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262 results on '"Kii, Isao"'

2. 1,3-Butadiynyl sulfide-based compact trialkyne platform molecule for sequential assembly of three azides.

Author

Taguchi, Jumpei, Tokunaga, Kento, Tabuchi, Hitomi, Nishiyama, Takashi, Kii, Isao, and Hosoya, Takamitsu

Subjects
TRIAZOLES, AZIDES, MOIETIES (Chemistry), SULFIDES, MOLECULES
Abstract

A compact trialkyne platform with a silyl-protected 1,3-butadiynyl sulfide moiety and a terminal alkyne group has been developed for sequential regioselective transition metal-catalyzed triazole formation reactions with three azides. This method enabled the facile construction of a low-molecular-weight triazole library and the synthesis of middle-molecular-weight trifunctional probes for protein modification. [ABSTRACT FROM AUTHOR]

Published
2024
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7. Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly

Author

Ohnishi, Takayuki, Yanazawa, Masako, Sasahara, Tomoya, Kitamura, Yasuki, Hiroaki, Hidekazu, Fukazawa, Yugo, Kii, Isao, Nishiyama, Takashi, Kakita, Akiyoshi, Takeda, Hiroyuki, Takeuchi, Akihide, Arai, Yoshie, Ito, Akane, Komura, Hitomi, Hirao, Hajime, Satomura, Kaori, Inoue, Masafumi, Muramatsu, Shin-ichi, Matsui, Ko, Tada, Mari, Sato, Michio, Saijo, Eri, Shigemitsu, Yoshiki, Sakai, Satoko, Umetsu, Yoshitaka, Goda, Natsuko, Takino, Naomi, Takahashi, Hitoshi, Hagiwara, Masatoshi, Sawasaki, Tatsuya, Iwasaki, Genji, Nakamura, Yu, Nabeshima, Yo-ichi, Teplow, David B, and Hoshi, Minako

Subjects
Alzheimer's Disease, Brain Disorders, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurodegenerative, Neurosciences, Dementia, Aging, Acquired Cognitive Impairment, Aetiology, 2.1 Biological and endogenous factors, Neurological, Alzheimer Disease, Amino Acid Sequence, Amyloid beta-Peptides, Animals, Calcium, Cell Death, Cells, Cultured, HEK293 Cells, Homeostasis, Humans, Mass Spectrometry, Models, Biological, Models, Molecular, Molecular Imaging, Molecular Sequence Data, Molecular Weight, Neurons, Peptides, Protein Aggregates, Protein Binding, Rats, Signal Transduction, Sodium, Sodium-Potassium-Exchanging ATPase, NMR, computational modeling, abnormal protein-protein interaction in synapse, hyperexcitotoxicity, protein-protein interaction inhibitors, abnormal protein–protein interaction in synapse, protein–protein interaction inhibitors
Abstract

Neurodegeneration correlates with Alzheimer's disease (AD) symptoms, but the molecular identities of pathogenic amyloid β-protein (Aβ) oligomers and their targets, leading to neurodegeneration, remain unclear. Amylospheroids (ASPD) are AD patient-derived 10- to 15-nm spherical Aβ oligomers that cause selective degeneration of mature neurons. Here, we show that the ASPD target is neuron-specific Na(+)/K(+)-ATPase α3 subunit (NAKα3). ASPD-binding to NAKα3 impaired NAKα3-specific activity, activated N-type voltage-gated calcium channels, and caused mitochondrial calcium dyshomeostasis, tau abnormalities, and neurodegeneration. NMR and molecular modeling studies suggested that spherical ASPD contain N-terminal-Aβ-derived "thorns" responsible for target binding, which are distinct from low molecular-weight oligomers and dodecamers. The fourth extracellular loop (Ex4) region of NAKα3 encompassing Asn(879) and Trp(880) is essential for ASPD-NAKα3 interaction, because tetrapeptides mimicking this Ex4 region bound to the ASPD surface and blocked ASPD neurotoxicity. Our findings open up new possibilities for knowledge-based design of peptidomimetics that inhibit neurodegeneration in AD by blocking aberrant ASPD-NAKα3 interaction.

