当前位置： SCI文献检索 > BIOCHEMISTRY期刊下所有文献 > Phenylthiazolyl-hydrazide and its derivatives are potent inhibitors of tau aggregation and toxicity in vitro and in cells.

Phenylthiazolyl-hydrazide and its derivatives are potent inhibitors of tau aggregation and toxicity in vitro and in cells.

Abstract：

:One of the key pathological features of Alzheimer's disease is the aggregation of tau protein. We are therefore searching for compounds capable of inhibiting this reaction. On the basis of an initial screen of 200000 compounds [Pickhardt, M., Gazova, Z., von Bergen, M., Khlistunova, I., Wang, Y., Hascher, A., Mandelkow, E. M., Biernat, J., and Mandelkow, E. (2005) Anthraquinones inhibit tau aggregation and dissolve Alzheimer's paired helical filaments in vitro and in cells, J. Biol. Chem. 280, 3628-3635], we performed an in silico screen and predicted a new phenylthiazolyl-hydrazide (PTH) compound as a possible hit [Larbig, G., Pickhardt, M., Lloyd, D. G., Schmidt, B., and Mandelkow, E. (2007) Screening for inhibitors of tau protein aggregation into Alzheimer paired helical filaments: A ligand based approach results in successful scaffold hopping. Curr. Alzheimer Res. 4 (3), 315-323.]. Synthesis of this compound showed that it was indeed active in terms of inhibiting de novo tau aggregation and disassembling preformed aggregates (IC50 = 7.7 microM and DC50 = 10.8 microM). We have now synthesized 49 similar structures and identified the core of the PTHs to be crucial for activity, thus representing a lead structure. Analysis of the binding epitope by saturation transfer difference NMR shows strong interactions between the tau protein and the ligand in the aromatic regions of the inhibitor. By chemical variation of the core, we improved the inhibitory potency five-fold. The compounds showed a low toxicity as judged by an N2A cell model of tau aggregation and lend themselves for further development.

journal_name

Biochemistry

journal_title

Biochemistry

authors

Pickhardt M,Larbig G,Khlistunova I,Coksezen A,Meyer B,Mandelkow EM,Schmidt B,Mandelkow E

doi

10.1021/bi700878g

subject

Has Abstract

pub_date

2007-09-04 00:00:00

pages

10016-23

issue

35

eissn

0006-2960

issn

1520-4995

journal_volume

46

pub_type

杂志文章

相关文献

BIOCHEMISTRY文献大全
  • Sequential DNA Binding and Dimerization Processes of the Photosensory Protein EL222.

    abstract：:EL222 is a blue light sensor protein, which consists of a light-oxygen-voltage domain as a light sensor and a LuxR-type helix-turn-helix DNA-binding domain. The reaction dynamics of the protein-DNA binding were observed for the first time using the time-resolved transient grating method. The reaction scheme was determ...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/acs.biochem.7b01206

    authors： Takakado A,Nakasone Y,Terazima M

    更新日期：2018-03-13 00:00:00

  • Blue-light-induced unfolding of the Jα helix allows for the dimerization of aureochrome-LOV from the diatom Phaeodactylum tricornutum.

    abstract：:Aureochromes have recently been shown to act as blue-light-regulated transcription factors in the stramenopile alga Vaucheria frigida. They comprise a light-, oxygen-, or voltage-sensitive (LOV) domain as a sensory module with flavin mononucleotide (FMN) as a chromophore and a basic region leucine zipper (bZIP) domain...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi400197u

    authors： Herman E,Sachse M,Kroth PG,Kottke T

    更新日期：2013-05-07 00:00:00

  • MAP4 is the in vivo substrate for CDC2 kinase in HeLa cells: identification of an M-phase specific and a cell cycle-independent phosphorylation site in MAP4.

