MEDCHEM NEWS
Online ISSN : 2432-8626
Print ISSN : 2432-8618
ISSN-L : 2432-8618
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Volume 32, Issue 3
Displaying 1-18 of 18 articles from this issue
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  • Construction of the platform to explore drug target for IPF in Public/Private R&D Investment Strategic Expansion PrograM（PRISM）
    Yoshinori Nakamura, Hideya Kitamura, Takashi Ogura, Yayoi Natsume-Kita ...
    2022 Volume 32 Issue 3 Pages 119-123
    Published: August 01, 2022
    Released on J-STAGE: August 01, 2022
    DOIhttps://doi.org/10.14894/medchem.32.3_119
    JOURNAL FREE ACCESS
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    National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN) and Kanagawa Cardiovascular and Respiratory Center have built an integrated multi-omics database that constitutes the world’s largest medical information repository for Idiopathic pulmonary fibrosis (Kanagawa Cohort Database) in Public/Private R&D Investment Strategic Expansion PrograM (PRISM). NIBIOHN have also developed AI for the data-driven exploration of drug targets by stratifying patients based on clinical and omics data (comprehensive biomolecular information). In addition to AI to explore drug targets, organizations participating in PRISM have also developed tools for the analysis of clinical text, automatic knowledge extraction, and automatic inference system. NIBOHN plan to launch an open platform to allow researchers both in industry and academia to widely use these systems in FY2022.
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WINDOW
  • Fragment-based Drug Discovery at Astex Pharmaceuticals
    Tatsuya Urushima, Tsuyoshi Nagase, Toshiki Sudo
    2022 Volume 32 Issue 3 Pages 124-129
    Published: August 01, 2022
    Released on J-STAGE: August 01, 2022
    DOIhttps://doi.org/10.14894/medchem.32.3_124
    JOURNAL FREE ACCESS
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    Founded in 1999 in Cambridge, UK, as a biotech venture, Astex has long been a leader in fragment-based drug discovery (FBDD), which has now become mainstream of drug discovery. A number of collaborations with academia and big pharma have resulted in a series of new drugs being launched and progressing in clinical trials in recent years, developing the presence of FBDD and Astex. Since its acquisition by Otsuka Pharmaceutical in 2013, the company has maintained its culture and expanded the scope of its disease areas and FBDD technology. This section introduces Cambridge, where Astex is located, Astex itself and FBDD.
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ESSAY
  • Disease Control Targeting Liquid-Liquid Phase Separation
    Kentaro Shiraki
    2022 Volume 32 Issue 3 Pages 130-131
    Published: August 01, 2022
    Released on J-STAGE: August 01, 2022
    DOIhttps://doi.org/10.14894/medchem.32.3_130
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    Proteins tend to form aggregates in aqueous solution. This assembled state of proteins is a so-called liquid-liquid phase-separation (LLPS), which contains water molecules and exhibits fluidity. In living cells, all of the biomolecules often form LLPS, which is associated with diverse biological phenomena such as gene transcription, translation, and signal transduction. This issue features disease control targeting LLPS.
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  • Understanding of protein solution and controlling of the formation of aggregates
    Kentaro Shiraki
    2022 Volume 32 Issue 3 Pages 132-135
    Published: August 01, 2022
    Released on J-STAGE: August 01, 2022
    DOIhttps://doi.org/10.14894/medchem.32.3_132
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    Proteins tend to form aggregates in aqueous solution. We have been developing methods to control the formation of reversible and irreversible aggregates of proteins. In this essay, we introduce four applications of the controlling method of proteins to biopharmaceuticals. We will outline (i) the opalescence created by solutions of highly concentrated antibodies, (ii) the formation of glass-like concentrates as an alternative to lyophilization, (iii) the concentration and stabilization of antibodies by the formation of polyelectrolyte and protein droplets, and (iv) phase-separating peptide tags as an application of isoelectric precipitation.
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  • Targeting intrinsically disordered proteins as drug targets: perspective and problems
    Hidekazu Hiroaki
    2022 Volume 32 Issue 3 Pages 136-139
    Published: August 01, 2022
    Released on J-STAGE: August 01, 2022
    DOIhttps://doi.org/10.14894/medchem.32.3_136
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    Intrinsically disordered protein (IDP) is a polypeptide that does not adopt a compact fold under a physiological condition. It tends to be appeared at the hub position in the intracellular protein-protein network, thereby considered as an attractive drug target. Recently, many examples of IDPs’ implication in liquid-liquid phase separation (LLPS) have also emerged. Nevertheless, targeting IDP sounds still difficult, because the lack of highly accurate three-dimensional structure of IDP may hamper application of many modern structure-guided drug design and discovery techniques. Only the solution NMR based strategy, but not either the X-ray crystallography or cryo-electron microscopy, is available to solve the structure of IDP for further virtual screening.
