川下 理日人(カワシタ ノリヒト)

理工学部 エネルギー物質学科准教授

Last Updated :2024/06/18

■教員コメント

コメント

バイオインフォマティクス、計算化学、感染症、蛋白質間相互作用、新規薬剤探索・設計

■研究者基本情報

学位

  • 博士(薬学)(2005年09月 大阪大学)

科研費研究者番号

00423111

プロフィール

  • 2005年~2007年 大阪大学微生物病研究所 タイ感染症共同研究センター バイオインフォマティクス部門 特任助手・特任助教
    2007年~2017年 大阪大学大学院薬学研究科 情報・計量薬学分野 助教
    2008年~2017年 大阪大学微生物病研究所附属遺伝情報実験センター 兼任
    2017年~2022年 近畿大学理工学部生命科学科 講師


    2022年~現在 近畿大学理工学部エネルギー物質学科 准教授

    日本薬学会、日本ウイルス学会、CBI学会、日本バイオインフォマティクス学会、日本人類遺伝学会、日本遺伝性腫瘍学会、日本遺伝子診療学会、日本遺伝カウンセリング学会など加入中
    FMO創薬コンソーシアム 加盟中

研究キーワード

  • 計算化学   蛋白質間相互作用   分子設計   遺伝性疾患   感染症   

現在の研究分野(キーワード)

バイオインフォマティクス、計算化学、感染症、蛋白質間相互作用、新規薬剤探索・設計

研究分野

  • ライフサイエンス / ウイルス学
  • ライフサイエンス / 薬系化学、創薬科学
  • ライフサイエンス / 薬系分析、物理化学

■経歴

経歴

  • 2022年04月 - 現在  近畿大学理工学部 エネルギー物質学科准教授
  • 2017年04月 - 2022年03月  近畿大学理工学部 生命科学科講師
  • 2008年04月 - 2017年03月  大阪大学微生物病研究所助教(兼任)
  • 2007年06月 - 2017年03月  大阪大学大学院薬学研究科助教
  • 2005年11月 - 2007年06月  大阪大学微生物病研究所特任助手、特任助教

■研究活動情報

受賞

  • 2016年10月 日本化学会情報化学部会 JCAC論文賞
  • 2009年 Poster Award at the 32th Symposium on Chemical Information and Computer Science
  • 2009年 第32回情報化学討論会ポスター賞
  • 2004年 第24回有機合成若手セミナー 優秀発表賞
     JPN

論文

  • Hiroko Ueda; Quynh Thuy Huong Tran; Linh Nguyen Truc Tran; Koichiro Higasa; Yoshiki Ikeda; Naoyuki Kondo; Masaki Hashiyada; Chika Sato; Yoshinori Sato; Akira Ashida; Saori Nishio; Yasunori Iwata; Hiroyuki Iida; Daisuke Matsuoka; Yoshihiko Hidaka; Kenji Fukui; Suzu Itami; Norihito Kawashita; Keisuke Sugimoto; Kandai Nozu; Motoshi Hattori; Hiroyasu Tsukaguchi
    Scientific reports 13 1 12003 - 12003 2023年07月 
    Focal segmental glomerulosclerosis (FSGS) is a common glomerular injury leading to end-stage renal disease. Monogenic FSGS is primarily ascribed to decreased podocyte integrity. Variants between residues 184 and 245 of INF2, an actin assembly factor, produce the monogenic FSGS phenotype. Meanwhile, variants between residues 57 and 184 cause a dual-faceted disease involving peripheral neurons and podocytes (Charcot-Marie-Tooth CMT/FSGS). To understand the molecular basis for INF2 disorders, we compared structural and cytoskeletal effects of INF2 variants classified into two subgroups: One (G73D, V108D) causes the CMT/FSGS phenotype, and the other (T161N, N202S) produces monogenic FSGS. Molecular dynamics analysis revealed that all INF2 variants show distinct flexibility compared to the wild-type INF2 and could affect stability of an intramolecular interaction between their N- and C-terminal segments. Immunocytochemistry of cells expressing INF2 variants showed fewer actin stress fibers, and disorganization of cytoplasmic microtubule arrays. Notably, CMT/FSGS variants caused more prominent changes in mitochondrial distribution and fragmentation than FSGS variants and these changes correlated with the severity of cytoskeletal disruption. Our results indicate that CMT/FSGS variants are associated with more severe global cellular defects caused by disrupted cytoskeleton-organelle interactions than are FSGS variants. Further study is needed to clarify tissue-specific pathways and/or cellular functions implicated in FSGS and CMT phenotypes.
  • 片麻痺性片頭痛の原因遺伝子CACNA1A遺伝子のバリアント評価
    小田 いつき; 團野 大介; 西郷 和真; 多田 陽香; 川下 理日人; 北村 重和; 平野 牧人; 寒川 真; 竹島 多賀夫; 永井 義隆
    日本頭痛学会誌 49 2 526 - 526 (一社)日本頭痛学会 2022年11月
  • Kouichi Matsumoto; Yuta Hayashi; Kengo Hamasaki; Mizuki Matsuse; Hiyono Suzuki; Keiji Nishiwaki; Norihito Kawashita
    Beilstein Journal of Organic Chemistry 18 1116 - 1122 2022年08月 
    The electrochemical reduction conditions of the reaction of alkyl 2-chloroacetates in Bu4NBr/DMF using a divided cell equipped with Pt electrodes to produce the corresponding cyclopropane derivatives in moderate yields were discovered. The reaction conditions were optimized, the scope and limitations, as well as scale-up reactions were investigated. The presented method for the electrochemical production of cyclopropane derivatives is an environmentally friendly and easy to perform synthetic procedure.
  • Kenichiro Takaba; Chiduru Watanabe; Atsushi Tokuhisa; Yoshinobu Akinaga; Biao Ma; Ryo Kanada; Mitsugu Araki; Yasushi Okuno; Yusuke Kawashima; Hirotomo Moriwaki; Norihito Kawashita; Teruki Honma; Kaori Fukuzawa; Shigenori Tanaka
    Journal of Computational Chemistry 43 20 1362 - 1371 2022年07月 
    Fragment molecular orbital (FMO) method is a powerful computational tool for structure-based drug design, in which protein-ligand interactions can be described by the inter-fragment interaction energy (IFIE) and its pair interaction energy decomposition analysis (PIEDA). Here, we introduced a dynamically averaged (DA) FMO-based approach in which molecular dynamics simulations were used to generate multiple protein-ligand complex structures for FMO calculations. To assess this approach, we examined the correlation between the experimental binding free energies and DA-IFIEs of six CDK2 inhibitors whose net charges are zero. The correlation between the experimental binding free energies and snapshot IFIEs for X-ray crystal structures was R2  = 0.75. Using the DA-IFIEs, the correlation significantly improved to 0.99. When an additional CDK2 inhibitor with net charge of -1 was added, the DA FMO-based scheme with the dispersion energies still achieved R2  = 0.99, whereas R2 decreased to 0.32 employing all the energy terms of PIEDA.
  • Mie Yoshimura; Kazuo Tamura; Tomoki Yamano; Nagahide Matsubara; Akihito Babaya; Michiko Yasuhara; Aya Yano; Miki Fukumoto; Norihito Kawashita; Junko Tatsumi-Miyajima; Naohiro Tomita
    Int. J. Gastroenterology 6 1 9 - 17 2022年05月 [査読有り]
  • Ituki Oda; Daisuke Danno; Kazumasa Saigoh; Johanna Wolf; Norihito Kawashita; Makito Hirano; Makoto Samukawa; Shigekazu Kitamura; Shoji Kikui; Takao Takeshima; Yoshiyuki Mitsui; Susumu Kusunoki; Yoshitaka Nagai
    Neurosci. Res. 180 83 - 89 2022年03月 [査読有り]
     
    We analyzed the clinical symptoms of hemiplegic migraine (HM) and their relevance in four Japanese patients considered to have ATP1A2 mutations as a cause. Sequencing of ATP1A2 was performed using the Sanger method in 43 blood samples from clinically suspected patients with familial HM. Subsequently, algorithm analysis, allele frequency determination, and three-dimensional structure analysis of the recognized variants were performed, and the recognized variants were evaluated. We found four heterozygous missense mutations in ATP1A2 (Case 1: p.R51C; Case 2: p.R65L; Case 3: p.A269P; Case 4: p.D999H), three of which had not been reported to date. These four mutations may also affect the structure of the protein products, as assessed using a three-dimensional structural analysis. In all four cases, the clinical symptoms included visual, sensory, motor, and verbal symptoms and the frequency and duration of headache attacks varied. Additionally, oral administration of a combination of lomerizine hydrochloride and topiramate had a partial effect in three cases. We report four missense mutations in ATP1A2. This report will be useful for the future analysis of mutations and clinical types in Asians, as well as Westerners, with migraine.
  • 片麻痺性片頭痛の原因遺伝子ATP1A2遺伝子のバリアント評価
    小田 いつき; 團野 大介; 西郷 和真; Johanna Wolf; 川下 理日人; 平野 牧人; 寒川 真; 竹島 多賀夫; 三井 良之; 永井 義隆
    日本頭痛学会誌 48 2 479 - 479 (一社)日本頭痛学会 2021年11月
  • Akira Nakamura; Kouhei Yamamoto; Ryo Murakami; Norihito Kawashita; Kouichi Matsumoto; Tomohiro Maegawa
    Synthesis 53 20 3862 - 3868 2021年06月 
    A method for synthesizing six-membered heterocyclic compounds was developed based on the features of O,P-acetals. Sequential reactions of intramolecular cyclization between the methylene carbon atom of O,P-acetal and its electrophilic functional group (ester or protected carbamate) was followed by Horner-Wadsworth-Emmons (HWE) olefination with various aldehydes. The developed one-pot method yielded isochroman-4-one and benzoxazin-3-one derivatives with an alkylidene moiety.
  • Emad Mohamed Elgendy; Yasuha Arai; Norihito Kawashita; Ayana Isobe; Tomo Daidoji; Madiha Salah Ibrahim; Takao Ono; Tatsuya Takagi; Takaaki Nakaya; Kazuhiko Matsumoto; Yohei Watanabe
    Journal of General Virology 102 6 2021年06月 
    Avian H9N2 influenza viruses in East Asia are genetically diversified and multiple genotypes (A-W) have been established in poultry. Genotype S strains are currently the most prevalent strains, have caused many human infections and pose a public health threat. In this study, human adaptation mutations in the PB2 polymerase in genotype S strains were identified by database screening. Several PB2 double mutations were identified that acted cooperatively to produce higher genotype S virus polymerase activity and replication in human cells than in avian cells and to increase viral growth and virulence in mice. These mutations were chronologically and phylogenetically clustered in a new group within genotype S viruses. Most of the relevant human virus isolates carry the PB2-A588V mutation together with another PB2 mutation (i.e. K526R, E627V or E627K), indicating a host adaptation advantage for these double mutations. The prevalence of PB2 double mutations in human H9N2 virus isolates has also been found in genetically related human H7N9 and H10N8 viruses. These results suggested that PB2 double mutations in viruses in the field acted cooperatively to increase human adaptation of the currently prevalent H9N2 genotype S strains. This may have contributed to the recent surge of H9N2 infections and may be applicable to the human adaptation of several other avian influenza viruses. Our study provides a better understanding of the human adaptation pathways of genetically related H9N2, H7N9 and H10N8 viruses in nature.
  • Kazuki Watanabe; Chiduru Watanabe; Teruki Honma; Yu-Shi Tian; Yusuke Kawashima; Norihito Kawashita; Kaori Fukuzawa; Tatsuya Takagi
    Bulletin of the Chemical Society of Japan 2021年05月
  • Kazuki Watanabe; Chiduru Watanabe; Teruki Honma; Yu-Shi Tian; Yusuke Kawashima; Norihito Kawashita; Tatsuya Takagi; Kaori Fukuzawa
    The Journal of Physical Chemistry Letters 12 16 4059 - 4066 2021年04月 
    The spike glycoprotein (S-protein) mediates SARS-CoV-2 entry via intermolecular interaction with human angiotensin-converting enzyme 2. The receptor binding domain (RBD) of the S-protein has been considered critical for this interaction and acts as the target of numerous neutralizing antibodies and antiviral peptides. This study used the fragment molecular orbital method to analyze the interactions between the RBD and antibodies/peptides and extracted crucial residues that can be used as epitopes. The interactions evaluated as interfragment interaction energy values between the RBD and 12 antibodies/peptides showed a fairly good correlation with the experimental activity pIC50 (R2 = 0.540). Nine residues (T415, K417, Y421, F456, A475, F486, N487, N501, and Y505) were confirmed as being crucial. Pair interaction energy decomposition analyses showed that hydrogen bonds, electrostatic interactions, and π-orbital interactions are important. Our results provide essential information for understanding SARS-CoV-2-antibody/peptide binding and may play roles in future antibody/antiviral drug design.
  • Yusuke Kawashima; Natsumi Mori; Norihito Kawashita; Yu-Shi Tian; Tatsuya Takagi
    Chem-Bio Informatics Journal 21 0 1 - 10 2021年01月
  • Daisuke Takaya; Chiduru Watanabe; Shunpei Nagase; Kikuko Kamisaka; Yoshio Okiyama; Hirotomo Moriwaki; Hitomi Yuki; Tomohiro Sato; Noriyuki Kurita; Yoichiro Yagi; Tatsuya Takagi; Norihito Kawashita; Kenichiro Takaba; Tomonaga Ozawa; Midori Takimoto-Kamimura; Shigenori Tanaka; Kaori Fukuzawa; Teruki Honma
    Journal of chemical information and modeling 61 2 777 - 794 2021年01月 
    We developed the world's first web-based public database for the storage, management, and sharing of fragment molecular orbital (FMO) calculation data sets describing the complex interactions between biomacromolecules, named FMO Database (https://drugdesign.riken.jp/FMODB/). Each entry in the database contains relevant background information on how the data was compiled as well as the total energy of each molecular system and interfragment interaction energy (IFIE) and pair interaction energy decomposition analysis (PIEDA) values. Currently, the database contains more than 13 600 FMO calculation data sets, and a comprehensive search function implemented at the front-end. The procedure for selecting target proteins, preprocessing the experimental structures, construction of the database, and details of the database front-end were described. Then, we demonstrated a use of the FMODB by comparing IFIE value distributions of hydrogen bond, ion-pair, and XH/π interactions obtained by FMO method to those by molecular mechanics approach. From the comparison, the statistical analysis of the data provided standard reference values for the three types of interactions that will be useful for determining whether each interaction in a given system is relatively strong or weak compared to the interactions contained within the data in the FMODB. In the final part, we demonstrate the use of the database to examine the contribution of halogen atoms to the binding affinity between human cathepsin L and its inhibitors. We found that the electrostatic term derived by PIEDA greatly correlated with the binding affinities of the halogen containing cathepsin L inhibitors, indicating the importance of QM calculation for quantitative analysis of halogen interactions. Thus, the FMO calculation data in FMODB will be useful for conducting statistical analyses to drug discovery, for conducting molecular recognition studies in structural biology, and for other studies involving quantum mechanics-based interactions.
  • Yasuha Arai; Norihito Kawashita; Emad Mohamed Elgendy; Madiha Salah Ibrahim; Tomo Daidoji; Takao Ono; Tatsuya Takagi; Takaaki Nakaya; Kazuhiko Matsumoto; Yohei Watanabe
    Journal of virology 95 1 2020年12月 [査読有り]
     