    abstract：:We reported previously that cdc2 kinase decreased the microtubule-stabilizing ability of a major HeLa cell microtubule-associated protein, MAP4, by phosphorylation in vitro [Ookata, K., et al. (1995) J. Cell Biol. 128, 849-862]. An important question raised by this study is whether MAP4 is indeed phosphorylated by cdc...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi971251w

    authors： Ookata K,Hisanaga S,Sugita M,Okuyama A,Murofushi H,Kitazawa H,Chari S,Bulinski JC,Kishimoto T

    更新日期：1997-12-16 00:00:00

  • Human secreted carbonic anhydrase: cDNA cloning, nucleotide sequence, and hybridization histochemistry.

    abstract：:Complementary DNA clones coding for the human secreted carbonic anhydrase isozyme (CA VI) have been isolated and their nucleotide sequences determined. These clones identify a 1.45-kb mRNA that is present in high levels in parotid submandibular salivary glands but absent in other tissues such as the sublingual gland, ...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi00216a035

    authors： Aldred P,Fu P,Barrett G,Penschow JD,Wright RD,Coghlan JP,Fernley RT

    更新日期：1991-01-15 00:00:00

  • Hydrogen bonding networks tune proton-coupled redox steps during the enzymatic six-electron conversion of nitrite to ammonia.

    abstract：:Multielectron multiproton reactions play an important role in both biological systems and chemical reactions involved in energy storage and manipulation. A key strategy employed by nature in achieving such complex chemistry is the use of proton-coupled redox steps. Cytochrome c nitrite reductase (ccNiR) catalyzes the ...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi500854p

    authors： Judd ET,Stein N,Pacheco AA,Elliott SJ

    更新日期：2014-09-09 00:00:00

  • Calcium-dependent regulation of caldesmon by an 11-kDa smooth muscle calcium-binding protein, caltropin.

    abstract：:Caldesmon from chicken gizzard muscle has been examined for its ability to interact with caltropin using affinity chromatography and the fluorescent probe acrylodan. The action of caltropin on the inhibitory effect of caldesmon on actomyosin ATPase was also studied. Like calmodulin, caltropin could release the inhibit...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi00162a031

    authors： Mani RS,McCubbin WD,Kay CM

    更新日期：1992-12-01 00:00:00

  • Sensation and signaling of alpha-ketoglutarate and adenylylate energy charge by the Escherichia coli PII signal transduction protein require cooperation of the three ligand-binding sites within the PII trimer.

    abstract：:PII proteins are sensors of alpha-ketoglutarate and adenylylate energy charge that regulate signal transduction proteins, metabolic enzymes, and permeases involved in nitrogen assimilation. Here, purified Escherichia coli PII and two of its receptors, ATase and NRII, were used to study the mechanisms of sensation by P...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi9011594

    authors： Jiang P,Ninfa AJ

    更新日期：2009-12-08 00:00:00

  • Structural and functional analysis of peptidyl oligosaccharyl transferase inhibitors.

    abstract：:The peptide cyclo(hex-Amb(1)-Cys(2))-Thr(3)-Val(4)-Thr(5)-Nph(6)-NH2 was previously shown to be a slow, tight-binding inhibitor (Ki = 37 nM) of the yeast oligosaccharyl transferase (OT) [Hendrickson et al. (1996) J. Am. Chem. Soc. 118, 7636-7637]. This enzyme catalyzes the transfer of a carbohydrate moiety to an aspar...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi971465d

    authors： Kellenberger C,Hendrickson TL,Imperiali B

    更新日期：1997-10-14 00:00:00

  • Crystallographic studies of isosteric NAD analogues bound to alcohol dehydrogenase: specificity and substrate binding in two ternary complexes.

    abstract：:CNAD (5-beta-D-ribofuranosylnicotinamide adenine dinucleotide) is an isosteric C-glycosidic analogue of NAD(H) containing a neutral pyridine ring. CPAD (5-beta-D-ribofuranosylpicolinamide adenine dinucleotide) is a closely related pyridine-containing analogue with the pyridine nitrogen on the opposite side of the ring...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi00205a009

    authors： Li H,Hallows WH,Punzi JS,Pankiewicz KW,Watanabe KA,Goldstein BM

    更新日期：1994-10-04 00:00:00

  • A hydroxyl group at residue 216 is essential for catalysis by human thymidylate synthase.

