研究者詳細 - 阿部　洋

論文 - 阿部　洋

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翻訳反応を最大化するための合成 mRNA の分子設計査読有り

稲垣雅仁, 多田瑞紀, 阿部洋

37 巻 ( 3 ) 頁： 196 - 208 2022年7月

Complete Chemical Synthesis of Minimal Messenger RNA by Efficient Chemical Capping Reaction 査読有り国際誌

Abe, N; Imaeda, A; Inagaki, M; Li, ZM; Kawaguchi, D; Onda, K; Nakashima, Y; Uchida, S; Hashiya, F; Kimura, Y; Abe, H

ACS CHEMICAL BIOLOGY 17 巻 ( 6 ) 頁： 1308 - 1314 2022年5月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ACS Chemical Biology

Site-specific chemical modification of mRNA can improve its translational efficiency and stability. For this purpose, it is desirable to develop a complete chemical synthesis method for chemically modified mRNA. The key is a chemical reaction that introduces a cap structure into the chemically synthesized RNA. In this study, we developed a fast and quantitative chemical capping reaction between 5′-phosphorylated RNA and N7-methylated GDP imidazolide in the presence of 1-methylimidazole in the organic solvent dimethyl sulfoxide. It enabled quantitative preparation of capping RNA within 3 h. We prepared chemically modified 107-nucleotide mRNAs, including N6-methyladenosine, insertion of non-nucleotide linkers, and 2′-O-methylated nucleotides at the 5′ end and evaluated their effects on translational activity in cultured HeLa cells. The results showed that mRNAs with non-nucleotide linkers in the untranslated regions were sufficiently tolerant to translation and that mRNAs with the Cap_2 structure had higher translational activity than those with the Cap_0 structure.

DOI： 10.1021/acschembio.1c00996

Development of Fluorophosphoramidate as a Biocompatibly Transformable Functional Group and its Application as a Phosphate Prodrug for Nucleoside Analogs 査読有り国際誌

Yoshida Yuki, Zheng Ti, Tanabe Wataru, Tomoike Fumiaki, Hashiya Fumitaka, Suzuki Tetsuro, Hirota Shuto, Saiki Yuriko, Horii Akira, Hirayama Akiyoshi, Soga Tomoyosi, Kimura Yasuaki, Abe Hiroshi

CHEMMEDCHEM 17 巻 ( 17 ) 頁： e202200188 2022年4月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ChemMedChem

Synthetic phosphate-derived functional groups are important for controlling the function of bioactive molecules in vivo. Herein we describe the development of a new type of biocompatible phosphate analog, a fluorophosphoramidate (FPA) functional group that has characteristic P−F and P−N bonds. We found that FPA with a primary amino group was relatively unstable in aqueous solution and was converted to a monophosphate, while FPA with a secondary amino group was stable. Furthermore, by improving the molecular design of FPA, we developed a reaction in which a secondary amino group is converted to a primary amino group in the intracellular environment and clarified that the FPA group functions as a phosphate prodrug of nucleoside. Various FPA-gemcitabine derivatives were synthesized and their toxicity to cancer cells were evaluated. One of the FPA-gemcitabine derivatives showed superior toxicity compared with gemcitabine and its ProTide prodrug, which methodology is widely used in various nucleoside analogs, including anti-cancer and anti-virus drugs.

DOI： 10.1002/cmdc.202200188

Ligandability Assessment of Human Glutathione Transferase M1-1 Using Pesticides as Chemical Probes 査読有り国際誌

Bodourian Charoutioun S., Poudel Nirmal, Papageorgiou Anastassios C., Antoniadi Mariana, Georgakis Nikolaos D., Abe Hiroshi, Labrou Nikolaos E.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 23 巻 ( 7 ) 2022年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：International Journal of Molecular Sciences

Glutathione transferases (GSTs; EC 2.5.1.18) form a group of multifunctional enzymes that are involved in phase II of the cellular detoxification mechanism and are associated with increased susceptibility to cancer development and resistance to anticancer drugs. The present study aims to evaluate the ligandability of the human GSTM1-1 isoenzyme (hGSTM1-1) using a broad range of struc-turally diverse pesticides as probes. The results revealed that hGSTM1-1, compared to other classes of GSTs, displays limited ligandability and ligand-binding promiscuity, as revealed by kinetic inhibition studies. Among all tested pesticides, the carbamate insecticide pirimicarb was identified as the strong-est inhibitor towards hGSTM1-1. Kinetic inhibition analysis showed that pirimicarb behaved as a mixed-type inhibitor toward glutathione (GSH) and 1-chloro-2,4-dinitrobenzene (CDNB). To shine a light on the restricted hGSTM1-1 ligand-binding promiscuity, the ligand-free crystal structure of hGSTM1-1 was determined by X-ray crystallography at 1.59 Å-resolution. Comparative analysis of ligand-free structure with the available ligand-bound structures allowed for the study of the enzyme’s plasticity and the induced-fit mechanism operated by hGSTM1-1. The results revealed important structural features of the H-site that contribute to xenobiotic-ligand binding and specificity. It was concluded that hGSTM1-1 interacts preferentially with one-ring aromatic compounds that bind at a discrete site which partially overlaps with the xenobiotic substrate binding site (H-site). The results of the study form a basis for the rational design of new drugs targeting hGSTM1-1.