    Adaptive mutations and/or reassortments in avian influenza virus polymerase subunits PA, PB1, and PB2 are one of the major factors enabling the virus to overcome the species barrier to infect humans. The majority of human adaptation polymerase mutations have been identified in PB2; fewer adaptation mutations have been characterized in PA and PB1. Clade 2.2.1 avian influenza viruses (H5N1) are unique to Egypt and generally carry the human adaptation PB2-E627K substitution during their dissemination in nature. In this study, we identified other human adaptation polymerase mutations by analyzing phylogeny-associated PA mutations that H5N1 clade 2.2.1 viruses have accumulated during their evolution in the field. This analysis identified several PA mutations that produced increased replication by contemporary clade 2.2.1.2 viruses in vitro in human cells and in vivo in mice compared to ancestral clade 2.2.1 viruses. The PA mutations acted cooperatively to increase viral polymerase activity and replication in both avian and human cells, with the effect being more prominent in human cells at 33°C than at 37°C. These results indicated that PA mutations have a role in establishing contemporary clade 2.2.1.2 virus infections in poultry and in adaptation to infect mammals. Our study provided data on the mechanism for PA mutations to accumulate during avian influenza virus evolution and extend the viral host range.IMPORTANCE Clade 2.2.1 avian influenza viruses (H5N1) are unique to Egypt and have caused the highest number of human H5N1 influenza cases worldwide, presenting a serious global public health threat. These viruses may have the greatest evolutionary potential for adaptation from avian hosts to human hosts. Using a comprehensive phylogenetic approach, we identified several novel clade 2.2.1 virus polymerase mutations that increased viral replication in vitro in human cells and in vivo in mice. These mutations were in the polymerase PA subunit and acted cooperatively with the E627K mutation in the PB2 polymerase subunit to provide higher replication in contemporary clade 2.2.1.2 viruses than in ancestral clade 2.2.1 viruses. These data indicated that ongoing clade 2.2.1 dissemination in the field has driven PA mutations to modify viral replication to enable host range expansion, with a higher public health risk for humans.
  • Yuko Kato-Mori; Taku Okamura; Norihito Kawashita; Katsuro Hagiwara
    Veterinary immunology and immunopathology 232 110167 - 110167 2020年12月 
    Monoclonal antibodies (mAbs) that recognize cluster of differentiation (CD) molecules on lymphocytes are useful tools for the study of different lymphocyte subsets in flow cytometry (FCM) analysis. CD4 is a glycoprotein found on the surfaces of helper T cells, monocytes, macrophages, and dendritic cells. In this study, we describe Japanese Black (JB) calves in a farm whose peripheral blood mononuclear cells (PBMCs) did not react with a CD4-specific mAb. To identify calves with PBMCs with low mAb reactivity, PBMCs from 21 JB calves (1-12 months of age) bred at the same farm were examined using two different bovine CD4 mAbs (clones #CC8 and #CACT138A). FCM analysis indicated that the calves fell into two groups based on reactivity against the two mAbs, i.e., double-positive (DP) calves, whose PBMCs were recognized by both mAbs clones, and single-positive (SP) calves, whose PBMCs were only recognized by #CACT138A. PBMCs from seven calves were not recognized by #CC8, although they had normal reactivity with another mAb, #CACT138A. Sequencing analysis of the CD4 gene in these calves revealed four nucleotide substitutions (G918 T, A930C, G970A, and G1074A) in the coding region in the SP group when compared to the DP group. Three of the four mutations were associated with amino acid substitution (Q306H, K310 N, and A324 T). The substitution at A324 T was located in the D4 domain of CD4 gene. Homology modeling based on the amino acid sequences revealed that the surface structure of this part of the molecule was significantly different between the SP and the DP groups. Therefore, the epitope recognized by the #CC8 CD4 mAb was altered in calves with this genetic mutation, and this led to the low reactivity of the PBMCs from calves in the SP group aginst the #CC8 mAb. In conclusion, this is the first study to identify CD4 variants in JB cattle. We confirmed that the variants did not affect lymphocyte functions, such as mitogen stimulation or lipopolysaccharide-induced cytokine gene expression.
  • 小田 いつき; 西郷 和真; 池川 敦子; 木戸 慈子; 江口 英孝; 岡崎 康司; 石田 秀行; 富田 尚祐; 川下 理日人; 巽 純子; 田村 和朗
    日本遺伝カウンセリング学会誌 41 2 123 - 123 (一社)日本遺伝カウンセリング学会 2020年06月
  • 井上 千鶴; 池川 敦子; 西郷 和真; 新井田 要; 平野 牧人; 木戸 滋子; 川下 理日人; 巽 純子; 田村 和朗; 三井 良之; 楠 進
    日本遺伝カウンセリング学会誌 41 2 124 - 124 (一社)日本遺伝カウンセリング学会 2020年06月
  • 巽 純子; 片山 瑠香; 竹本 翔太; 荒木 もも子; 西郷 和真; 川下 理日人; 田村 和朗
    日本遺伝カウンセリング学会誌 41 2 135 - 135 (一社)日本遺伝カウンセリング学会 2020年06月
  • Asuka Hatabu; Xinhua Mao; Yi Zhou; Norihito Kawashita; Zheng Wen; Mikiko Ueda; Tatsuya Takagi; Yu-Shi Tian
    PloS one 15 12 e0244350  2020年 
    The coronavirus disease (COVID-19) pandemic has greatly altered peoples' daily lives, and it continues spreading as a crucial concern globally. Knowledge, attitudes, and practices (KAP) toward COVID-19 are related to individuals' adherence to government measures. This study evaluated KAP toward COVID-19 among university students in Japan between May 22 and July 16, 2020, via an online questionnaire, and it further investigated the associated determining KAP factors. Among the eligible respondents (n = 362), 52.8% were female, 79.0% were undergraduate students, 32.9% were students whose major university subjects were biology-related, 35.4% were from the capital region, and 83.7% were Japanese. The overall KAP of university students in Japan was high. All respondents (100%) showed they possessed knowledge on avoiding enclosed spaces, crowded areas, and close situations. Most respondents showed a moderate or higher frequency of washing their hands or wearing masks (both at 96.4%). In addition, 68.5% of respondents showed a positive attitude toward early drug administration. In the logistic regressions, gender, major subjects, education level, nationality, residence, and psychological factors (private self-consciousness and extroversion) were associated with knowledge or attitudes toward COVD-19 (p < 0.05). In the logistic and multiple linear regressions, capital regions, high basic knowledge, high information acquisition, correct information explanations contributed positively to preventative action (p < 0.05). Non-capital regions, male gender, non-bio-backgrounds, high public self-consciousness, high advanced knowledge, incorrect information explanations, and high extroversion contributed negatively to self-restraint (p < 0.05). Moreover, self-restraint was decreasing over time. These findings clarify the Japanese university students' KAP and the related factors in the early period of the COVID-19 pandemic, and they may help university managers, experts, and policymakers control the future spread of COVID-19 and other emerging infections.
  • Kouichi Matsumoto; Hiroki Shimao; Yuta Fujiki; Norihito Kawashita; Shigenori Kashimura
    ELECTROCHEMISTRY 88 4 262 - 264 2020年 [査読有り]
     
    We show that a catalytic amount of electro-generated acid (EGA) prepared from the oxidation of a Bu4NB(C6F5)(4)/CH2Cl2 solution catalyzes effectively the tandem cyclization of epoxyolefins, producing the corresponding polycyclized compounds in 23%-57% yields. The scope and limitations of the substrates are examined, and we compare the stability of the intermediates through theoretical calculations. The success of the current reactions might be due to the high reactivity of EGA, because the counter anion is bulky and stabilized B(C6E5)(4)(-) derived from Bu4NB(C6F5)(4) as the supporting electrolyte. (C) The Author(s) 2020. Published by ECSJ.
  • Kazuki Watanabe; Yusuke Kawashima; Chisato Mukai; Tatsuya Takagi; Yukinori Suwa; Yu-Shi Tian; Norihito Kawashita
    Chemical & pharmaceutical bulletin 68 8 737 - 741 2020年 [査読有り]
     
    Cycloaddition catalyzed by transition metals such as rhodium (I) is an important way to synthesize functionalized molecules in medicinal chemistry. When the reagent has a saturated ring containing more than five carbons (or heavy atoms), the reaction can progress when the compound has an allenyl group, but not for a vinyl group. Here, we constructed two computational models for allenylcyclopentane-alkyne and vinylcyclopentane-alkyne, and obtained their reaction pathways using density functional theory (DFT). From the reaction pathways, we confirmed that the former model has a much lower reaction energy than the latter. We also found that the molecular orbitals of the transition state structure at the rate-controlling step contribute significantly to the difference in reactivity between the two models.
  • 認定遺伝カウンセラー®の雇用に対する検査会社の視点
    仲間美奈; 白山大揮; 田村和朗; 川下理日人; 萩原央記; 巽 純子; 南 武志
    日本遺伝カウンセリング学会誌 40 3 85 - 93 2019年10月 [査読有り]
  • Kazuo Tamura; Motohide Kaneda; Mashu Futagawa; Miho Takeshita; Sanghyuk Kim; Mina Nakama; Norihito Kawashita; Junko Tatsumi-Miyajima
    International journal of clinical oncology 24 9 999 - 1011 2019年09月 [査読有り]
     
    Lynch syndrome is a cancer-predisposing syndrome inherited in an autosomal-dominant manner, wherein colon cancer and endometrial cancer develop frequently in the family, it results from a loss-of-function mutation in one of four different genes (MLH1, MSH2, MSH6, and PMS2) encoding mismatch repair proteins. Being located immediately upstream of the MSH2 gene, EPCAM abnormalities can affect MSH2 and cause Lynch syndrome. Mismatch repair proteins are involved in repairing of incorrect pairing (point mutations and deletion/insertion of simple repetitive sequences, so-called microsatellites) that can arise during DNA replication. MSH2 forms heterodimers with MSH6 or MSH3 (MutSα, MutSβ, respectively) and is involved in mismatch-pair recognition and initiation of repair. MLH1 forms a complex with PMS2, and functions as an endonuclease. If the mismatch repair system is thoroughly working, genome integrity is maintained completely. Lynch syndrome is a state of mismatch repair deficiency due to a monoallelic abnormality of any mismatch repair genes. The phenotype indicating the mismatch repair deficiency can be frequently shown as a microsatellite instability in tumors. Children with germline biallelic mismatch repair gene abnormalities were reported to develop conditions such as gastrointestinal polyposis, colorectal cancer, brain cancer, leukemia, etc., and so on, demonstrating the need to respond with new concepts in genetic counseling. In promoting cancer genome medicine in a new era, such as by utilizing immune checkpoints, it is important to understand the genetic and genomic molecular background, including the status of mismatch repair deficiency.
  • Kazuo Tamura; Motohide Kaneda; Mashu Futagawa; Miho Takeshita; Sanghyuk Kim; Mina Nakama; Norihito Kawashita; Junko Tatsumi-Miyajima
    International journal of clinical oncology 24 9 1012 - 1012 2019年09月 
    In the original publication, part d of Figure 2 was mistakenly not included.
  • Yasuha Arai; Norihito Kawashita; Madiha Salah Ibrahim; Emad Mohamed Elgendy; Tomo Daidoji; Takao Ono; Tatsuya Takagi; Takaaki Nakaya; Kazuhiko Matsumoto; Yohei Watanabe
    PLoS pathogens 15 7 e1007919  2019年07月 [査読有り]
     
    Avian influenza virus H9N2 has been endemic in birds in the Middle East, in particular in Egypt with multiple cases of human infections since 1998. Despite concerns about the pandemic threat posed by H9N2, little is known about the biological properties of H9N2 in this epicentre of infection. Here, we investigated the evolutionary dynamics of H9N2 in the Middle East and identified phylogeny-associated PB2 mutations that acted cooperatively to increase H9N2 replication/transcription in human cells. The accumulation of PB2 mutations also correlated with an increase in H9N2 virus growth in the upper and lower airways of mice and in virulence. These mutations clustered on a solvent-exposed region in the PB2-627 domain in proximity to potential interfaces with host factors. These PB2 mutations have been found at high prevalence during evolution of H9N2 in the field, indicating that they have provided a selective advantage for viral adaptation to infect poultry. Therefore, continuous prevalence of H9N2 virus in the Middle East has generated a far more fit or optimized replication phenotype, leading to an expanded viral host range, including to mammals, which may pose public health risks beyond the current outbreaks.
  • Three-Dimensional Classification Structure–Activity Relationship Analysis Using Convolutional Neural Network
    Hirotomo Moriwaki; Yu-Shi Tian; Norihito Kawashita; Tatsuya Takagi
    Chemical and Pharmaceutical Bulletin 67 5 1 - 8 Pharmaceutical Society Japan 2019年05月 [査読有り]
     