    abstract：:Structural analyses of bacterial thymidylate synthases (TSs) implicate a serine residue corresponding to Ser216 in human TS in hydrogen bond networks that are involved in binding of the nucleotide substrate, 2'-deoxyuridylate (dUMP), and that stabilize a beta-bulge in the protein. Utilizing site-directed mutagenesis, ...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi972562+

    authors： Williams AW,Dunlap RB,Berger SH

    更新日期：1998-05-19 00:00:00

  • Characterization of the nuclease activity of Drosophila Rrp1 on phosphoglycolate- and phosphate-modified DNA 3'-termini.

    abstract：:Drosophila Rrp1 includes a carboxy-terminal region homologous to Escherichia coli exonuclease III which is sufficient to repair both oxidative and alkylation damage to DNA. An apurinic/apyrimidinic endonuclease activity intrinsic to Rrp1 was characterized previously. In this work, the 3'-phosphodiesterase and 3'-phosp...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi00004a021

    authors： Sander M,Huang SM

    更新日期：1995-01-31 00:00:00

  • Conformation and stability of the constant fragment of the immunoglobulin light chain containing an intramolecular mercury bridge.

    abstract：:The constant fragment of the immunoglobulin light chain in which the intramolecular disulfide bond is reduced (reduced CL fragment) assumes a conformation very similar to that of the intact CL fragment and contains two sulfhydryl groups buried in the interior of the molecule [Goto, Y., & Hamaguchi, K. (1979) J. Bioche...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi00358a013

    authors： Goto Y,Hamaguchi K

    更新日期：1986-05-20 00:00:00

  • The CD4 determinant for downregulation by HIV-1 Nef directly binds to Nef. Mapping of the Nef binding surface by NMR.

    abstract：:Using heteronuclear NMR spectroscopy, we demonstrate that a 13-residue peptide (MS-QIKRLLSEKKT) from the cytoplasmic tail of CD4 binds to Nef protein. This part of CD4 is critical for downregulation of CD4 by HIV-1 Nef [Aiken et al. (1994) Cell 76, 853-864]. We show that a control peptide without the central dileucine...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi9611164

    authors： Grzesiek S,Stahl SJ,Wingfield PT,Bax A

    更新日期：1996-08-13 00:00:00

  • Structural determinants for plant annexin-membrane interactions.

    abstract：:The interactions of two plant annexins, annexin 24(Ca32) from Capsicum annuum and annexin Gh1 from Gossypium hirsutum, with phospholipid membranes have been characterized using liposome-based assays and adsorption to monolayers. These two plant annexins show a preference for phosphatidylserine-containing membranes and...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi0516226

    authors： Dabitz N,Hu NJ,Yusof AM,Tranter N,Winter A,Daley M,Zschörnig O,Brisson A,Hofmann A

    更新日期：2005-12-13 00:00:00

  • Mapping of DNA alkylation sites induced by adozelesin and bizelesin in human cells by ligation-mediated polymerase chain reaction.

    abstract：:In this study, we have mapped the intracellular alkylation sites of adozelesin and bizelesin, two potent analogs of CC-1065, in individual genes at the single-nucleotide level. Human colon carcinoma cells were treated with adozelesin and bizelesin, and the position of adducts were mapped within the PGK-1 and p53 genes...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi00185a043

    authors： Lee CS,Pfeifer GP,Gibson NW

    更新日期：1994-05-17 00:00:00

  • Spectroscopic studies of quinonoid species from pyridoxal 5'-phosphate.