Published
2015

24. CDK9 inhibitor FIT-039 prevents replication of multiple DNA viruses

Author

Yamamoto, Makoto, Onogi, Hiroshi, Kii, Isao, Yoshida, Suguru, Iida, Kei, Sakai, Hiroyuki, Abe, Minako, Tsubota, Toshiaki, Ito, Nobutoshi, and Hosoya, Takamitsu

Subjects
Physiological aspects, Research, Health aspects, Protein kinases -- Physiological aspects -- Research, DNA viruses -- Research -- Health aspects, Virus replication -- Analysis -- Health aspects -- Research
Abstract

Introduction The number of available antiviral drugs has increased continually since the development of azidothymidine and acyclovir (ACV) in the 1970s (1,2). However, this has resulted in the emergence of [...], A wide range of antiviral drugs is currently available; however, drug-resistant viruses have begun to emerge and represent a potential public health risk. Here, we explored the use of compounds that inhibit or interfere with the action of essential host factors to prevent virus replication. In particular, we focused on the cyclin-dependent kinase 9 (CDK9) inhibitor, FIT-039, which suppressed replication of a broad spectrum of DNA viruses through inhibition of mRNA transcription. Specifically, FIT-039 inhibited replication of herpes simplex virus 1 (HSV-1), HSV-2, human adenovirus, and human cytomegalovirus in cultured cells, and topical application of FIT-039 ointment suppressed skin legion formation in a murine HSV-1 infection model. FIT-039 did not affect cell cycle progression or cellular proliferation in host cells. Compared with the general CDK inhibitor flavopiridol, transcriptome analyses of FIT-039-treated cells revealed that FIT-039 specifically inhibited CDK9. Given at concentrations above the inhibitory concentration, FIT-039 did not have a cytotoxic effect on mammalian cells. Importantly, administration of FIT-039 ameliorated the severity of skin lesion formation in mice infected with an acyclovir-resistant HSV-1, without noticeable adverse effects. Together, these data indicate that FIT-039 has potential as an antiviral agent for clinical therapeutics.

Published
2014
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37. HaloTag-based conjugation of proteins to barcoding-oligonucleotides

Author

Yazaki, Junshi, primary, Kawashima, Yusuke, additional, Ogawa, Taisaku, additional, Kobayashi, Atsuo, additional, Okoshi, Mayu, additional, Watanabe, Takashi, additional, Yoshida, Suguru, additional, Kii, Isao, additional, Egami, Shohei, additional, Amagai, Masayuki, additional, Hosoya, Takamitsu, additional, Shiroguchi, Katsuyuki, additional, and Ohara, Osamu, additional

Published
2019
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38. This title is unavailable for guests, please login to see more information.

Author

Komura, Hitomi, Kakio, Shota, Sasahara, Tomoya, Arai, Yoshie, Takino, Naomi, Sato, Michio, Satomura, Kaori, Ohnishi, Takayuki, Nabeshima, Yo-ichi, Muramatsu, Shin-ichi, Kii, Isao, Hoshi, Minako, Komura, Hitomi, Kakio, Shota, Sasahara, Tomoya, Arai, Yoshie, Takino, Naomi, Sato, Michio, Satomura, Kaori, Ohnishi, Takayuki, Nabeshima, Yo-ichi, Muramatsu, Shin-ichi, Kii, Isao, and Hoshi, Minako

Published
2019

41. DYRK1B mutations associated with metabolic syndrome impair the chaperone-dependent maturation of the kinase domain

Author

Abu Jhaisha, Samira, Widowati, Esti W., Kii, Isao, Sonamoto, Rie, Knapp, Stefan, Papadopoulos, Chrisovalantis, and Becker, Walter

Subjects
Protein Folding, Chaperonins, Protein Conformation, Science, Forschungszentren » Zentrum für Medizinische Biotechnologie (ZMB), Cell Cycle Proteins, Kinases, Protein Serine-Threonine Kinases, Article, Protein Domains, Catalytic Domain, ddc:570, Chaperones, Humans, ddc:610, Phosphorylation, ddc:576, Metabolic Syndrome, Protein-Tyrosine Kinases, Triazoles, Mechanisms of disease, Mutation, Tyrosine, Medicine, Biologie, HeLa Cells, Cell signalling
Abstract

Scientific reports 7(1), 6420 (2017). doi:10.1038/s41598-017-06874-w, Published by Nature Publishing Group, London

Published
2017
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48. Development of an orally available inhibitor of CLK1 for skipping a mutated dystrophin exon in Duchenne muscular dystrophy

Author

00372524, 20600505, 10208423, Sako, Yukiya, Ninomiya, Kensuke, Okuno, Yukiko, Toyomoto, Masayasu, Nishida, Atsushi, Koike, Yuka, Ohe, Kenji, Kii, Isao, Yoshida, Suguru, Hashimoto, Naohiro, Hosoya, Takamitsu, Matsuo, Masafumi, Hagiwara, Masatoshi, 00372524, 20600505, 10208423, Sako, Yukiya, Ninomiya, Kensuke, Okuno, Yukiko, Toyomoto, Masayasu, Nishida, Atsushi, Koike, Yuka, Ohe, Kenji, Kii, Isao, Yoshida, Suguru, Hashimoto, Naohiro, Hosoya, Takamitsu, Matsuo, Masafumi, and Hagiwara, Masatoshi