    Quantitative structure–activity relationship (QSAR) techniques, especially those that possess three-dimensional attributes, such as the comparative molecular field analysis (CoMFA), are frequently used in modern-day drug design and other related research domains.
    However, the requirement for accurate alignment of compounds in CoMFA increases the difficulties encountered in its use. This has led to the development of several techniques—such as VolSurf, grid-independent descriptor (GRIND), and Anchor-GRIND—which do not require such an alignment. We propose a technique to construct the prediction model that uses molecular interaction field grid potentials as inputs to convolutional neural network. The proposed model has been found to demonstrate higher accuracy compared to the conventional descriptor based QSAR models as well as Anchor-GRIND techniques. In addition, the method is target independent, and is capable of providing useful information regarding the importance of individual atoms constituting the compounds contained in the chemical dataset used in the proposed analysis. In view of these advantages, the proposed technique is expected to find wide applications in futu
  • Yuki Fujii; Yukinori Suwa; Yuki Wada; Tsunayoshi Takehara; Takeyuki Suzuki; Yusuke Kawashima; Norihito Kawashita; Tatsuya Takagi; Hiromichi Fujioka; Mitsuhiro Arisawa
    ACS omega 4 3 5064 - 5075 2019年03月 [査読有り]
     
    We have synthesized and theoretically calculated 5-methylisoindolo[2,1-a]quinoline derivatives as novel near-infrared absorption dyes via a ruthenium-catalyzed one-pot metathesis/oxidation/1,3-dipolar cycloaddition protocol. The reactivity in 1,3-dipolar cycloaddition was governed by the electronic effect of aromatic ring substituents. Substrates with an electron-withdrawing group on the aromatic ring afforded higher yields. The maximal absorption wavelength of 3,5-dimethyl-11-phenylisoindolo[2,1-a]quinoline-7,10-dione and 11-(4-methoxyphenyl)-5-methylisoindolo[2,1-a]quinoline-7,10-dione in MeOH increased to 736 and 737 nm, although that of 3a was 727 nm.
  • ロジウム触媒による環化付加反応の計算化学的検討
    諏訪 志典; 渡邉 一樹; 川嶋 裕介; 田 雨時; 川下 理日人; 高木 達也
    日本薬学会年会要旨集 139年会 2 258 - 258 (公社)日本薬学会 2019年03月
  • 肺がんの遺伝子に基づく病原遺伝子判別モデルの構築
    婁 殿宇; 川下 理日人; 高木 達也; 田 雨時
    日本薬学会年会要旨集 139年会 2 259 - 259 (公社)日本薬学会 2019年03月
  • Hirotomo Moriwaki; Yu-Shi Tian; Norihito Kawashita; Tatsuya Takagi
    Chemical & pharmaceutical bulletin 67 5 426 - 432 2019年 [査読有り]
     
    Quantitative structure-activity relationship (QSAR) techniques, especially those that possess three-dimensional attributes, such as the comparative molecular field analysis (CoMFA), are frequently used in modern-day drug design and other related research domains. However, the requirement for accurate alignment of compounds in CoMFA increases the difficulties encountered in its use. This has led to the development of several techniques-such as VolSurf, Grid-independent descriptors (GRIND), and Anchor-GRIND-which do not require such an alignment. We propose a technique to construct the prediction model that uses molecular interaction field grid potentials as inputs to convolutional neural network. The proposed model has been found to demonstrate higher accuracy compared to the conventional descriptor-based QSAR models as well as Anchor-GRIND techniques. In addition, the method is target independent, and is capable of providing useful information regarding the importance of individual atoms constituting the compounds contained in the chemical dataset used in the proposed analysis. In view of these advantages, the proposed technique is expected to find wide applications in future drug-design operations.
  • Yasuha Arai; Norihito Kawashita; Kozue Hotta; Phuong Vu Mai Hoang; Hang Le Khanh Nguyen; Thach Co Nguyen; Cuong Duc Vuong; Thanh Thi Le; Mai Thi Quynh Le; Kosuke Soda; Madiha S Ibrahim; Tomo Daidoji; Tatsuya Takagi; Tatsuo Shioda; Takaaki Nakaya; Toshihiro Ito; Futoshi Hasebe; Yohei Watanabe
    Scientific reports 8 1 13066 - 13066 2018年08月 [査読有り]
     
    The role of the influenza virus polymerase complex in host range restriction has been well-studied and several host range determinants, such as the polymerase PB2-E627K and PB2-D701N mutations, have been identified. However, there may be additional, currently unknown, human adaptation polymerase mutations. Here, we used a database search of influenza virus H5N1 clade 1.1, clade 2.3.2.1 and clade 2.3.4 strains isolated from 2008-2012 in Southern China, Vietnam and Cambodia to identify polymerase adaptation mutations that had been selected in infected patients. Several of these mutations acted either alone or together to increase viral polymerase activity in human airway cells to levels similar to the PB2-D701N and PB2-E627K single mutations and to increase progeny virus yields in infected mouse lungs to levels similar to the PB2-D701N single mutation. In particular, specific mutations acted synergistically with the PB2-D701N mutation and showed synergistic effects on viral replication both in human airway cells and mice compared with the corresponding single mutations. Thus, H5N1 viruses in infected patients were able to acquire multiple polymerase mutations that acted cooperatively for human adaptation. Our findings give new insight into the human adaptation of AI viruses and help in avian influenza virus risk assessment.
  • Yohei Watanabe; Yasuha Arai; Norihito Kawashita; Madiha S Ibrahim; Emad M Elgendy; Tomo Daidoji; Junichi Kajikawa; Hiroaki Hiramatsu; Nongluk Sriwilaijaroen; Takao Ono; Tatsuya Takagi; Kazuo Takahashi; Tatsuo Shioda; Kazuhiko Matsumoto; Yasuo Suzuki; Takaaki Nakaya
    Journal of virology 92 11 2018年06月 [査読有り]
     
    Transmission of avian influenza (AI) viruses to mammals involves phylogenetic bottlenecks that select small numbers of variants for transmission to new host species. However, little is known about the AI virus quasispecies diversity that produces variants for virus adaptation to humans. Here, we analyzed the hemagglutinin (HA) genetic diversity produced during AI H5N1 single-virus infection of primary human airway cells and characterized the phenotypes of these variants. During single-virus infection, HA variants emerged with increased fitness to infect human cells. These variants generally had decreased HA thermostability, an indicator of decreased transmissibility, that appeared to compensate for their increase in α2,6-linked sialic acid (α2,6 Sia) binding specificity and/or in the membrane fusion pH threshold, each of which is an advantageous mutational change for viral infection of human airway epithelia. An HA variant with increased HA thermostability also emerged but could not outcompete variants with less HA thermostability. These results provided data on HA quasispecies diversity in human airway cells.IMPORTANCE The diversity of the influenza virus quasispecies that emerges from a single infection is the starting point for viral adaptation to new hosts. A few studies have investigated AI virus quasispecies diversity during human adaptation using clinical samples. However, those studies could be appreciably affected by individual variability and multifactorial respiratory factors, which complicate identification of quasispecies diversity produced by selective pressure for increased adaptation to infect human airway cells. Here, we found that detectable HA genetic diversity was produced by H5N1 single-virus infection of human airway cells. Most of the HA variants had increased fitness to infect human airway cells but incurred a fitness cost of less HA stability. To our knowledge, this is the first report to characterize the adaptive changes of AI virus quasispecies produced by infection of human airway cells. These results provide a better perspective on AI virus adaptation to infect humans.
  • 抗デングウイルスのHTS & In Silico医薬品設計
    松田 仁志; 川下 理日人; 田 雨時; 高木 達也
    日本薬学会年会要旨集 138年会 3 184 - 184 (公社)日本薬学会 2018年03月
  • Hirotomo Moriwaki; Yu-Shi Tian; Norihito Kawashita; Tatsuya Takagi
    Journal of cheminformatics 10 1 4 - 4 2018年02月 [査読有り]
     
    Molecular descriptors are widely employed to present molecular characteristics in cheminformatics. Various molecular-descriptor-calculation software programs have been developed. However, users of those programs must contend with several issues, including software bugs, insufficient update frequencies, and software licensing constraints. To address these issues, we propose Mordred, a developed descriptor-calculation software application that can calculate more than 1800 two- and three-dimensional descriptors. It is freely available via GitHub. Mordred can be easily installed and used in the command line interface, as a web application, or as a high-flexibility Python package on all major platforms (Windows, Linux, and macOS). Performance benchmark results show that Mordred is at least twice as fast as the well-known PaDEL-Descriptor and it can calculate descriptors for large molecules, which cannot be accomplished by other software. Owing to its good performance, convenience, number of descriptors, and a lax licensing constraint, Mordred is a promising choice of molecular descriptor calculation software that can be utilized for cheminformatics studies, such as those on quantitative structure-property relationships.
  • Ryo Ishinishi; Hideyuki Matsuura; Satoshi Tanaka; Saaya Nozawa; Keisuke Tanada; Norihito Kawashita; Kazuhito Fujiyama; Hitoshi Miyasaka; Kazumasa Hirata
    Gene 640 14 - 20 2018年01月 [査読有り]
     
    The genetic basis of stress resistance in extremophilic microalgae is not well studied. In this study, a gene of unknown function, the cluster58 or CL58 gene, was identified from the halotolerant green alga Chlamydomonas W80 and characterized. The CL58 gene encodes a protein containing a domain of unknown function, the CHRD domain, and a putative secretory signaling sequence at its N-terminus. The levels of CL58 mRNA increased in response to high copper levels and low temperatures. When the CL58 gene was heterologously expressed as a fusion gene with the NanoLuc luciferase gene in Chlamydomonas reinhardtii, a majority of the NanoLuc activity was detected in the culture medium compared with that in the intracellular fraction. A mutagenic analysis revealed that the putative secretory signaling sequence was sufficient for the secretion of the CL58-NanoLuc fusion protein. In addition, we expressed the protein encoded by the CL58 gene in Escherichia coli; the recombinant, soluble protein was then purified. In summary, we identified a novel gene from C. W80 that appears to encode a stress-responsive, CHRD domain-containing secreted protein.
  • Yu-Shi Tian; Yi Zhou; Tatsuya Takagi; Masanori Kameoka; Norihito Kawashita
    Chemical & pharmaceutical bulletin 66 3 191 - 206 2018年 [査読有り]
     
    The global occurrence of viral infectious diseases poses a significant threat to human health. Dengue virus (DENV) infection is one of the most noteworthy of these infections. According to a WHO survey, approximately 400 million people are infected annually; symptoms deteriorate in approximately one percent of cases. Numerous foundational and clinical investigations on viral epidemiology, structure and function analysis, infection source and route, therapeutic targets, vaccines, and therapeutic drugs have been conducted by both academic and industrial researchers. At present, CYD-TDV or Dengvaxia® is the only approved vaccine, but potent inhibitors are currently under development. In this review, an overview of the viral life circle and the history of DENVs is presented, and the most recently reported antiviral candidates and newly discovered promising targets are focused and summarized. We believe that these successes and failures have enabled progress in anti-DENV drug discovery and hope that our review will stimulate further innovation in this area.
  • Asuka Hatabu; Masafumi Harada; Yoshitake Takahashi; Shunsuke Watanabe; Kenya Sakamoto; Kousuke Okamoto; Norihito Kawashita; Yu-Shi Tian; Tatsuya Takagi
    Chem-Bio Informatics Journal 17 112 - 124 Chem-Bio Informatics Society 2017年12月 [査読有り]
  • Akihiro Watari; Miki Kodaka; Koji Matsuhisa; Yuta Sakamoto; Kota Hisaie; Norihito Kawashita; Tatsuya Takagi; Yoshiaki Yamagishi; Hidehiko Suzuki; Hirofumi Tsujino; Kiyohito Yagi; Masuo Kondoh
    Scientific reports 7 1 14514 - 14514 2017年11月 [査読有り]
     
    Claudins are key functional and structural components of tight junctions (TJs) in epithelial cell sheets. The C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE) binds to claudin-4 and reversibly modulates intestinal TJ seals, thereby enhancing paracellular transport of solutes. However, the use of C-CPE as an absorption enhancer is limited by the molecule's immunogenicity and manufacturing cost. Here, we developed a high-throughput screening system based on the Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) method to identify claudin-4 binders in a library collection of 32,560 compounds. Thiostrepton, identified from the screen, decreased transepithelial electrical resistance and increased flux of 4-kDa fluorescein isothiocyanate-labelled dextran (FD-4) in Caco-2 cell monolayers, a model of intestinal epithelium. Thiostrepton changed the expression, but not the localisation, of TJ components. Treatment of rat jejunum with thiostrepton increased the absorption of FD-4 without tissue toxicity, indicating that thiostrepton is a novel claudin-4 binder that enhances intestinal permeability. The screening system may therefore be a useful tool for identifying claudin-4 binders to enhance drug absorption in mucosa.
  • Characterization of H5N1 influenza virus variants with HA mutations diversified in human airway epithelial cells as minor variants
    Watanabe Y; Arai Y; Kawashita N; Kawashita N; Daidoji T; Elgendy M E; Ibrahim MS; Kajiwara J; Hiramatsu H; Takagi T; Takahashi K; Shioda T; Suzuki Y; Nakaya T
    2017年10月 [査読有り]
  • Emad Mohamed Elgendy; Yasuha Arai; Norihito Kawashita; Tomo Daidoji; Tatsuya Takagi; Madiha Salah Ibrahim; Takaaki Nakaya; Yohei Watanabe
    The Journal of general virology 98 1 6 - 17 2017年01月 [査読有り]
     