DOI： 10.3390/ijms23073606

Design of Synthetic mRNAs for Highly Ef ficient Translation 招待有り査読有り Open Access

Inagaki M., Tada M., Abe H.

Drug Delivery System 37 巻 ( 3 ) 頁： 196 - 208 2022年

担当区分：最終著者,　責任著者記述言語：日本語掲載種別：研究論文（研究会，シンポジウム資料等）出版者・発行元：Drug Delivery System

Recently messenger RNA （mRNA）therapeutics is received much attention as one of the vaccination therapies to compete against the coronavirus disease 2019（COVID-19）pandemic. DDS mRNA therapeutics are generally produced by in vitro transcription utilizing RNA polymerase mediated elongation. However, its purity, stability, and protein synthesis ability, are difficult to be precisely controlled, which is pointed out as drawbacks that must be overcome. To overcome these issues, the introduction of chemically modified nucleic acids is focusing attention. However, it is difficult to flexible molecular design due to the requirement of RNA polymerase recognition ability of chemically modified nucleic acids under in vitro transcription reaction. In the future, the development of a new mRNA design concept based on a flexible molecular design by the progress of chemically modified mRNA therapeutics synthesis method. Under the situation, the authors are focusing on the translation mechanism of mRNA and proposing a new mRNA molecular design to accelerate the translation reaction cycle. In this paper, we introduce an update on therapeutic mRNA design.

DOI： 10.2745/dds.37.196

Open Access

Scopus

Completely Chemically Synthesized Long DNA Can be Transcribed in Human Cells

Yamaoka Kazuki, Oikawa Ryota, Abe Naoko, Nakamoto Kosuke, Tomoike Fumiaki, Hashiya Fumitaka, Kimura Yasuaki, Abe Hiroshi

CHEMBIOCHEM 22 巻 ( 23 ) 頁： 3273 - 3276 2021年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ChemBioChem

Chemical ligation reaction of DNA is useful for the construction of long functional DNA using oligonucleotide fragments that are prepared by solid phase chemical synthesis. However, the unnatural linkage structure formed by the ligation reaction generally impairs the biological function of the resulting ligated DNA. We achieved the complete chemical synthesis of 78 and 258 bp synthetic DNAs via multiple chemical ligation reactions with phosphorothioate and haloacyl-modified DNA fragments. The latter synthetic DNA, coding shRNA for luciferase genes with a designed truncated SV promoter sequence, successfully induced the expected gene silencing effect in HeLa cells.

DOI： 10.1002/cbic.202100312

Antisense Oligonucleotide Modified with Disulfide Units Induces Efficient Exon Skipping in <i>mdx</i> Myotubes through Enhanced Membrane Permeability and Nucleus Internalization 査読有り

Hiraoka, H; Shu, ZM; Le, BT; Masuda, K; Nakamoto, K; Fangjie, L; Abe, N; Hashiya, F; Kimura, Y; Shimizu, Y; Veedu, RN; Abe, H

CHEMBIOCHEM 22 巻 ( 24 ) 頁： 3437 - 3442 2021年10月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ChemBioChem

We have found that antisense oligonucleotides and siRNA molecules modified with repeat structures of disulfide units can be directly introduced into the cytoplasm and exhibit a suppressive effect on gene expression. In this study, we analyzed the mechanism of cellular uptake of these membrane-permeable oligonucleotides (MPONs). Time-course analysis by confocal microscopy showed that the uptake of MPONs from the plasma membrane to the cytoplasm reached 50 % of the total uptake in about 5 min. In addition, analysis of the plasma membrane proteins to which MPONs bind, identified several proteins, including voltage-dependent anion channel. Next, we analyzed the behavior of MPONs in the cell and found them to be abundant in the nucleus as early as 24 h after addition with the amount increasing further after 48 and 72 h. The amount of MPONs was 2.5-fold higher than that of unmodified oligonucleotides in the nucleus after 72 h. We also designed antisense oligonucleotides and evaluated the effect of MPONs on mRNA exon skipping using DMD model cells; MPONs caused exon skipping with 69 % efficiency after 72 h, which was three times higher than the rate of the control. In summary, the high capacity for intracytoplasmic and nuclear translocation of MPONs is expected to be useful for therapeutic strategies targeting exon skipping.