    abstract：:To establish the state of protonation of quinonoid species formed nonenzymically from pyridoxal phosphate (PLP) and diethyl aminomalonate, we have studied absorption spectra of the rapidly established steady-state mixture of species. We have evaluated the formation constant and the spectrum of the mixture of Schiff ba...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi00413a050

    authors： Metzler CM,Harris AG,Metzler DE

    更新日期：1988-06-28 00:00:00

  • Time-resolved fluorescence studies of genetically engineered Escherichia coli glutamine synthetase. Effects of ATP on the tryptophan-57 loop.

    abstract：:Single-tryptophan-containing mutants of low adenylation state Escherichia coli glutamine synthetase (wild type has two tryptophans at positions 57 and 158) have been constructed and studied by multifrequency phase/modulation fluorescence spectroscopy. The W57L mutant (retains tryptophan at residue 158) and the W158S m...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi00228a008

    authors： Atkins WM,Stayton PS,Villafranca JJ

    更新日期：1991-04-09 00:00:00

  • Investigation of quercetin binding sites on chloroplast coupling factor 1.

    abstract：:The quercetin binding sites on spinach chloroplast coupling factor 1 (CF1) have been investigated using direct and competitive binding, stopped-flow, temperature-jump, and fluorescence resonance energy transfer measurements. It was found that 8-anilino-1-naphthalensulfonic acid (ANS) competes with quercetin binding at...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi00646a001

    authors： Cantley LC Jr,Hammes GG

    更新日期：1976-01-13 00:00:00

  • Protein stability and surface electrostatics: a charged relationship.

    abstract：:Engineering proteins to withstand a broad range of conditions continues to be a coveted objective, holding the potential to advance biomedicine, industry, and our understanding of disease. One way of achieving this goal lies in elucidating the underlying interactions that define protein stability. It has been shown th...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi0600143

    authors： Strickler SS,Gribenko AV,Gribenko AV,Keiffer TR,Tomlinson J,Reihle T,Loladze VV,Makhatadze GI

    更新日期：2006-03-07 00:00:00

  • Transcriptional regulation of the nuclear gene encoding the alpha-subunit of the mammalian mitochondrial F1F0 ATP synthase complex: role for the orphan nuclear receptor, COUP-TFII/ARP-1.

    abstract：:Our laboratory has been studying the transcriptional regulation of the nuclear gene (ATPA) that encodes the alpha-subunit of the mammalian mitochondrial F1F0 ATP synthase complex. We have previously determined that the regulatory factor, upstream stimulatory factor 2 (USF2), can stimulate transcription of the ATPA gen...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi0268347

    authors： Jordan EM,Worley T,Breen GA

    更新日期：2003-03-11 00:00:00

  • Energy coupling in Escherichia coli DNA gyrase: the relationship between nucleotide binding, strand passage, and DNA supercoiling.

    abstract：:Binding of the nonhydrolyzable ATP analogue 5'-adenylyl-beta, gamma-imidodiphosphate (ADPNP) to Escherichia coli DNA gyrase can lead to a limited noncatalytic supercoiling of DNA. Here we examine the efficiency of coupling between ADPNP binding and the change in linking number either of positively or negatively superc...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi952433y

    authors： Bates AD,O'Dea MH,Gellert M

    更新日期：1996-02-06 00:00:00

  • Substantial Decrease in Plasmalogen in the Heart Associated with Tafazzin Deficiency.

    abstract：:Tafazzin is the mitochondrial enzyme that catalyzes transacylation between a phospholipid and a lysophospholipid in remodeling. Mutations in tafazzin cause Barth syndrome, a potentially life-threatening disease with the major symptom being cardiomyopathy. In the tafazzin-deficient heart, cardiolipin (CL) acyl chains b...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/acs.biochem.8b00042

    authors： Kimura T,Kimura AK,Ren M,Berno B,Xu Y,Schlame M,Epand RM

    更新日期：2018-04-10 00:00:00

  • Cholera toxin mediated agglutination of ganglioside Gm1 containing phospholipid vesicles and Gm1-coated polystyrene spheres.