    Highly pathogenic avian influenza virus H5N1 infects a wide range of host species, with a few cases of sporadic pigeon infections reported in the Middle East and Asia. However, the role of pigeons in the ecology and evolution of H5N1 viruses remains unclear. We previously reported two H5N1 virus strains, isolated from naturally infected pigeons in Egypt, that have several unique mutations in their viral polymerase genes. Here, we investigated the effect of these mutations on H5N1 polymerase activity and viral growth and identified three mutations that affected viral polymerase activity. The results showed that the PB1-V3D mutation significantly decreased polymerase activity and viral growth in both mammalian and avian cells. In contrast, the PB2-K627E and PA-K158R mutations had moderate effects: PB2-K627E decreased and PA-K158R increased polymerase activity. Structural homology modelling indicated that the PB1-V3D residue was located in the PB1 core region that interacts with PA, predicting that the PB1 mutation would produce a stronger interaction between PB1 and PA that results in decreased replication of pigeon-derived H5N1 viruses. Our results identified several unique mutations responsible for changes in polymerase activity in H5N1 virus strains isolated from infected pigeons, emphasizing the importance of avian influenza surveillance in pigeons and in studying the possible role of pigeon-derived H5N1 viruses in avian influenza virus evolution.
  • Yu-Shi Tian; Norihito Kawashita; Masanori Kameoka; Tatsuya Takagi
    Journal of Prevention & Infection Control 2 2:12 1 - 5 iMedPub Journals 2016年11月 [査読有り]
     
    The high impact of the acquired immunodeficiency syndrome caused by human immunodeficiency virus has represented a significant public health threat in the last four decades. Recently, the development of new antiviral drugs
    has led to great progress in overcoming this virus. Antiretroviral therapy coverage has been increasing, even in low-income countries, resulting in an overall decline of HIV/AIDS-related deaths worldwide. Nonetheless, new
    infections still appear, and the era of clearance of this virus has not yet been reached. Moreover, the resistance of the virus to drugs during treatments remains a serious problem.
    Therefore, researchers are actively seeking to discover and characterize new molecule(s) that could be suitable for anti-HIV treatment. Cyclophilin A, a host molecular chaperone or folder protein, is suspected to be one such attractive target. We and others are searching for inhibitor(s) of this molecule and investigating its mechanism of action throughout the viral life cycle. In this review, we focus on studies related to cyclophilin A and the candidate inhibitors.
  • Takahiro Murai; Norihito Kawashita; Yu-Shi Tian; Tatsuya Takagi
    Journal of Pharmaceutics 2016 9520361 1 - 6 Hindawi Publishing Corporation 2016年11月 [査読有り]
     
    The underlying mechanisms of these HLA-induced Drug Hypersensitivity Reactions (DHRs) are still unclear, especially for drug-induced immediate activation of T-cell clones (TCCs). Recently, a novel hypothesis involving partial detachment between self-peptide(s) and the HLA molecule (altered peptide-HLA (pHLA) model) has been proposed to explain these phenomena. In order to clarify this hypothesis, we performed long-timescale molecular dynamics (MD) simulations. We focused on HLA-B∗57:01-restricted abacavir hypersensitivity reactions (AHRs), one of the most famous DHRs. One of the simulation results showed that this altered-pHLA model might be driven by an increase in the distance not only between HLA and self-peptides but also between the alpha1 and alpha2 helices of HLA. Our findings provide novel insights into abacavir-induced immediate activation of TCCs and these findings might also be applied to other DHRs, such as HLA-B∗58:01-restricted allopurinol hypersensitivity reactions.
  • Yasuha Arai; Norihito Kawashita; Tomo Daidoji; Madiha S Ibrahim; Emad M El-Gendy; Tatsuya Takagi; Kazuo Takahashi; Yasuo Suzuki; Kazuyoshi Ikuta; Takaaki Nakaya; Tatsuo Shioda; Yohei Watanabe
    PLoS pathogens 12 4 e1005583  2016年04月 [査読有り]
     
    A major determinant in the change of the avian influenza virus host range to humans is the E627K substitution in the PB2 polymerase protein. However, the polymerase activity of avian influenza viruses with a single PB2-E627K mutation is still lower than that of seasonal human influenza viruses, implying that avian viruses require polymerase mutations in addition to PB2-627K for human adaptation. Here, we used a database search of H5N1 clade 2.2.1 virus sequences with the PB2-627K mutation to identify other polymerase adaptation mutations that have been selected in infected patients. Several of the mutations identified acted cooperatively with PB2-627K to increase viral growth in human airway epithelial cells and mouse lungs. These mutations were in multiple domains of the polymerase complex other than the PB2-627 domain, highlighting a complicated avian-to-human adaptation pathway of avian influenza viruses. Thus, H5N1 viruses could rapidly acquire multiple polymerase mutations that function cooperatively with PB2-627K in infected patients for optimal human adaptation.
  • 金子 弘昌; 中村 真也; 川下 理日人
    YAKUGAKU ZASSHI 136 1 95 - 96 公益社団法人 日本薬学会 2016年
  • Z. -Y. Li; A. Yamashita; N. Kawashita; T. Sasaki; Y. Pan; K. -I. Ono; K. Ikuta; Y. -G. Li
    ACTA VIROLOGICA 60 2 166 - 173 2016年 
    The global spread of the four dengue virus (DENV) serotypes (dengue-1 to -4) has made this virus a major and growing public health concern. Generally, pre-existing neutralizing antibodies derived from primary infection play a significant role in protecting against subsequent infection with the same serotype. By contrast, these pre-existing antibodies are believed to mediate a non-protective response to subsequent heterotypic DENV infections, leading to the onset of dengue illness. In this study, two monoclonal antibodies prepared by using peripheral blood mononuclear cells (PBMCs) from patients with dengue fever were characterized. Epitope mapping revealed that amino acid residues 254-278 in domain II of the viral envelope protein E were the target region of these antibodies. A database search revealed that certain sequences in this epitope region showed high conservation among the four serotypes of DENV. These two human monoclonal antibodies could neutralize DENV-2,-4 more effectively than DENV-1,-3. The amino acid sequences could not explain this difference in neutralizing activity. However, the 3D structure results showed that amino acid 274 could be the critical residue for the difference in neutralization. These results may provide basic information for the development of a dengue vaccine.
  • Takahiro Murai; Norihito Kawashita; Yu-Shi Tian; Tatsuya Takagi
    SpringerPlus 5 1 1122 - 1122 2016年 [査読有り]
     
    BACKGROUND: Thalidomide and its analogs, lenalidomide and pomalidomide (referred to as immunomodulatory imide drugs or IMiDs) have been known to treat multiple myeloma and other hematologic malignancies as well as to cause teratogenicity. Recently the protein cereblon was identified as the primary target of IMiDs, and crystallographic studies of the cereblon-IMiDs complex showed strong enantioselective binding for the (S)-enantiomer of IMiDs. RESULTS: Using the structures of cereblon and IMiDs [both (S)-enantiomers and (R)-enantiomers] we performed docking simulations in order to replicate this enantiomeric selectivity and to identify the region(s) contributing to this selectivity. We confirmed the enantioselective binding of IMiDs to cereblon with high accuracy, and propose that the hairpin connecting the β10-β11 region of cereblon (residues 351-355) contributes to this selectivity and to the increased affinity with IMiDs. CONCLUSIONS: Our docking results provide novel insights into the binding mode of IMiD-like molecules and contribute to a deeper understanding of cereblon-related biology.
  • Takahiro Murai; Norihito Kawashita; Yu-Shi Tian; Tatsuya Takagi
    Journal of pharmaceutics 2016 9520361 - 9520361 2016年 [査読有り]
     
    The discovery that several drug hypersensitivity reactions (DHRs) are associated with specific human leukocyte antigen (HLA) alleles has attracted increasing research interest. However, the underlying mechanisms of these HLA-induced DHRs remain unclear, especially for drug-induced immediate activation of T-cell clones (TCCs). Recently, a novel hypothesis involving partial detachment between self-peptide(s) and the HLA molecule (altered peptide-HLA (pHLA) model) has been proposed to explain these phenomena. In order to clarify this hypothesis, we performed long-timescale molecular dynamics (MD) simulations. We focused on HLA-B⁎57:01-restricted abacavir hypersensitivity reactions (AHRs), one of the most famous DHRs. One of the simulation results showed that this altered-pHLA model might be driven by an increase in the distance not only between HLA and self-peptides but also between the α1 and α2 helices of HLA. Our findings provide novel insights into abacavir-induced immediate activation of TCCs and these findings might also be applied to other DHRs, such as HLA-B⁎58:01-restricted allopurinol hypersensitivity reactions.
  • Yu-Shi Tian; Norihito Kawashita; Yuki Arai; Kousuke Okamoto; Tatsuya Takagi
    Bioinformation 11 8 401 - 406 2015年08月 [査読有り]
  • Chris Verathamjamras; Yu-Shi Tian; Norihito Kawashita; Kousuke Okamoto; Teruo Yasunaga; Kazuyoshi Ikuta; Kazushi Motomura; Naokazu Takeda; Tatsuya Takagi; Masanori Kameoka
    J. Infect. Dis. Ther. 3 3 1 - 8 2015年05月 [査読有り]
  • Yohei Watanabe; Yasuha Arai; Tomo Daidoji; Norihito Kawashita; Madiha S Ibrahim; Emad El-Din M El-Gendy; Hiroaki Hiramatsu; Ritsuko Kubota-Koketsu; Tatsuya Takagi; Takeomi Murata; Kazuo Takahashi; Yoshinobu Okuno; Takaaki Nakaya; Yasuo Suzuki; Kazuyoshi Ikuta
    mBio 6 2 2015年04月 [査読有り]
     