Abstract

Duchenne muscular dystrophy (DMD) is a fatal progressive muscle-wasting disease. Various attempts are underway to convert severe DMD to a milder phenotype by modulating the splicing of the dystrophin gene and restoring its expression. In our previous study, we reported TG003, an inhibitor of CDC2-like kinase 1 (CLK1), as a splice-modifying compound for exon-skipping therapy; however, its metabolically unstable feature hinders clinical application. Here, we show an orally available inhibitor of CLK1, named TG693, which promoted the skipping of the endogenous mutated exon 31 in DMD patient-derived cells and increased the production of the functional exon 31-skipped dystrophin protein. Oral administration of TG693 to mice inhibited the phosphorylation of serine/arginine-rich proteins, which are the substrates of CLK1, and modulated pre-mRNA splicing in the skeletal muscle. Thus, TG693 is a splicing modulator for the mutated exon 31 of the dystrophin gene in vivo, possibly possessing therapeutic potential for DMD patients.

Published
2017

49. DYRK1B mutations associated with metabolic syndrome impair the chaperone-dependent maturation of the kinase domain

Author

Jhaisha, Samira Abu, Widowati, Esti W., Kii, Isao, Sonamoto, Rie, Knapp, Stefan, Papadopoulos, Chrisovalantis, Becker, Walter, Jhaisha, Samira Abu, Widowati, Esti W., Kii, Isao, Sonamoto, Rie, Knapp, Stefan, Papadopoulos, Chrisovalantis, and Becker, Walter

Abstract

Two missense mutations of the DYRK1B gene have recently been found to co-segregate with a rare autosomal-dominant form of metabolic syndrome. This gene encodes a member of the DYRK family of protein kinases, which depend on tyrosine autophosphorylation to acquire the catalytically active conformation. The mutations (H90P and R102C) affect a structural element named DYRK homology (DH) box and did not directly interfere with the conformation of the catalytic domain in a structural model of DYRK1B. Cellular assays showed that the mutations did not alter the specific activity of mature kinase molecules. However, a significant part of the mutant DYRK1B protein accumulated in detergent-insoluble cytoplasmic aggregates and was underphosphorylated on tyrosine. The mutant DYRK1B variants were more vulnerable to the HSP90 inhibitor ganetespib and showed enhanced binding to the co-chaperone CDC37 as compared to wild type DYRK1B. These results support the hypothesis that the mutations in the DH box interfere with the maturation of DYRK1B by tyrosine autophosphorylation and compromise the conformational stability of the catalytic domain, which renders the kinase susceptible to misfolding.

Published
2017

50. Selective inhibition of the kinase DYRK1A by targeting its folding process

Author

00372524, 10208423, Kii, Isao, Sumida, Yuto, Goto, Toshiyasu, Sonamoto, Rie, Okuno, Yukiko, Yoshida, Suguru, Kato-Sumida, Tomoe, Koike, Yuka, Abe, Minako, Nonaka, Yosuke, Ikura, Teikichi, Ito, Nobutoshi, Shibuya, Hiroshi, Hosoya, Takamitsu, Hagiwara, Masatoshi, 00372524, 10208423, Kii, Isao, Sumida, Yuto, Goto, Toshiyasu, Sonamoto, Rie, Okuno, Yukiko, Yoshida, Suguru, Kato-Sumida, Tomoe, Koike, Yuka, Abe, Minako, Nonaka, Yosuke, Ikura, Teikichi, Ito, Nobutoshi, Shibuya, Hiroshi, Hosoya, Takamitsu, and Hagiwara, Masatoshi

Abstract

Autophosphorylation of amino-acid residues is part of the folding process of various protein kinases. Conventional chemical screening of mature kinases has missed inhibitors that selectively interfere with the folding process. Here we report a cell-based assay that evaluates inhibition of a kinase at a transitional state during the folding process and identify a folding intermediate-selective inhibitor of dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A), which we refer to as FINDY. FINDY suppresses intramolecular autophosphorylation of Ser97 in DYRK1A in cultured cells, leading to its degradation, but does not inhibit substrate phosphorylation catalysed by the mature kinase. FINDY also suppresses Ser97 autophosphorylation of recombinant DYRK1A, suggesting direct inhibition, and shows high selectivity for DYRK1A over other DYRK family members. In addition, FINDY rescues DYRK1A-induced developmental malformations in Xenopus laevis embryos. Our study demonstrates that transitional folding intermediates of protein kinases can be targeted by small molecules, and paves the way for developing novel types of kinase inhibitors.

Published
2016

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