DOI： 10.1002/cbic.202100413

その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/cbic.202100413

Variety of Nucleotide Polymerase Mutants Aiming to Synthesize Modified RNA 査読有り国際誌

Ohashi, S; Hashiya, F; Abe, H

CHEMBIOCHEM 22 巻 ( 14 ) 頁： 2398 - 2406 2021年4月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ChemBioChem

Significant efforts have been made to develop therapeutic RNA aptamers that exploit synthetic RNA to capture target molecules. However, ensuring RNA aptamers are resistant against intrinsic nucleases remains an issue and restricts their use as therapeutics. Introduction of chemical modifications to the 2′ sugar moiety of RNA improves their stability effectively and can be achieved by chemical synthesis using modified phosphoramidites; however, this approach is not suitable for preparing long RNA molecules. Although recombinant nucleotide polymerases can transcribe RNA, these polymerases cannot synthesize modified RNA because they do not recognize 2′ modified nucleoside triphosphates. In this review, we focus on several polymerase mutants that tolerate substrates containing modifications of the 2′ sugar moiety to synthesize RNA, and the problems that must be overcome to prepare chemically modified RNA with high efficacy by in vitro transcription.

DOI： 10.1002/cbic.202100004

Structure, Synthesis and Inhibition Mechanism of Nucleoside Analogues as HIV-1 Reverse Transcriptase Inhibitors (NRTIs) 査読有り国際誌

Yoshida, Y; Honma, M; Kimura, Y; Abe, H

CHEMMEDCHEM 16 巻 ( 5 ) 頁： 743 - 766 2021年3月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ChemMedChem

Acquired immunodeficiency syndrome (AIDS) is caused by infection with the human immunodeficiency virus (HIV). Although treatments against HIV infection are available, AIDS remains a serious disease that causes many deaths annually. Although a variety of anti-HIV drugs have been synthesized and marketed to treat HIV-infected patients, nucleoside analogue reverse transcriptase inhibitors (NRTIs), which mimic nucleosides, are used extensively and remain a subject of interest to medicinal chemists. However, HIV has acquired drug resistance against NRTIs, and thus the struggle to find novel therapies continues. In this review, we trace the trajectory of NRTIs, focusing on the synthesis, mechanisms of action and applications of NRTIs that have been developed.

DOI： 10.1002/cmdc.202000695

その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/cmdc.202000695

Chemical Synthesis of Circular RNAs with Phosphoramidate Linkages for Rolling-Circle Translation.

Nakamoto K, Abe H

Current protocols 1 巻 ( 3 ) 頁： e43 2021年3月

化学修飾核酸の合成と核酸医薬への応用

野村浩平, 村瀬裕貴, 中本航介, 木村康明, 阿部奈保子, 安成鎮, 小林芳明, 程久美子, 阿部洋

日本薬学会年会要旨集 141年会巻頁： 27V05 - pm02S 2021年3月

Phosphorothioate Modification of mRNA Accelerates the Rate of Translation Initiation to Provide More Efficient Protein Synthesis 査読有り

Kawaguchi Daisuke, Kodama Ayumi, Abe Naoko, Takebuchi Kei, Hashiya Fumitaka, Tomoike Fumiaki, Nakamoto Kosuke, Kimura Yasuaki, Shimizu Yoshihiro, Abe Hiroshi

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION 59 巻 ( 40 ) 頁： 17403 - 17407 2020年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Angewandte Chemie - International Edition

Messenger RNAs (mRNAs) with phosphorothioate modification (PS-mRNA) to the phosphate site of A, G, C, and U with all 16 possible combinations were prepared, and the translation reaction was evaluated using an E. coli cell-free translation system. Protein synthesis from PS-mRNA increased in 12 of 15 patterns when compared with that of unmodified mRNA. The protein yield increased 22-fold when the phosphorothioate modification at A/C sites was introduced into the region from the 5′-end to the initiation codon. Single-turnover analysis of PS-mRNA translation showed that phosphorothioate modification increases the number of translating ribosomes, thus suggesting that the rate of translation initiation (rate of ribosome complex formation) is positively affected by the modification. The method provides a new strategy for improving translation by using non-natural mRNA.