    UNLABELLED: A change in viral hemagglutinin (HA) receptor binding specificity from α2,3- to α2,6-linked sialic acid is necessary for highly pathogenic avian influenza (AI) virus subtype H5N1 to become pandemic. However, details of the human-adaptive change in the H5N1 virus remain unknown. Our database search of H5N1 clade 2.2.1 viruses circulating in Egypt identified multiple HA mutations that had been selected in infected patients. Using reverse genetics, we found that increases in both human receptor specificity and the HA pH threshold for membrane fusion were necessary to facilitate replication of the virus variants in human airway epithelia. Furthermore, variants with enhanced replication in human cells had decreased HA stability, apparently to compensate for the changes in viral receptor specificity and membrane fusion activity. Our findings showed that H5N1 viruses could rapidly adapt to growth in the human airway microenvironment by altering their HA properties in infected patients and provided new insights into the human-adaptive mechanisms of AI viruses. IMPORTANCE: Circulation between bird and human hosts may allow H5N1 viruses to acquire amino acid changes that increase fitness for human infections. However, human-adaptive changes in H5N1 viruses have not been adequately investigated. In this study, we found that multiple HA mutations were actually selected in H5N1-infected patients and that H5N1 variants with some of these HA mutations had increased human-type receptor specificity and increased HA membrane fusion activity, both of which are advantageous for viral replication in human airway epithelia. Furthermore, HA mutants selected during viral replication in patients were likely to have less HA stability, apparently as a compensatory mechanism. These results begin to clarify the picture of the H5N1 human-adaptive mechanism.
  • Yohei Watanabe; Yasuha Arai; Tomo Daidoji; Norihito Kawashita; Madiha S. Ibrahim; Emad El-Din M. El-Gendy; Hiroaki Hiramatsu; Ritsuko Kubota-Koketsu; Tatsuya Takagi; Takeomi Murata; Kazuo Takahashi; Yoshinobu Okuno; Takaaki Nakaya; Yasuo Suzuki; Kazuyoshi Ikuta
    mBio 6 2 2015年04月 
    A change in viral hemagglutinin (HA) receptor binding specificity from α 2,3- to α 2,6-linked sialic acid is necessary for highly pathogenic avian influenza (AI) virus subtype H5N1 to become pandemic. However, details of the human-adaptive change in the H5N1 virus remain unknown. Our database search of H5N1 clade 2.2.1 viruses circulating in Egypt identified multiple HA mutations that had been selected in infected patients. Using reverse genetics, we found that increases in both human receptor specificity and the HA pH threshold for membrane fusion were necessary to facilitate replication of the virus variants in human airway epithelia. Furthermore, variants with enhanced replication in human cells had decreased HA stability, apparently to compensate for the changes in viral receptor specificity and membrane fusion activity. Our findings showed that H5N1 viruses could rapidly adapt to growth in the human airway microenvironment by altering their HA properties in infected patients and provided new insights into the human-adaptive mechanisms of AI viruses. IMPORTANCE Circulation between bird and human hosts may allow H5N1 viruses to acquire amino acid changes that increase fitness for human infections. However, human-adaptive changes in H5N1 viruses have not been adequately investigated. In this study, we found that multiple HA mutations were actually selected in H5N1-infected patients and that H5N1 variants with some of these HA mutations had increased human-type receptor specificity and increased HA membrane fusion activity, both of which are advantageous for viral replication in human airway epithelia. Furthermore, HA mutants selected during viral replication in patients were likely to have less HA stability, apparently as a compensatory mechanism. These results begin to clarify the picture of the H5N1 human-adaptive mechanism. IMPORTANCE Circulation between bird and human hosts may allow H5N1 viruses to acquire amino acid changes that increase fitness for human infections. However, human-adaptive changes in H5N1 viruses have not been adequately investigated. In this study, we found that multiple HA mutations were actually selected in H5N1-infected patients and that H5N1 variants with some of these HA mutations had increased human-type receptor specificity and increased HA membrane fusion activity, both of which are advantageous for viral replication in human airway epithelia. Furthermore, HA mutants selected during viral replication in patients were likely to have less HA stability, apparently as a compensatory mechanism. These results begin to clarify the picture of the H5N1 human-adaptive mechanism.
  • Yu-Shi Tian; Norihito Kawashita; Yuki Arai; Kousuke Okamoto; Tatsuya Takagi
    Bioinformation 11 8 401 - 6 2015年 
    High-risk human papillomaviruses (HPVs) are known to cause cervical cancer. Vaccines are now available to prevent HPV infection. However, a clinically approved drug is yet not available to treat HPV. The PDZ(PSD-95/Dlg/ZO-1)-binding motif (PBM) in the E6 protein of HPVs targets the PDZ domain (known to be associated with oncogenesis) for degradation. Therefore, it is of interest to study PBM-PDZ interaction towards its possible inhibition with a potential inhibitor. Thus, four pharmocophore models of PBM-PDZ complex were developed. In order to obtain potent small molecules for its inhibition, a commercial compound database was screened using both these pharmacophore models and molecule docking method. These efforts identified four potential compounds (1-4) towards its inhibition with the docking scores range -18.2 to -15.0.
  • KAWASHITA Norihito; KAWASHITA Norihito; YAMASAKI Hiroyuki; MIYAO Tomoyuki; KAWAI Kentaro; SAKAE Yoshitake; ISHIKAWA Takeshi; MORI Kenichi; NAKAMURA Shinya; KANEKO Hiromasa
    J Comput Aided Chem (Web) 16 15-29 (J-STAGE) - 29 Division of Chemical Information and Computer Sciences The Chemical Society of Japan 2015年 
    We have reviewed chemoinformatics approaches for drug discovery such as aromatic interactions, aromatic clusters, structure generation, virtual screening, de novo design, evolutionary algorithm, inverse-QSPR/QSAR, Monte Carlo, molecular dynamics, fragment molecular orbital method and matched molecular pair analysis from the viewpoint of young researchers. We intend to introduce various fields of chemoinformatics for non-expert researchers. The structure of this review is given as follows: 1. Introduction, 2. Analysis of Aromatic Interactions, 2.1 Aromatic Interactions, 2.2 Aromatic Clusters, 3. Ligand Based Structure Generation, 3.1 Virtual Screening, 3.2 De Novo Ligand Design, 3.3 Combinatorial Explosion, 3.4 Inverse-QSPR/QSAR, 4. Trends in Chemoinformatics-Based De Novo Drug Design, 5. Conformational Search Method Using Genetic Crossover for Bimolecular Systems, 6. Interaction Analysis using Fragment Molecular Orbital Method for Drug Discovery, 7. Matched Molecular Pair Analysis and SAR Analysis by Fragment Molecular Orbital Method, 8. Chemoinformatics Approach in Pharmaceutical Processes, 9. Conclusion.
  • Kenichi Murai; Daisuke Endo; Norihito Kawashita; Tatsuya Takagi; Hiromichi Fujioka
    Chemical & pharmaceutical bulletin 63 4 245 - 7 2015年 
    A halogen-induced oxidative rearrangement of N,O-ketals prepared from cyclobutanones, leading to pyrrolidone derivatives, is developed. The reaction proceeds via an iminium ether intermediate and, depending on the reaction medium, two types of pyrrolidone derivative, containing a halogen atom or hydroxyl group, can be obtained.
  • Mikiko Sasayama; Surachet Benjathummarak; Norihito Kawashita; Prasert Rukmanee; Suntaree Sangmukdanun; Promsin Masrinoul; Pannamthip Pitaksajjakul; Orapim Puiprom; Pitak Wuthisen; Takeshi Kurosu; Panjaporn Chaichana; Pannamas Maneekan; Kazuyoshi Ikuta; Pongrama Ramasoota; Tamaki Okabayashi; Pratap Singhasivanon; Natthanej Luplertlop
    Virus genes 49 3 485 - 9 2014年12月 
    Chikungunya fever (CHIKF) is an acute febrile illness caused by a mosquito-borne alphavirus, chikungunya virus (CHIKV). This disease re-emerged in Kenya in 2004, and spread to the countries in and around the Indian Ocean. The re-emerging epidemics rapidly spread to regions like India and Southeast Asia, and it was subsequently identified in Europe in 2007, probably as a result of importation of chikungunya cases. On the one hand, chikungunya is one of the neglected diseases and has only attracted strong attention during large outbreaks. In 2008-2009, there was a major outbreak of chikungunya fever in Thailand, resulting in the highest number of infections in any country in the region. However, no update of CHIKV circulating in Thailand has been published since 2009. In this study, we examined the viral growth kinetics and sequences of the structural genes derived from CHIKV clinical isolates obtained from the serum specimens of CHIKF-suspected patients in Central Thailand in 2010. We identified the CHIKV harboring two mutations E1-A226V and E2-I211T, indicating that the East, Central, and South African lineage of CHIKV was continuously circulating as an indigenous population in Thailand.
  • 渡邊 洋平; 荒井 泰葉; 大道寺 智; 川下 理日人; Madiha S. Ibrahim; 平松 宏明; 纐纈 律子; 高橋 和郎; 奥野 良信; 中屋 隆明; 鈴木 康夫; 塩田 達雄; 生田 和良
    日本ウイルス学会学術集会プログラム・抄録集 62nd 2014年11月 [査読有り]
  • Yoshinari Oka; Kousuke Okamoto; Norihito Kawashita; Yuko Shirakuni; Tatsuya Takagi
    Biological & pharmaceutical bulletin 37 6 947 - 53 2014年 [査読有り]
     
    It is thought that both selective serotonin reuptake inhibitors (SSRIs) and non-steroidal anti-inflammatory drugs (NSAIDs) can cause the adverse reaction of upper gastrointestinal hemorrhage (UGIH). To evaluate differences in the probability of UGIH occurring when SSRIs, NSAIDs, or both combined are administered, the authors performed a systematic review of related articles and a meta-analysis of data in those articles, which were identified by searching the literature published between 1999 and 2012 using PubMed, Scirus, and Google Scholar. The odds ratios were calculated using the Mantel-Haenszel method. The integrated odds ratios for SSRIs only, NSAIDs only, and the combination were 1.73 (0.65-2.82), 2.55 (1.51-3.59), and 4.02 (2.89-5.15), respectively. Use of the combination resulted in an odds ratio 2.32 times higher than use of either alone. Since the combination of SSRIs and NSAIDs resulted in a significantly higher risk of UGIH than either type of drug alone, clinicians should avoid use of the combination as much as possible. If it is necessary to administer both kinds of drugs, the minimum dosage should be prescribed for the shortest time period possible, and patients, particularly elderly patients, should be closely monitored for development of UGIH and other complications.
  • Sabar Pambudi; Norihito Kawashita; Supranee Phanthanawiboon; Magot Diata Omokoko; Promsin Masrinoul; Akifumi Yamashita; Kriengsak Limkittikul; Teruo Yasunaga; Tatsuya Takagi; Kazuyoshi Ikuta; Takeshi Kurosu
    Biochemical and biophysical research communications 440 3 393 - 8 2013年10月 
    The non-structural protein NS2B/NS3 serine-protease complex of the dengue virus (DENV) is required for the maturation of the viral polyprotein. Dissociation of the NS2B cofactor from NS3 diminishes the enzymatic activity of the complex. In this study, we identified a small molecule inhibitor that interferes with the interaction between NS2B and NS3 using structure-based screening and a cell-based viral replication assay. A library containing 661,417 small compounds derived from the Molecular Operating Environment lead-like database was docked to the NS2B/NS3 structural model. Thirty-nine compounds with high scores were tested in a secondary screening using a cell-based viral replication assay. SK-12 was found to inhibit replication of all DENV serotypes (EC50=0.74-4.92 μM). In silico studies predicted that SK-12 pre-occupies the NS2B-binding site of NS3. Steady-state kinetics using a fluorogenic short peptide substrate demonstrated that SK-12 is a noncompetitive inhibitor against the NS2B/NS3 protease. Inhibition to Japanese encephalitis virus by SK-12 was relatively weak (EC50=29.81 μM), and this lower sensitivity was due to difference in amino acid at position 27 of NS3. SK-12 is the promising small-molecule inhibitor that targets the interaction between NS2B and NS3.
  • Yuko Shirakuni; Kousuke Okamoto; Etuko Uejima; Shigeki Inui; Jun-Ichi Takahara; Takanori Ohgaru; Hiroyuki Yamasaki; Yushi Tian; Norihito Kawashita; Ran Inoue; Teruo Yasunaga; Tatsuya Takagi
    Therapeutic innovation & regulatory science 47 2 235 - 241 2013年03月 
    This study aimed to determine the potentially severe chemical properties of drugs that can cause adverse drug reactions (ADRs) such as erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) by using a data mining method. The study data were extracted from the Adverse Event Reporting System database of the FDA. EM was considered a mild reaction, and SJS and TEN were considered severe reactions. In this study, a new concept termed the "risk of aggravation" (ROA) was defined as whether a certain drug is more likely to cause severe adverse reactions than mild ones. Partial least squares and logistic regression analysis were applied using binary response variable ROAs. These analyses correctly predicted 50 of the 72 drugs associated with SJS and/or TEN and 28 of the 38 drugs associated with EM using binary chemical descriptors that are the same as those using the metric chemical descriptors.
  • Yuko Shirakuni; Kousuke Okamoto; Etuko Uejima; Shigeki Inui; Jun-ichi Takahara; Takanori Ohgaru; Hiroyuki Yamasaki; Yushi Tian; Norihito Kawashita; Ran Inoue; Teruo Yasunaga; Tatsuya Takagi
    THERAPEUTIC INNOVATION & REGULATORY SCIENCE 47 2 235 - 241 2013年03月 [査読有り]
     
    This study aimed to determine the potentially severe chemical properties of drugs that can cause adverse drug reactions (ADRs) such as erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) by using a data mining method. The study data were extracted from the Adverse Event Reporting System database of the FDA. EM was considered a mild reaction, and SJS and TEN were considered severe reactions. In this study, a new concept termed the "risk of aggravation" (ROA) was defined as whether a certain drug is more likely to cause severe adverse reactions than mild ones. Partial least squares and logistic regression analysis were applied using binary response variable ROAs. These analyses correctly predicted 50 of the 72 drugs associated with SJS and/or TEN and 28 of the 38 drugs associated with EM using binary chemical descriptors that are the same as those using the metric chemical descriptors.
  • Mayo Yasugi; Ritsuko Kubota-Koketsu; Akifumi Yamashita; Norihito Kawashita; Anariwa Du; Tadahiro Sasaki; Mitsuhiro Nishimura; Ryo Misaki; Motoki Kuhara; Naphatsawan Boonsathorn; Kazuhito Fujiyama; Yoshinobu Okuno; Takaaki Nakaya; Kazuyoshi Ikuta
    PLOS PATHOGENS 9 2 2013年02月 [査読有り]
     
    Influenza virus has the ability to evade host immune surveillance through rapid viral genetic drift and reassortment; therefore, it remains a continuous public health threat. The development of vaccines producing broadly reactive antibodies, as well as therapeutic strategies using human neutralizing monoclonal antibodies (HuMAbs) with global reactivity, has been gathering great interest recently. Here, three hybridoma clones producing HuMAbs against influenza B virus, designated 5A7, 3A2 and 10C4, were prepared using peripheral lymphocytes from vaccinated volunteers, and were investigated for broad cross-reactive neutralizing activity. Of these HuMAbs, 3A2 and 10C4, which recognize the readily mutable 190-helix region near the receptor binding site in the hemagglutinin (HA) protein, react only with the Yamagata lineage of influenza B virus. By contrast, HuMAb 5A7 broadly neutralizes influenza B strains that were isolated from 1985 to 2006, belonging to both Yamagata and Victoria lineages. Epitope mapping revealed that 5A7 recognizes 316G, 318C and 321W near the C terminal of HA1, a highly conserved region in influenza B virus. Indeed, no mutations in the amino acid residues of the epitope region were induced, even after the virus was passaged ten times in the presence of HuMAb 5A7. Moreover, 5A7 showed significant therapeutic efficacy in mice, even when it was administered 72 hours post-infection. These results indicate that 5A7 is a promising candidate for developing therapeutics, and provide insight for the development of a universal vaccine against influenza B virus.
  • Mayo Yasugi; Ritsuko Kubota-Koketsu; Akifumi Yamashita; Norihito Kawashita; Anariwa Du; Tadahiro Sasaki; Mitsuhiro Nishimura; Ryo Misaki; Motoki Kuhara; Naphatsawan Boonsathorn; Kazuhito Fujiyama; Yoshinobu Okuno; Takaaki Nakaya; Kazuyoshi Ikuta
    PLoS pathogens 9 2 e1003150  2013年02月 
    Influenza virus has the ability to evade host immune surveillance through rapid viral genetic drift and reassortment; therefore, it remains a continuous public health threat. The development of vaccines producing broadly reactive antibodies, as well as therapeutic strategies using human neutralizing monoclonal antibodies (HuMAbs) with global reactivity, has been gathering great interest recently. Here, three hybridoma clones producing HuMAbs against influenza B virus, designated 5A7, 3A2 and 10C4, were prepared using peripheral lymphocytes from vaccinated volunteers, and were investigated for broad cross-reactive neutralizing activity. Of these HuMAbs, 3A2 and 10C4, which recognize the readily mutable 190-helix region near the receptor binding site in the hemagglutinin (HA) protein, react only with the Yamagata lineage of influenza B virus. By contrast, HuMAb 5A7 broadly neutralizes influenza B strains that were isolated from 1985 to 2006, belonging to both Yamagata and Victoria lineages. Epitope mapping revealed that 5A7 recognizes 316G, 318C and 321W near the C terminal of HA1, a highly conserved region in influenza B virus. Indeed, no mutations in the amino acid residues of the epitope region were induced, even after the virus was passaged ten times in the presence of HuMAb 5A7. Moreover, 5A7 showed significant therapeutic efficacy in mice, even when it was administered 72 hours post-infection. These results indicate that 5A7 is a promising candidate for developing therapeutics, and provide insight for the development of a universal vaccine against influenza B virus.
  • Yuko Shirakuni; Kousuke Okamoto; Etuko Uejima; Shigeki Inui; Jun-Ichi Takahara; Takanori Ohgaru; Hiroyuki Yamasaki; Yushi Tian; Norihito Kawashita; Ran Inoue; Teruo Yasunaga; Tatsuya Takagi
    Drug Information Journal 47 2 235 - 241 2013年 [査読有り]
     