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  • Designer phase-separated droplets that sequester and release protein activity
    Shinya Tsukiji, Masaru Yoshikawa
    2022 Volume 32 Issue 3 Pages 140-144
    Published: August 01, 2022
    Released on J-STAGE: August 01, 2022
    DOIhttps://doi.org/10.14894/medchem.32.3_140
    JOURNAL FREE ACCESS
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    Rapid control of protein activity in living cells with chemogenetics and optogenetics is a valuable tool for drug development and biomedical applications such as cell-based therapies. However, most of current strategies require extensive trial and error to generate engineered proteins whose activity can be switched on or off effectively by small molecules or light. We introduce a conceptually new approach to control protein activity using designer phase-separated droplets. This method uses synthetic self-assembling protein-based designer phase-separated droplets that are programmed to sequester and/or release target proteins in response to a small molecule or light. Because enforced sequestration of proteins into designer droplets is expected to offer a universal approach to blocking normal protein localization and activity within cells, the designer droplet system should enable rapid, conditional control of various exogenously and endogenously expressed proteins that have been difficult to regulate by existing techniques.
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  • Disrupting phase modifiers and targeting phase disruptors
    Eiichiro Mori, Takuya Yoshizawa, Tomohide Saio
    2022 Volume 32 Issue 3 Pages 145-148
    Published: August 01, 2022
    Released on J-STAGE: August 01, 2022
    DOIhttps://doi.org/10.14894/medchem.32.3_145
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    In 2010s, researchers realized that biomolecules, such as proteins and nucleic acids (DNA/RNA), associate to form liquid-like droplets, and called this as biological phase separation. Genetic studies of neurodegeneration provided information that RNA binding proteins with intrinsically disordered regions are prone to self-associate to drive phase separation, and studies about phase separation with disease-related mutations led us better understanding of pathophysiology of these diseases. These proteins are driven and regulated to phase separate, and if dysregulated, result in aggregation. Further, molecular chaperones and post-translational modifications serve as modifiers of biological phase separation. The release of AlphaFold2 in 2021 enables life scientists to predict three-dimensional protein structures with high accuracy, and this was a real game changer. We discuss how the future drug discoveries will be like in 2020s.
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  • Intracellular macromolecule-delivery peptide inducing liquid-liquid phase separation
    Shiroh Futaki, Hisaaki Hirose
    2022 Volume 32 Issue 3 Pages 149-153
    Published: August 01, 2022
    Released on J-STAGE: August 01, 2022
    DOIhttps://doi.org/10.14894/medchem.32.3_149
    JOURNAL FREE ACCESS
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    Our research group developed the L17E peptide, which is a modified peptide of spider venom, M-lycotoxin, for intracellular delivery of proteins including antibodies. The liquid-liquid phase separation was induced by mixing the conjugate of the trimer of L17E with a Fc-binding peptide ［FcB(L17E)3］ with a fluorescently labeled antibody. When the generated liquid droplets contacted the cell membrane, a marked influx of antibody signals into cells was observed.
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DISCOVERY
  • Discovery of Apararenone (MT-3995) as a Novel Nonsteroidal Mineralocorticoid Receptor Antagonist
    Toru Iijima, Hidenori Akatsuka, Kei Takedomi
    2022 Volume 32 Issue 3 Pages 154-159
    Published: August 01, 2022
    Released on J-STAGE: August 01, 2022
    DOIhttps://doi.org/10.14894/medchem.32.3_154
    JOURNAL FREE ACCESS
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    Overactivation of the mineralocorticoid receptor (MR) is involved in many diseases, such as hypertension, heart failure, and kidney disease. Thus, MR antagonists are expected to be beneficial to patients with these diseases. Steroidal MR antagonists are already marketed and exhibit clinical efficacy. However, they suffer from substantial drawbacks that limit their clinical use. To overcome these issues, we searched for selective and potent nonsteroidal MR antagonists. Based on the structural features of intrinsic ligands and the mechanism of steroid hormone receptor activation, we hypothesized that T-shaped compounds with a hydrophobic core structure, two polar functional groups at both extremities able to interact with MR, and a protruding bulky substituent that can interfere with the folding of the C-terminal helix 12 may exhibit antagonist activity toward MR. As a result of the search guided by the hypothesis, we discovered apararenone (MT-3995), as a highly selective, potent, and novel nonsteroidal MR antagonist.
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Coffee Break
REPORT
  • LINK-J’s initiative to create innovation ecosystem in life science fields in Japan
    Akihiko Soyama
    2022 Volume 32 Issue 3 Pages 162-166
    Published: August 01, 2022
    Released on J-STAGE: August 01, 2022
    DOIhttps://doi.org/10.14894/medchem.32.3_162
    JOURNAL FREE ACCESS
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    LINK-J has been creating an innovation ecosystem in the field of life science through “exchange and collaboration” events and “incubation and acceleration” programs. In a wide range of life science fields, ranging from drug discovery, medical devices, regenerative medicine, digital health, to prevention and healthy longevity, it has been connecting and networking business organizations such as startups, SMEs and corporates, government organizations, academia and individuals covering from research to commercialization. Based in Nihonbashi, Tokyo, the drug discovery town since the Edo period (about 250 years ago), LINK-J has various facilities such as conference rooms, co-working spaces, a shared wet lab for startups, and exclusive lounges for members. It has held 524 events and programs in 2021 with its 573 members (as of April 2022). LINK-J also collaborates with various academia and industry bodies both in Japan and overseas and its network will continue to expand for open innovation in the life science field.
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