paper (international conference proceedings)  

DOI： 10.1002/masy.200750351

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DOI： 10.1080/15257770701257434

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DOI： 10.1089/oli.2006.0047

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DOI： 10.1016/j.stam.2006.05.010

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Other Link： http://orcid.org/0000-0002-7495-2974

Publishing type：Research paper (international conference proceedings)  

DOI： 10.1093/nass/nrl014

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Other Link： http://orcid.org/0000-0002-7495-2974

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Other Link： http://orcid.org/0000-0002-7495-2974

Publishing type：Research paper (international conference proceedings)  

DOI： 10.1093/nass/nrl162

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Other Link： http://orcid.org/0000-0002-7495-2974

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Other Link： http://orcid.org/0000-0002-7495-2974

Publishing type：Research paper (international conference proceedings)  

DOI： 10.1093/nass/49.1.223

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Publishing type：Research paper (scientific journal)  

DOI： 10.1093/nass/49.1.331

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Other Link： http://orcid.org/0000-0002-7495-2974

Publishing type：Research paper (international conference proceedings)  

DOI： 10.1093/nass/49.1.53

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Language：Japanese   Publisher：The Biophysical Society of Japan General Incorporated Association  

DOI： 10.2142/biophys.43.S222_4

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DOI： 10.1039/b302291a

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DOI： 10.1093/nass/42.1.223

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

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Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：高分子刊行会  

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Language：Japanese   Publisher：日本産科婦人科学会  

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Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：金原出版  

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Other Link： http://search.jamas.or.jp/link/ui/2005253089

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Applicant：アークレイ株式会社, 国立大学法人京都工芸繊維大学

Application no：JP2016051925  Date applied：2016.1

Announcement no：WO2016-117700  Date announced：2016.7

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Applicant：丸山 厚, 旭化成株式会社

Application no：特願2006-238752  Date applied：2006.9

Announcement no：特開2008-054642  Date announced：2008.3

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Applicant：丸山 厚, 旭化成株式会社

Application no：特願2006-238752  Date applied：2006.9

Announcement no：特開2008-054642  Date announced：2008.3

Patent/Registration no：特許第5180453号  Date issued：2013.1

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Applicant：株式会社産学連携機構九州

Application no：特願2002-148521  Date applied：2002.5

Announcement no：特開2003-339376  Date announced：2003.12

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Application no：特願2015-10639 

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Application no：特願2016-011018 

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