    This study aimed to determine the potentially severe chemical properties of drugs that can cause adverse drug reactions (ADRs) such as erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) by using a data mining method. The study data were extracted from the Adverse Event Reporting System database of the FDA. EM was considered a mild reaction, and SJS and TEN were considered severe reactions. In this study, a new concept termed the "risk of aggravation" (ROA) was defined as whether a certain drug is more likely to cause severe adverse reactions than mild ones. Partial least squares and logistic regression analysis were applied using binary response variable ROAs. These analyses correctly predicted 50 of the 72 drugs associated with SJS and/or TEN and 28 of the 38 drugs associated with EM using binary chemical descriptors that are the same as those using the metric chemical descriptors. © The Author(s) 2012.
  • Yu-Shi Tian; Chris Verathamjamras; Norihito Kawashita; Kousuke Okamoto; Teruo Yasunaga; Kazuyoshi Ikuta; Masanori Kameoka; Tatsuya Takagi
    Journal of molecular modeling 19 1 465 - 75 2013年01月 
    Cyclophilin A has attracted attention recently as a new target of anti-human immunodeficiency virus type 1 (HIV-1) drugs. However, so far no drug against HIV-1 infection exhibiting this mechanism of action has been approved. To identify new potent candidates for inhibitors, we performed in silico screening of a commercial database of more than 1,300 drug-like compounds by using receptor-based docking studies. The candidates selected from docking studies were subsequently tested using biological assays to assess anti-HIV activities. As a result, two compounds were identified as the most active. Specifically, both exhibited anti-HIV activity against viral replication at a low concentration and relatively low cytotoxicity at the effective concentration inhibiting viral growth by 50%. Further modification of these molecules may lead to the elucidation of potent inhibitors of HIV-1.
  • Mayo Yasugi; Ritsuko Kubota-Koketsu; Akifumi Yamashita; Norihito Kawashita; Anariwa Du; Ryo Misaki; Motoki Kuhara; Naphatsawan Boonsathorn; Kazuhito Fujiyama; Yoshinobu Okuno; Takaaki Nakaya; Kazuyoshi Ikuta
    PloS one 8 10 e77892  2013年 
    The swine-origin pandemic A(H1N1)2009 virus, A(H1N1)pdm09, is still circulating in parts of the human population. To monitor variants that may escape from vaccination specificity, antigenic characterization of circulating viruses is important. In this study, a hybridoma clone producing human monoclonal antibody against A(H1N1)pdm09, designated 5E4, was prepared using peripheral lymphocytes from a vaccinated volunteer. The 5E4 showed viral neutralization activity and inhibited hemagglutination. 5E4 escape mutants harbored amino acid substitutions (A189T and D190E) in the hemagglutinin (HA) protein, suggesting that 5E4 recognized the antigenic site Sb in the HA protein. To study the diversity of Sb in A(H1N1)pdm09, 58 viral isolates were obtained during the 2009/10 and 2010/11 winter seasons in Osaka, Japan. Hemagglutination-inhibition titers were significantly reduced against 5E4 in the 2010/11 compared with the 2009/10 samples. Viral neutralizing titers were also significantly decreased in the 2010/11 samples. By contrast, isolated samples reacted well to ferret anti-A(H1N1)pdm09 serum from both seasons. Nonsynonymous substitution rates revealed that the variant Sb and Ca2 sequences were being positively selected between 2009/10 and 2010/11. In 7,415 HA protein sequences derived from GenBank, variants in the antigenic sites Sa and Sb increased significantly worldwide from 2009 to 2013. These results indicate that the antigenic variants in Sb are likely to be in global circulation currently.
  • Yohei Watanabe; Madiha S Ibrahim; Hany F Ellakany; Norihito Kawashita; Tomo Daidoji; Tatsuya Takagi; Teruo Yasunaga; Takaaki Nakaya; Kazuyoshi Ikuta
    The Journal of general virology 93 Pt 10 2215 - 2226 2012年10月 
    Highly pathogenic avian influenza virus H5N1 has spread across Eurasia and Africa, and outbreaks are now endemic in several countries, including Indonesia, Vietnam and Egypt. Continuous circulation of H5N1 virus in Egypt, from a single infected source, has led to significant genetic diversification with phylogenetically separable sublineages, providing an opportunity to study the impact of genetic evolution on viral phenotypic variation. In this study, we analysed the phylogeny of H5 haemagglutinin (HA) genes in influenza viruses isolated in Egypt from 2006 to 2011 and investigated the effect of conserved amino acid mutations in the HA genes in each of the sublineages on their antigenicity. The analysis showed that viruses in at least four sublineages still persisted in poultry in Egypt as of 2011. Using reverse genetics to generate HA-reassortment viruses with specific HA mutations, we found antigenic drift in the HA in two influenza virus sublineages, compared with the other currently co-circulating influenza virus sublineages in Egypt. Moreover, the two sublineages with significant antigenic drift were antigenically distinguishable. Our findings suggested that phylogenetically divergent H5N1 viruses, which were not antigenically cross-reactive, were co-circulating in Egypt, indicating that there was a problem in using a single influenza virus strain as seed virus to produce influenza virus vaccine in Egypt and providing data for designing more efficacious control strategies in H5N1-endemic areas.
  • Yuko Shirakuni; Chizuko Hattori; Nobuyasu Yamaguchi; Teruyoshi Kubo; Norihito Kawashita; Tatsuya Takagi; Masao Nasu
    PHARMACOEPIDEMIOLOGY AND DRUG SAFETY 21 208 - 208 2012年08月 [査読有り]
  • C. Verathamjamras; Y. -S. Tian; T. Yasunaga; T. Takagi; N. Kawashita; M. Kameoka
    INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES 16 E194 - E194 2012年06月
  • Norihito Kawashita; Yu-Shi Tian; U. Chandimal de Silva; Kousuke Okamoto; Tatsuya Takagi
    MINI-REVIEWS IN ORGANIC CHEMISTRY 9 1 20 - 26 2012年02月 [査読有り]
     
    Over the past few years, remarkable progress has been made in the development of human immunodeficiency virus (HIV) membrane fusion inhibitors. The focus has been on peptide inhibitors, which were developed by mimicking HIV sequences; however, these types of inhibitors generally lack oral bioavailability and are expensive. Therefore, development of small-molecule inhibitors has gained importance and recently progressed. This paper reviews the rapid advancements in the development of small-molecule HIV inhibitors over the last decade.
  • Mayo Yasugi; Shota Nakamura; Tomo Daidoji; Norihito Kawashita; Ririn Ramadhany; Cheng-Song Yang; Teruo Yasunaga; Tetsuya Iida; Toshihiro Horii; Kazuyoshi Ikuta; Kazuo Takahashi; Takaaki Nakaya
    PloS one 7 2 e30946  2012年 
    BACKGROUND: In April 2009, a novel swine-derived influenza A virus (H1N1pdm) emerged and rapidly spread around the world, including Japan. It has been suggested that the virus can bind to both 2,3- and 2,6-linked sialic acid receptors in infected mammals, in contrast to contemporary seasonal H1N1 viruses, which have a predilection for 2,6-linked sialic acid. METHODS/RESULTS: To elucidate the existence and transmissibility of α2,3 sialic acid-specific viruses in H1N1pdm, amino acid substitutions within viral hemagglutinin molecules were investigated, especially D187E, D222G, and Q223R, which are related to a shift from human to avian receptor specificity. Samples from individuals infected during the first and second waves of the outbreak in Japan were examined using a high-throughput sequencing approach. In May 2009, three specimens from mild cases showed D222G and/or Q223R substitutions in a minor subpopulation of viruses infecting these individuals. However, the substitutions almost disappeared in the samples from five mild cases in December 2010. The D187E substitution was not widespread in specimens, even in May 2009. CONCLUSIONS: These results suggest that α2,3 sialic acid-specific viruses, including G222 and R223, existed in humans as a minor population in the early phase of the pandemic, and that D222 and Q223 became more dominant through human-to-human transmission during the first and second waves of the epidemic. These results are consistent with the low substitution rates identified in seasonal H1N1 viruses in 2008.
  • Norihito Kawashita; Yu-Shi Tian; Chandimal U. de Silva; Kousuke Okamoto; Tatsuya Takagi
    Mini-Reviews in Organic Chemistry 9 1 20 - 26 2012年 
    Over the past few years, remarkable progress has been made in the development of human immunodeficiency virus (HIV) membrane fusion inhibitors. The focus has been on peptide inhibitors, which were developed by mimicking HIV sequences however, these types of inhibitors generally lack oral bioavailability and are expensive. Therefore, development of small-molecule inhibitors has gained importance and recently progressed. This paper reviews the rapid advancements in the development of small-molecule HIV inhibitors over the last decade. © 2012 Bentham Science Publishers.
  • Norihito Kawashita; Masashi Yasuda; Yu-Shi Tian; Kousuke Okamoto; Masaya Kawase; Teruo Yasunaga; Tatsuya Takagi
    ANTIVIRAL RESEARCH 90 2 A71 - A71 2011年05月 [査読有り]
  • Yohei Watanabe; Madiha S Ibrahim; Hany F Ellakany; Norihito Kawashita; Rika Mizuike; Hiroaki Hiramatsu; Nogluk Sriwilaijaroen; Tatsuya Takagi; Yasuo Suzuki; Kazuyoshi Ikuta
    PLoS pathogens 7 5 e1002068  2011年05月 
    Highly pathogenic avian influenza A virus subtype H5N1 is currently widespread in Asia, Europe, and Africa, with 60% mortality in humans. In particular, since 2009 Egypt has unexpectedly had the highest number of human cases of H5N1 virus infection, with more than 50% of the cases worldwide, but the basis for this high incidence has not been elucidated. A change in receptor binding affinity of the viral hemagglutinin (HA) from α2,3- to α2,6-linked sialic acid (SA) is thought to be necessary for H5N1 virus to become pandemic. In this study, we conducted a phylogenetic analysis of H5N1 viruses isolated between 2006 and 2009 in Egypt. The phylogenetic results showed that recent human isolates clustered disproportionally into several new H5 sublineages suggesting that their HAs have changed their receptor specificity. Using reverse genetics, we found that these H5 sublineages have acquired an enhanced binding affinity for α2,6 SA in combination with residual affinity for α2,3 SA, and identified the amino acid mutations that produced this new receptor specificity. Recombinant H5N1 viruses with a single mutation at HA residue 192 or a double mutation at HA residues 129 and 151 had increased attachment to and infectivity in the human lower respiratory tract but not in the larynx. These findings correlated with enhanced virulence of the mutant viruses in mice. Interestingly, these H5 viruses, with increased affinity to α2,6 SA, emerged during viral diversification in bird populations and subsequently spread to humans. Our findings suggested that emergence of new H5 sublineages with α2,6 SA specificity caused a subsequent increase in human H5N1 influenza virus infections in Egypt, and provided data for understanding the virus's pandemic potential.
  • 高原 勇介; 岡本 晃典; 川下 理日人; 高木 達也
    情報化学討論会講演要旨集 2011 P7 - P7 公益社団法人 日本化学会 2011年 
    化学物質には人体や生態系に有害であるものが少なからず存在し、環境中に放出されている。その懸念から化学物質の環境リスクを評価するシステムは様々な形で開発されているが、実験値を必要とすることが多く、広範な化学物質に適用するのは難しい。本研究では広範な化学物質に対する環境リスク評価が可能なシステムの構築を目的に、実験値に替わり化学物質の構造に基づく予測モデルによる推定値を導入することを試みた。
  • Akikazu Sakudo; Koichi Baba; Megumi Tsukamoto; Atsuko Sugimoto; Takashi Okada; Takanori Kobayashi; Norihito Kawashita; Tatsuya Takagi; Kazuyoshi Ikuta
    BIOORGANIC & MEDICINAL CHEMISTRY 19 2 1010 - 1010 2011年01月
  • Bongkot Soonthornsata; Yu-Shi Tian; Piraporn Utachee; Sompong Sapsutthipas; Panasda Isarangkura-na-Ayuthaya; Wattana Auwanit; Tatsuya Takagi; Kazuyoshi Ikuta; Pathom Sawanpanyalert; Norihito Kawashita; Masanori Kameoka
    Virology 405 1 157 - 64 2010年09月 [査読有り]
     
