MEDCHEM NEWS
Online ISSN : 2432-8626
Print ISSN : 2432-8618
ISSN-L : 2432-8618
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Volume 31, Issue 4
Displaying 1-18 of 18 articles from this issue
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  • Drug Discovery Research at Nippon Shinyaku Co., Ltd. -The Pursuit of Originality-
    Kazuchika Takagaki, Keiichi Kuwano
    2021 Volume 31 Issue 4 Pages 163-168
    Published: 2021
    Released on J-STAGE: November 17, 2021
    DOIhttps://doi.org/10.14894/medchem.31.4_163
    JOURNAL FREE ACCESS
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    Nippon Shinyaku Co., Ltd., is an R&D-oriented new-drug manufacturer that celebrated its 100th anniversary in 2019. In recent years, we have had two major R&D products: selexipag, our first global new drug, and viltolarsen, the first antisense nucleic acid drug developed in Japan. This paper describes three aspects of our approach to drug-discovery research: modality in drug discovery, data-driven drug discovery and the promotion of open innovation. Our unique system of driving exploratory research through venture-based organizational management is also described. Under the slogan “creating world-class new drugs” and with the goal of creating original and distinctive pharmaceuticals that will be of great value to patients, we have begun to take on the challenge of the next 100 years.
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  • New modalities that control human diseases at the RNA level
    Takao Inoue
    2021 Volume 31 Issue 4 Pages 174-179
    Published: 2021
    Released on J-STAGE: November 17, 2021
    DOIhttps://doi.org/10.14894/medchem.31.4_174
    JOURNAL FREE ACCESS
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    In recent years, the clinical development of oligonucleotide therapeutics, such antisense oligonucleotides and siRNAs, have been progressing rapidly, and they are attracting attention as new modalities for genetic diseases and intractable diseases for which there have been few therapeutic options. In addition, the development of the COVID-19 vaccine has brought the medical application of mRNA into the limelight, and it is being recognized as a next-generation modality. These therapeutics have in common that they control human diseases at the level of RNA, and the fact that they generally have high medicinal efficacy has made them an area of high interest. In this paper, we will review the overall picture of these modalities and summarize the development trends and characteristics of them.
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  • Recent Progress and Future Prospects of Antisense Oligonucleotide Therapeutics
    Satoshi Obika
    2021 Volume 31 Issue 4 Pages 180-185
    Published: 2021
    Released on J-STAGE: November 17, 2021
    DOIhttps://doi.org/10.14894/medchem.31.4_180
    JOURNAL FREE ACCESS
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    A single-stranded oligonucleotide with a complimentary sequence to the mRNA or pre-mRNA of a disease-causing gene is called an antisense oligonucleotide. It can form a stable duplex structure with the target RNA in the cell, thereby inhibiting the translation step from mRNA to protein or controlling the splicing process from pre-mRNA to mRNA. However, in order to maximize the effect of antisense oligonucleotides, the use of appropriate artificial nucleic acids and chemical modification techniques is essential. Here, I will outline the current status of research and development of antisense oligonucleotides, introducing examples of bridged nucleic acids that we are studying and chemical modifications that have been used in the approved oligonucleotide therapeutics. I will also discuss the importance of medicinal chemistry and future prospects for the development of antisense oligonucleotides.
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  • siRNA Drug: Development of method avoiding off-target effect
    Yoshiaki Kobayashi, Kumiko Ui-Tei
    2021 Volume 31 Issue 4 Pages 186-189
    Published: 2021
    Released on J-STAGE: November 17, 2021
    DOIhttps://doi.org/10.14894/medchem.31.4_186
    JOURNAL FREE ACCESS
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    siRNA is a promising modality in the nucleic acid therapeutics whose development is strongly promoted currently. After first siRNA drug was approved by FDA in 2018, siRNA drugs were launched one after another. siRNA is 21-nucleotide long double-stranded RNA and recognizes the target mRNA with perfect sequence complementarity, resulting in the repression of the expression of target gene. On the other hand, siRNA also induces off-target effect, repressing unintended mRNAs with complementary sequences mainly with siRNA seed region. Since off-target effect often induces serious side effects, it is important to avoid such effect for therapeutic application of siRNA. In this review, we summarize our methods avoiding off-target effects based on the functional machinery of siRNA.
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  • RNA editing oligonucleotide: A new nucleic acid medicine based on A-to-I RNA editing
    Masatora Fukuda
    2021 Volume 31 Issue 4 Pages 190-193
    Published: 2021
    Released on J-STAGE: November 17, 2021
    DOIhttps://doi.org/10.14894/medchem.31.4_190
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    In recent years, an A-to-I RNA editing technology that converts the target adenosine （A） in RNA with inosine （I） has been developed and started to apply for the treatment of human diseases as a new gene regulation technology. RNA editing enzymes are endogenously expressed, and A-to-I RNA editing is constantly occured in the human body. In addition, inosine generated on mRNA is recognized as guanosine （G） during protein translation, so A-to-I RNA editing can modify genetic information at the RNA level. RNA editing oligonucleotide are functional nucleic acids that enable targeted A-to-I RNA editing by utilizing the activity of RNA editing enzymes, and are attracting attention as a new modality different from conventional nucleic acid drugs. This paper describes the outline of RNA editing technology and RNA editing oligonucleotide including its prospects of RNA editing nucleic acid medicine.
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  • mRNA technology: mRNAs that accelerate a turn-over of the translation reaction cycle
    Naoko Abe, Hiroshi Abe
    2021 Volume 31 Issue 4 Pages 194-199
    Published: 2021
    Released on J-STAGE: November 17, 2021
    DOIhttps://doi.org/10.14894/medchem.31.4_194
    JOURNAL FREE ACCESS
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    Currently, mRNA is used for vaccine therapy against COVID-19. However, the mRNA vaccine is urgently approved under a pandemic, there are still issues to be solved in terms of delivery method, quality/ purity, stability/ effect sustainability, protein synthesis efficiency, and so on. Research and development of mRNA drugs have been mainly focused on the development of delivery methods, and only biological methods are used for mRNA production. It is important to develop molecular design methods and synthetic methods hereafter. We focus on the translation mechanism of mRNA and propose a molecular design that can promote the translation by accelerate its rate-determining step. Based on experimental data, we will explain here the strategy for the molecule design that can improve the translation efficiency and stability of mRNA.
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  • Novel siRNA production method by combination of liquid-phase method AJIPHASE® and Enzymatic approach
    Daisuke Takahashi
    2021 Volume 31 Issue 4 Pages 200-205
    Published: 2021
    Released on J-STAGE: November 17, 2021
    DOIhttps://doi.org/10.14894/medchem.31.4_200
    JOURNAL FREE ACCESS
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    Oligonucleotide drug discovery is attracting attention worldwide as a new modality. The number of oligo pipeline on the market is increasing. Under such circumstances, various oligonucleotides have been developed to solve the challenge of the drug discovery, such as delivery, stability and toxicity. The demand of oligonucleotide is growing and the practical manufacturing method for large volume is strongly required in the world. In particular, the double-stranded siRNA, which requires “double large volume” compared to single-stranded antisense oligonucleotides. We have newly established a solution for large scale manufacturing by combination with AJIPHASE® synthetic method and an enzymatic approach to synthesize siRNA very efficiently and with high purity.
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