DOI： 10.1002/anie.202007111

Free-Energy Calculation of Ribonucleic Inosines and Its Application to Nearest-Neighbor Parameters

Sakuraba Shun, Iwakiri Junichi, Hamada Michiaki, Kameda Tomoshi, Tsuji Genichiro, Kimura Yasuaki, Abe Hiroshi, Asai Kiyoshi

JOURNAL OF CHEMICAL THEORY AND COMPUTATION 16 巻 ( 9 ) 頁： 5923 - 5935 2020年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Chemical Theory and Computation

Can current simulations quantitatively predict the stability of ribonucleic acids (RNAs)? In this research, we apply a free-energy perturbation simulation of RNAs containing inosine, a modified ribonucleic base, to the derivation of RNA nearest-neighbor parameters. A parameter set derived solely from 30 simulations was used to predict the free-energy difference of the RNA duplex with a mean unbiased error of 0.70 kcal/mol, which is a level of accuracy comparable to that obtained with parameters derived from 25 experiments. We further show that the error can be lowered to 0.60 kcal/mol by combining the simulation-derived free-energy differences with experimentally measured differences. This protocol can be used as a versatile method for deriving nearest-neighbor parameters of RNAs with various modified bases.

DOI： 10.1021/acs.jctc.0c00270

Developments in siRNA Modification and Ligand Conjugated Delivery To Enhance RNA Interference Ability 国際誌

Maguregui Ander, Abe Hiroshi

CHEMBIOCHEM 21 巻 ( 13 ) 頁： 1808 - 1815 2020年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ChemBioChem

There is great potential for siRNA in the treatment of diseases through the reduction of damaging protein translation by RNA interference. However, the delivery and cell uptake of siRNA pose a serious problem in its therapeutic application. Methods to overcome this issue include chemical modification of the siRNA duplex to improve pharmacokinetics, stability and efficacy, and conjugation to small ligand molecules to enable membrane penetration, targetability and potency. In this review, the most common modifications of siRNA will be discussed, along with ligand conjugates that are believed to be the most promising in advancing the field of targeted siRNA delivery.

DOI： 10.1002/cbic.202000009

Chemically synthesized circular RNAs with phosphoramidate linkages enable rolling circle translation 査読有り

Nakamoto Kosuke, Abe Naoko, Tsuji Genichiro, Kimura Yasuaki, Tomoike Fumiaki, Shimizu Yoshihiro, Abe Hiroshi

CHEMICAL COMMUNICATIONS 56 巻 ( 46 ) 頁： 6217 - 6220 2020年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Chemical Communications

Circular RNA without a stop codon enables rolling circle translation. To produce circular RNAs, we carried out one-pot chemical synthesis of circular RNA from RNA fragments with the use of an EDC/HOBt-based chemical ligation reaction. The synthesized circular RNAs acted as translation templates, despite the presence of unnatural phosphoramidate linkages.

DOI： 10.1039/d0cc02140g

Quantification of native mRNA dynamics in living neurons using fluorescence correlation spectroscopy and reduction-triggered fluorescent probes 査読有り

Fujita Hirotaka, Oikawa Ryota, Hayakawa Mayu, Tomoike Fumiaki, Kimura Yasuaki, Okuno Hiroyuki, Hatashita Yoshiki, Fiallos Oliveros Carolina, Bito Haruhiko, Ohshima Toshio, Tsuneda Satoshi, Abe Hiroshi, Inoue Takafumi

JOURNAL OF BIOLOGICAL CHEMISTRY 295 巻 ( 23 ) 頁： 7923 - 7940 2020年6月

Disulfide-unit Conjugation Enables Ultrafast Cytosolic Internalization of Antisense DNA and siRNA 査読有り

Nakamoto Kosuke, Shu Zhaoma, Abe Hiroshi

JOURNAL OF SYNTHETIC ORGANIC CHEMISTRY JAPAN 78 巻 ( 5 ) 頁： 456 - 464 2020年5月

Translational control by secondary-structure formation in mRNA in a eukaryotic system 招待有り

Kawaguchi Daisuke, Shimizu Saaya, Abe Naoko, Hashiya Fumitaka, Tomoike Fumiaki, Kimura Yasuaki, Abe Hiroshi

NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS 39 巻 ( 1-3 ) 頁： 195 - 203 2020年2月

SYNTHESIS AND BIOLOGICAL EVALUATION OF NMDI14 DERIVATIVES AS ANTI-MESOTHELIOMA AGENTS 査読有り

Hong Nhung Nguyen, Suzuki Koya, Kimura Yasuaki, Hirokawa Takatsugu, Murakami-Tonami Yuko, Abe Hiroshi

HETEROCYCLES 100 巻 ( 2 ) 頁： 253 - 266 2020年2月

A robust model for quantitative prediction of the silencing efficacy of wild-type and A-to-I edited miRNAs 査読有り

Tian Shen, Terai Goro, Kobayashi Yoshiaki, Kimura Yasuaki, Abe Hiroshi, Asai Kiyoshi, Ui-Tei Kumiko

RNA BIOLOGY 17 巻 ( 2 ) 頁： 264 - 280 2020年2月

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