    Two alpha-helical heptad repeats, N-HR and C-HR, located in the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp41, play an important role in membrane fusion by forming a 6-helix bundle. C34, a peptide mimicking C-HR, inhibits the formation of the 6-helix bundle; thus, it has potential as a novel antiretroviral compound. In order to improve the inhibitory effect of C34 on HIV-1 replication, we designed new C34-derived peptides based on computational analysis of the stable conformation of the 6-helix bundle. Newly designed peptides showed a stronger inhibitory effect on the replication of recombinant viruses containing CRF01_AE, subtype B or subtype C Env than C34 or a fusion inhibitor, T-20. In addition, these peptides inhibited the replication of a T-20-resistant virus. We propose that these peptides could be applied to develop novel antiretroviral compounds to inhibit the replication of various subtypes of HIV-1 as well as of T-20-resistant variants.
  • Bongkot Soonthornsata; Yu-Shi Tian; Piraporn Utachee; Sompong Sapsutthipas; Panasda Isarangkura-na-ayuthaya; Wattana Auwanit; Tatsuya Takagi; Kazuyoshi Ikuta; Pathom Sawanpanyalert; Norihito Kawashita; Masanori Kameoka
    VIROLOGY 405 1 157 - 164 2010年09月 
    Two alpha-helical heptad repeats. N-HR and C-HR, located in the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp41, play an important role in membrane fusion by forming a 6-helix bundle. C34, a peptide mimicking C-HR, inhibits the formation of the 6-helix bundle, thus, it has potential as a novel antiretroviral compound In order to improve the inhibitory effect of C34 on HIV-1 replication, we designed new C34-derived peptides based on computational analysis of the stable conformation of the 6-helix bundle Newly designed peptides showed a stronger inhibitory effect on the replication of recombinant viruses containing CRF01_AE, subtype B or subtype C Env than C34 or a fusion inhibitor, T-20 In addition, these peptides inhibited the replication of a T-20-resistant virus We propose that these peptides could be applied to develop novel antiretroviral compounds to inhibit the replication of various subtypes of HIV-I as well as of T-20-resistant variants (C) 2010 Elsevier Inc All rights reserved
  • Shinnosuke Hidaka; Hiroyuki Yamasaki; Yoshihiro Ohmayu; Akiko Matsuura; Kousuke Okamoto; Norihito Kawashita; Tatsuya Takagi
    JOURNAL OF TOXICOLOGICAL SCIENCES 35 3 393 - 399 2010年06月 
    The side effects that occur in the central nervous system and circulatory system due to medicines are expected to be prevented by research and development. However, many of the compounds in medicines have the possibility of causing arrhythmia, and methods developed to detect this problem at the early stage of drug development are not always successful. In the present study, we classified drug compounds according to their activity using only structural information. To classify compounds, we used a self-organizing map (SUM), which is a nonlinear unsupervised classification method. We first analyzed a small-scale dataset, and an excellent classification result was obtained. We then applied our method to a large-scale dataset containing numerous inert compounds and were again able to classify the compounds according to their activity. Both classifications showed some compound activity, although a few differences between the two SOM maps were seen.
  • Shinnosuke Hidaka; Hiroyuki Yamasaki; Yoshihiro Ohmayu; Akiko Matsuura; Kousuke Okamoto; Norihito Kawashita; Tatsuya Takagi
    The Journal of toxicological sciences 35 3 393 - 9 2010年06月 [査読有り]
     
    The side effects that occur in the central nervous system and circulatory system due to medicines are expected to be prevented by research and development. However, many of the compounds in medicines have the possibility of causing arrhythmia, and methods developed to detect this problem at the early stage of drug development are not always successful. In the present study, we classified drug compounds according to their activity using only structural information. To classify compounds, we used a self-organizing map (SOM), which is a nonlinear unsupervised classification method. We first analyzed a small-scale dataset, and an excellent classification result was obtained. We then applied our method to a large-scale dataset containing numerous inert compounds and were again able to classify the compounds according to their activity. Both classifications showed some compound activity, although a few differences between the two SOM maps were seen.
  • Akifumi Yamashita; Norihito Kawashita; Ritsuko Kubota-Koketsu; Yuji Inoue; Yohei Watanabe; Madiha S Ibrahim; Shoji Ideno; Mikihiro Yunoki; Yoshinobu Okuno; Tatsuya Takagi; Teruo Yasunaga; Kazuyoshi Ikuta
    Biochemical and biophysical research communications 393 4 614 - 8 2010年03月 [査読有り]
     
    The epitope sequences within the hemagglutinin (HA) of influenza A virus H3N2 at amino acid residues 173-181 and 227-239 that forms anti-parallel beta-sheet structure are similarly recognized by human monoclonal antibodies (HuMAbs), B-1 and D-1 that we recently obtained using the peripheral blood lymphocytes from two influenza-vaccinated volunteers. Both HuMAbs showed strong global neutralization of H3N2 strains. Here we show the significant conservation of the beta-sheet region consisting of the above-mentioned two epitope regions in H3N2. In addition, we also identified the corresponding regions with similar structure in other subtypes such as H1N1 and H5N1. These two regions are similarly located underneath the receptor-binding sites of individual subtypes. Analysis of those regions using sequences available from the Influenza Virus Resource at the National Center for Biotechnology Information revealed that compared with those in the known neutralizing epitopes A-E, those sequences were fairly conserved in human H3N2 (n=7955), swine H1N1 (n=360) and swine H3N2 (n=235); and highly conserved in human H1N1 (n=2722), swine-origin pandemic H1N1 (n=1474), human H5N1 (n=319) and avian H5N1 (n=2349). Phylogenetic tree for these regions formed clearly separable clusters for H1N1, H3N2 and H5N1, irrespective of different host origin. These data may suggest a possible significance of those regions for development of alternative vaccine that could induce neutralizing antibodies reactive against wide-range of influenza virus strains.
  • Akikazu Sakudo; Guangai Xue; Norihito Kawashita; Yasuhisa Ano; Tatsuya Takagi; Hideharu Shintani; Yasuharu Tanaka; Takashi Onodera; Kazuyoshi Ikuta
    Current protein & peptide science 11 2 166 - 79 2010年03月 
    Prion protein (PrP) gene encodes cellular PrP (PrPC), a glycosylphosphatidylinositol (GPI)-anchored cell membrane protein indispensable for infections of prion, which causes Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE) in cattle, and scrapie in sheep. Although PrPC is known to be converted into an abnormal isoform (PrPSc) upon prion infection and play an important role in prion diseases, the mechanisms involved remain unclear, partly due to the insolubility of PrPSc, which prevents experimental biochemical and biophysical analyses. Recently, with improvements in computer power and methods, computer analyses have been contributing more to prion studies. A comparison of PrP gene sequences revealed mutations and polymorphisms in the open reading frame (ORF) of the human PrP gene related to prion diseases. In contrast, little mutations or polymorphisms related to susceptibility to BSE were found in the ORF of the bovine PrP gene, though relationships between insertion/deletion (Ins/Del) polymorphisms of the PrP gene promoter and susceptibility to BSE have been found. Our results have shown that the specific protein 1 (Sp1) plays important role in the activity of PrP gene promoter, which is influenced by polymorphisms in the Sp1 binding sites. The potential structural dynamics of PrP have been simulated by computational methods such as molecular dynamics (MD) and quantum mechanics (QM). The proposed mechanisms of conversion have revealed new insights in prion diseases. In this review, we will introduce the gene structure, polymorphisms, and potential structural dynamics of PrP revealed by basic and advanced computational analyses. The possible contribution of these methods to elucidation of the pathogenicity of prion diseases and functions of PrPC is discussed.
  • Akikazu Sakudo; Guangai Xue; Norihito Kawashita; Yasuhisa Ano; Tatsuya Takagi; Hideharu Shintani; Yasuharu Tanaka; Takashi Onodera; Kazuyoshi Ikuta
    CURRENT PROTEIN & PEPTIDE SCIENCE 11 2 166 - 179 2010年03月 [査読有り]
     
    Prion protein (PrP) gene encodes cellular PrP (PrPC), a glycosylphosphatidylinositol (GPI)-anchored cell membrane protein indispensable for infections of prion, which causes Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE) in cattle, and scrapie in sheep. Although PrPC is known to be converted into an abnormal isoform (PrPSc) upon prion infection and play an important role in prion diseases, the mechanisms involved remain unclear, partly due to the insolubility of PrPSc, which prevents experimental biochemical and biophysical analyses. Recently, with improvements in computer power and methods, computer analyses have been contributing more to prion studies. A comparison of PrP gene sequences revealed mutations and polymorphisms in the open reading frame (ORF) of the human PrP gene related to prion diseases. In contrast, little mutations or polymorphisms related to susceptibility to BSE were found in the ORF of the bovine PrP gene, though relationships between insertion/deletion (Ins/Del) polymorphisms of the PrP gene promoter and susceptibility to BSE have been found. Our results have shown that the specific protein 1 (Sp1) plays important role in the activity of PrP gene promoter, which is influenced by polymorphisms in the Sp1 binding sites. The potential structural dynamics of PrP have been simulated by computational methods such as molecular dynamics (MD) and quantum mechanics (QM). The proposed mechanisms of conversion have revealed new insights in prion diseases. In this review, we will introduce the gene structure, polymorphisms, and potential structural dynamics of PrP revealed by basic and advanced computational analyses. The possible contribution of these methods to elucidation of the pathogenicity of prion diseases and functions of PrPC is discussed.
  • Shinnosuke Hidaka; Hiroaki Shiraishi; Yoshihiro Ohmayu; Hiroyuki Yamasaki; Kousuke Okamoto; Norihito Kawashita; Teruo Yasunaga; Tatsuya Takagi
    Journal of Computer Aided Chemistry vol.11, 11-18 11 - 18 日本化学会情報化学部会 2010年02月 [査読有り]
     
    A vast quantity of chemicals are present in our environment and are considered indispensable to our high technological society. However, there are some chemicals that are hazardous and that can extensively impact both human health and the global environment. In Japan, ecotoxicity tests of chemical substances have been conducted with the goal of contributing to the Organization for Economic Cooperation and Development (OECD) evaluation program for harmful high-production volume (HPV) chemicals since 1995. To date, only about 500 compounds have been tested. There is a possibility that quantitative structure-activity relationships (QSARs) may enable us to predict environmental toxicities and fates as well as the physical and chemical properties of compounds; therefore, the toxicity prediction by QSARs is a possible alternative to the measurements of their ecotoxicities. In this study, we generated QSAR models from toxicity tests of Daphnids using only 3D descriptors to examine the availability of particular 3D descriptors for predicting of the ecotoxicity of compounds with various structures. Predicton accuracy of the model generated in this study was adequate and improved compared to
  • 井上 藍; 白國 優子; 川下 理日人; 岡本 晃典; 高木 達也
    情報化学討論会講演要旨集 2010 JP08 - JP08 公益社団法人 日本化学会 2010年 
    重篤な皮膚疾患であるStevens-Johnson syndrome(SJS)とSJS類似疾患であるerythema multiforme(EM)やtoxic epidermal necrolysis(TEN)との差異を明らかにすることで、有害事象の早期発見、重篤化防止に役立つ情報の提供を行う。FDAデータベースから情報を抽出し、ロジスティック回帰分析を用いて、重症化する要因となる部分構造や化学的性質を見出した。
  • Yuko Shirakuni; Kousuke Okamoto; Norihito Kawashita; Teruo Yasunaga; Tatsuya Takagi
    Journal of Computer Aided Chemistry 10, 118-127 118 - 127 日本化学会情報化学部会 2009年11月 [査読有り]
     
    The adverse events induced by drugs have been complicated, when two or more drugs are administrated for a patient. We selected "Stevens-Johnson Syndrome (SJS) " as a research object, which is one of the severe skin manifestations. The data source is a database constructed by the Food and Drug Administration (FDA). FDA's post-marketing safety surveillance program is supported by the Adverse Event Reporting System (AERS). AERS is designed with a computerized information database. To analyze the relationships between the concurrent medication and SJS in this study, we applied association rule learning. Our purpose is to propose an efficient procedure that enables the detection of signals for drugs related to an adverse event, without assuming the involvement of a specific drug. We defined new value K for the evaluation of existing signal detection. Association rule was evaluated according to criterion K value. As a result, it was suggested to obtain a strong signal by combining two concomitant drugs. Association rule learning in this study was applicable for the analysis of the relationships between adverse events and pairs of drugs.
  • Akikazu Sakudo; Koichi Baba; Megumi Tsukamoto; Atsuko Sugimoto; Takashi Okada; Takanori Kobayashi; Norihito Kawashita; Tatsuya Takagi; Kazuyoshi Ikuta
    Bioorganic & medicinal chemistry 17 2 752 - 7 2009年01月 [査読有り]
     
    An anionic magnetic beads-based method was developed for the capture of human influenza A and B viruses from nasal aspirates, allantoic fluid and culture medium. A polymer, poly(methyl vinyl ether-maleic anhydride) [poly(MVE-MA)], was used to endow magnetic beads with a negative charge and bioadhesive properties. After incubation with samples containing human influenza virus, the beads were separated from supernatants by applying a magnetic field. The adsorption [corrected] of the virus by the beads was confirmed by hemagglutinin assay, immunochromatography, Western blotting, egg infection, and cell infection. Successful capture was proved using 5 H1N1 influenza A viruses, 10 H3N2 influenza A viruses, and 6 influenza B viruses. Furthermore, the infectivity in chicken embryonated eggs and Madin-Darby canine kidney (MDCK) cells of the captured human influenza virus was similar to that of the total viral quantity of starting materials. Therefore, this method of capture using magnetic beads coated with poly(MVE-MA) can be broadly used for the recovery of infectious human influenza viruses.
  • Y. Shirakuni; E. Uejima; J. Takahara; K. Okamoto; N. Kawashita; T. Yasunaga; S. Inui; T. Takagi
    DRUG SAFETY 32 10 920 - 920 2009年
  • Norihito Kawashita
    JOURNAL OF PHARMACOLOGICAL SCIENCES 109 32P - 32P 2009年 [査読有り]
  • Norihito Kawashita; Yu-Shi Tian; Masashi Yasuda; U. Chandimal de Silva; Rie Kashiwada; Shota Nakamura; Naohisa Goto; Rika Nishikiori; Kousuke Okamoto; Masanori Kameoka; Teruo Yasunaga; Masaya Kawase; Kazuyoshi Ikuta; Tatsuya Takagi
    ANTIVIRAL RESEARCH 78 2 A42 - A42 2008年05月 [査読有り]
  • Takanori Ohgaru; Ryo Shimizu; Kosuke Okamoto; Norihito Kawashita; Masaya Kawase; Yuko Shirakuni; Rika Nishikiori; Tatsuya Takagi
    Journal of chemical information and modeling 48 4 910 - 7 2008年04月 
    Conventional comparative molecular field analysis (CoMFA) requires at least 3 orders of experimental data, such as IC 50 and K i, to obtain a good model, although practically there are many screening assays where biological activity is measured only by rating scale. To improve three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis, we developed in this study a modified ordinal classification-oriented CoMFA using partial-least-squares generalized linear regression and ridge estimation. The modified Logistic CoMFA was validated using a corticosteroid binding globulin receptor binding data set, a benchmark for 3D-QSAR, and an acetylcholine esterase inhibitor data set. Our results show that modification of Logistic CoMFA enhanced both prediction accuracy and 3D graphical analysis. In addition, the 3D graphical analysis of the modified Logistic CoMFA was much improved. This improvement resulted in more accurate information on the binding mode between proteins and ligands than in the case of conventional CoMFA.
  • Takanori Ohgaru; Ryo Shimizu; Kosuke Okamoto; Norihito Kawashita; Masaya Kawase; Yuko Shirakuni; Rika Nishikiori; Tatsuya Takagi
    JOURNAL OF CHEMICAL INFORMATION AND MODELING 48 4 910 - 917 2008年04月 [査読有り]
     
    Conventional comparative molecular field analysis (CoMFA) requires at least 3 orders of experimental data, such as IC50 and K-i, to obtain a good model, although practically there are many screening assays where biological activity is measured only by rating scale. To improve three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis, we developed in this study a modified ordinal classification-oriented CoMFA using partial-least-squares generalized linear regression and ridge estimation. The modified Logistic CoMFA was validated using a corticosteroid binding globulin receptor binding data set, a benchmark for 3D-QSAR, and an acetylcholine esterase inhibitor data set. Our results show that modification of Logistic CoMFA enhanced both prediction accuracy and 3D graphical analysis. In addition, the 3D graphical analysis of the modified Logistic CoMFA was much improved. This improvement resulted in more accurate information on the binding mode between proteins and ligands than in the case of conventional CoMFA.
  • Rika Nishikiori; Mariko Yamaguchi; Keisuke Takano; Tokujiro Enatsu; Masahiko Tani; U Chandimal de Silva; Norihito Kawashita; Tatsuya Takagi; Shotaro Morimoto; Masanori Hangyo; Masaya Kawase
    Chemical & pharmaceutical bulletin 56 3 305 - 7 2008年03月 
    Absorption spectra of polycrystalline L-, D-, and DL-tartaric acid have been measured by terahertz time domain spectroscopy (THz-TDS). Different absorption bands are observed for DL-tartaric acid and its enantiomers (L- and D-tartaric acid). This result shows that the THz-TDS can be used for distinguishing between DL-tartaric acid and enantiomers (L- and D-tartaric acid). Moreover, partial least square (PLS) can be found to improve the quantitation of L-tartaric acid in L- and DL-tartaric acid mixture by THz-TDS.
  • Rika Nishikiori; Mariko Yamaguchi; Keisuke Takano; Tokujiro Enatsu; Masahiko Tani; U. Chandimal De Silva; Norihito Kawashita; Tatsuya Takagi; Shotaro Morimoto; Masanori Hangyo; Masaya Kawase
    Chemical and Pharmaceutical Bulletin 56 3 305 - 307 2008年03月 [査読有り]
     
    Absorption spectra of polycrystalline L-, D-, and DL-tartaric acid have been measured by terahertz time domain spectroscopy (THz-TDS). Different absorption bands are observed for DL-tartaric acid and its enantiomers (L- and D-tartaric acid). This result shows that the THz-TDS can be used for distinguishing between DL-tartaric acid and enantiomers (L- and D-tartaric acid). Moreover, partial least square (PLS) can be found to improve the quantitation of L-tartaric acid in L- and DL-tartaric acid mixture by THz-TDS. © 2008 Pharmaceutical Society of Japan.
  • Rika Nishikiori; Yukiko Makino; Yukino Ochi; Noriyuki Yamashita; Kousuke Okamoto; Norihito Kawashita; Jun-ichi Takahara; Teruo Yasunaga; Tatsuya Takagi; Masaya Kawase
    J. Comput. Aided Chem. 9, 30-36 30 - 36 2008年03月 [査読有り]
  • Shuji Akai; Norihito Kawashita; Yasufumi Wada; Hideharu Satoh; Anahita; Hessamian Alinejad; Keisuke Kakiguchi; Ikumi Kuriwaki; Yasuyuki Kita
    Tetrahedron Letters 47 12 1881 - 1884 Elsevier 2006年03月 [査読有り]
     
    The treatment of the 5-(phenylsulfinyl)indoles with trifluoroacetic anhydride in the presence of carbon nucleophiles achieved the title reactions with complete regioselectivity.
  • Shuji Akai; Norihito Kawashita; Hideharu Satoh; Yasufumi Wada; Keisuke Kakiguchi; Ikumi Kuriwaki; Yasuyuki Kita
    Organic letters 6 21 3793 - 6 2004年10月 [査読有り]
     
    [reaction: see text] The reactions of (phenylsulfinyl)furans or -thiophenes with carbon nucleophiles in the presence of trifluoroacetic anhydride allowed the nucleophilic installation of carbon functional groups on the furan and thiophene nuclei with complete regioselectivity.
  • S Akai; N Kawashita; N Morita; Y Nakamura; K Iio; Y Kita
    HETEROCYCLES 58 75 - 78 2002年11月 
    A novel and convergent synthesis of 2,3,5-trisubstituted indoles (6) from p-sulfinylaniline (1) is described. The single p-sulfinyl group was repeatedly employed in two ways; viz., the construction of the 2,3-disubstituted indole/indoline skeleton and the introduction of a carbon substituent at the C-5 position.

MISC

書籍等出版物

担当経験のある科目_授業

  • 量子化学近畿大学
  • 数理情報処理近畿大学
  • エネルギー物質化学実験近畿大学
  • 基礎化学情報処理近畿大学
  • 物理数学演習近畿大学理工学部(エネルギー物質学科)
  • 化学数学演習近畿大学理工学部(エネルギー物質学科)
  • エネルギー物質概論近畿大学理工学部(エネルギー物質学科)
  • 臨床遺伝学Ⅰ近畿大学
  • 遺伝カウンセリングⅡ近畿大学大学院(遺伝カウンセラー養成課程)
  • 機能性物質開発特論近畿大学大学院(東大阪モノづくり専攻)
  • 遺伝サービス情報学近畿大学大学院(遺伝カウンセラー養成課程)
  • 人類遺伝学演習近畿大学大学院(遺伝カウンセラー養成課程)
  • 生命分子・環境化学総論近畿大学大学院(理学専攻)
  • 計算生命科学特論近畿大学大学院(理学専攻)
  • 化学実験近畿大学理工学部(生命科学科)
  • バイオインフォマティクス(生物情報学)近畿大学理工学部(生命科学科)
  • 生命科学序論近畿大学理工学部(生命科学科)
  • 生物統計学近畿大学理工学部(生命科学科)
  • 細胞生物学実験近畿大学理工学部(生命科学科)
  • 分析化学近畿大学理工学部(生命科学科)
  • 臨床遺伝学Ⅱ近畿大学大学院(遺伝カウンセラー養成課程)
  • 基礎生物学近畿大学理工学部
  • 公衆衛生学近畿大学理工学部(生命科学科)
  • 生物無機化学近畿大学理工学部(生命科学科)
  • 衛生薬学2大阪大学
  • 衛生薬学特論大阪大学大学院
  • 環境と化学物質大阪大学
  • くすりの効くわけ大阪大学
  • くすりと生体大阪大学
  • バイオ医薬品大阪大学
  • 健康情報学大阪大学
  • 薬学統計入門大阪大学
  • 生物情報科学特論大阪大学
  • 情報活用基礎大阪大学
  • 医薬品開発学大阪大学

所属学協会

  • 日本薬学会(構造活性相関部会、医薬化学部会)   日本遺伝性腫瘍学会   日本人類遺伝学会   日本ウイルス学会   日本バイオインフォマティクス学会   日本遺伝子診療学会   CBI学会   

Works_作品等

  • オーファンドラッグのリスク管理システム構築に関する基盤的研究
    2011年
  • 多剤耐性HIVにおける将来的な変異・構造予測と新規抗HIV薬開発
    2009年
  • 化学物質の光分解・加水分解反応データベースの構築とそのデータマイニングによる予測手法開発
    2009年
  • データマイニングを用いた医薬品併用による有害事象の発見
    2009年
  • 大阪大学感染症国際研究拠点 タイ感染症共同研究センター
    2009年
  • 多剤耐性HIVにおける将来的な変異・構造予測と新規抗HIV薬開発
    2009年
  • NEDO知的基盤研究開発事業、「分解生成物予測のための光分解、加水分解反応データベースの構築」
    2009年
  • 多剤耐性HIVにおける将来的な変異・構造予測と新規抗HIV薬開発
    2008年
  • 多剤耐性HIVにおける将来的な変異・構造予測と新規抗HIV薬開発
    2008年
  • 大阪大学感染症国際研究拠点 タイ感染症共同研究センター
    2008年
  • 大阪大学感染症国際研究拠点 タイ感染症共同研究センター
    2007年
  • 多剤耐性HIVにおける将来的な変異・構造予測と新規抗HIV薬開発
    2007年
  • 量子化学・分子力学的手法を利用した抗ウイルス剤開発指向ドッキングスタディ
    2007年
  • Research Collaboration Center on Emerging and Re-emerging Infections
    2006年
  • 量子化学・分子力学的手法を利用した抗ウイルス剤開発指向ドッキングスタディ
    2006年
  • 大阪大学感染症国際研究拠点 タイ感染症共同研究センター
    2006年
  • Research Collaboration Center on Emerging and Re-emerging Infections
    2005年
  • 大阪大学感染症国際研究拠点 タイ感染症共同研究センター
    2005年

共同研究・競争的資金等の研究課題

  • 遺伝性消化管腫瘍症候群の遺伝学的検査の深化と次世代型遺伝医療の基盤研究
    日本学術振興会:科学研究費助成事業 基盤研究(C)
    研究期間 : 2019年04月 -2022年03月 
    代表者 : 田村 和朗
  • エントロピー変化に依存しない新規自由エネルギー変化予測手法の開発
    日本学術振興会:科学研究費助成事業 基盤研究(C)
    研究期間 : 2017年04月 -2020年03月 
    代表者 : 川下 理日人
  • 医薬品候補化合物の副作用発症確率を予測する数理モデルの創成
    日本学術振興会:科学研究費助成事業 基盤研究(B)
    研究期間 : 2015年 -2019年03月 
    代表者 : 高木 達也
  • 新規潜在変数型回帰分析法、PCLSの開発とその医薬学データへの応用
    日本学術振興会:科学研究費助成事業 基盤研究(C)
    研究期間 : 2013年04月 -2017年03月 
    代表者 : 高木 達也
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2012年05月 -2016年03月 
    代表者 : 小比賀 聡; 兒玉 哲也; 高木 達也; 森廣 邦彦; 川下 理日人
     
    アンチセンス医薬において解決すべき4つの課題に焦点を絞り研究を推進し以下の成果を得た。まず、アンチセンス分子の高精度な定性的配列予測モデルを構築した。また、設計概念の異なる3種類のアンチセンス分子素材候補の創出に成功した。さらに、オリゴヌクレオチドをこれら人工核酸で修飾する時の注意点を明らかにした。そして、アンチセンス分子を生体機能調節化合物により複合体化することで、これまで移行性が議論されたことのなかった特定細胞への移行性をアンチセンス分子に付与できることを示した。
  • 未知の薬剤耐性予測を目的としたインシリコ薬剤耐性評価法の確立
    日本学術振興会:科学研究費助成事業 若手研究(B)
    研究期間 : 2012年04月 -2014年03月 
    代表者 : 川下 理日人
  • 医薬学分野で要する統計解析の理解促進に資するWebアプリケーションの構築
    厚生労働省:厚生労働科学研究費補助金
    研究期間 : 2010年 -2012年03月 
    代表者 : 岡本 晃典
  • データマイニングを用いた、医薬品併用による有害事象の発見
    日本学術振興会:科学研究費助成事業 基盤研究(C)
    研究期間 : 2009年04月 -2011年03月 
    代表者 : 高木 達也
  • 多剤耐性HIVにおける将来的な変異・構造予測と新規抗HIV薬開発
    厚生労働省:厚生労働科学研究費補助金
    研究期間 : 2007年 -2009年03月 
    代表者 : 川下 理日人
     
    1)耐性ウイルスに対する網羅的配列解析と正の淘汰圧を持つ変異部位の確定 2)多剤耐性ウイルス蛋白質に対する構造予測および阻害剤予測 3)今後起こりうる耐性変異の予測とそれら変異蛋白質の構造予測 4)構造未知蛋白質のX線結晶構造解析
  • 量子化学・分子力学的手法を利用した抗ウイルス剤開発指向ドッキングスタディ
    日本学術振興会:科学研究費補助金 若手研究(スタートアップ)
    研究期間 : 2006年 -2007年03月 
    代表者 : 川下 理日人
     
    コンピューターシミュレーションを利用して、実際にPDBファイルとして存在するインフルエンザ蛋白質と、リン酸オゼルタミビルやザナミビルなど、既知阻害剤とのドッキングスタディを行い、これら既知阻害剤の効果を評価する。さらにインフルエンザ蛋白質の高変異部位におけるアミノ酸変異と蛋白質の三次構造との関連を考察する。また、それらの三次構造と既知阻害剤とのドッキングスタディを行い、アミノ酸の一点変異が阻害剤の効果といかなる関係があるかを考察する。
  • Development of Novel Organic Reaction
    The Other Research Programs
    研究期間 : 2000年 -2005年

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