    abstract：:Quasi-elastic laser light scattering is used to examine the cholera toxin mediated agglutination of ganglioside GM1 containing phospholipid vesicles and Gm1-coated polystyrene spheres. We find that the ability of cholera toxin to agglutinate Gm1-containing phospholipid vesicles depends markedly on the lipid compositio...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi00256a031

    authors： Dwyer JD,Bloomfield VA

    更新日期：1982-06-22 00:00:00

  • Primary quinone (QA) binding site of bacterial photosynthetic reaction centers: mutations at residue M265 probed by FTIR spectroscopy.

    abstract：:In the primary quinone (Q(A)) binding site of Rb. sphaeroides reaction centers (RCs), isoleucine M265 is in extensive van der Waals contact with the ubiquinone headgroup. Substitution of threonine or serine for this residue (mutants M265IT and M265IS), but not valine (mutant M265IV), lowers the redox midpoint potentia...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi026958j

    authors： Wells TA,Takahashi E,Wraight CA

    更新日期：2003-04-15 00:00:00

  • Comparison of the Forward and Reverse Photocycle Dynamics of Two Highly Similar Canonical Red/Green Cyanobacteriochromes Reveals Unexpected Differences.

    abstract：:Cyanobacteriochromes (CBCRs) are cyanobacterial photoreceptors that exhibit photochromism between two states: a thermally stable dark-adapted state and a metastable light-adapted state with bound linear tetrapyrrole (bilin) chromophores possessing 15Z and 15E configurations, respectively. The photodynamics of canonica...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/acs.biochem.0c00796

    authors： Kirpich JS,Chang CW,Franse J,Yu Q,Escobar FV,Jenkins AJ,Martin SS,Narikawa R,Ames JB,Lagarias JC,Larsen DS

    更新日期：2021-01-13 00:00:00

  • Binding of protein synthesis initiation factor 4E to oligoribonucleotides: effects of cap accessibility and secondary structure.

    abstract：:The binding of rabbit globin mRNA to the 25-kDa cap binding protein eIF-4E from human erythrocytes was found to be 5.3-fold stronger than the binding of the cap analogue m7GpppG to eIF-4E [Gross et al. (1990) Biochemistry 29, 5008-5012]. In order to investigate whether this effect is due to the longer sequence of nucl...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi00120a020

    authors： Carberry SE,Friedland DE,Rhoads RE,Goss DJ

    更新日期：1992-02-11 00:00:00

  • Detailed structural characterization of unbound protein phosphatase 1 inhibitors.

    abstract：:Protein phosphatase 1 (PP1) is an essential and ubiquitous serine/threonine protein phosphatase that is regulated by more than 100 known inhibitor and targeting proteins. It is currently unclear how protein inhibitors distinctly and specifically regulate PP1 to enable rapid responses to cellular alterations. We demons...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi801308y

    authors： Dancheck B,Nairn AC,Peti W

    更新日期：2008-11-25 00:00:00

  • Effects of peptide length and composition on binding to an empty class I MHC heterodimer.

    abstract：:Class I major histocompatibility complex (MHC) proteins present peptide antigens to T cells during the immune response against viruses. Peptides are loaded into newly synthesized class I heterodimers in the endoplasmic reticulum such that most or all cell surface class I molecules contain peptides derived from endogen...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi00192a020

    authors： Fahnestock ML,Johnson JL,Feldman RM,Tsomides TJ,Mayer J,Narhi LO,Bjorkman PJ

    更新日期：1994-07-05 00:00:00

  • Melatonin reverses the profibrillogenic activity of apolipoprotein E4 on the Alzheimer amyloid Abeta peptide.

    abstract：:Inheritance of apoE4 is a strong risk factor for the development of late-onset sporadic Alzheimer's disease (AD). Several lines of evidence suggest that apoE4 binds to the Alzheimer Abeta protein and, under certain experimental conditions, promotes formation of beta-sheet structures and amyloid fibrils. Deposition of ...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi0114269

    authors： Poeggeler B,Miravalle L,Zagorski MG,Wisniewski T,Chyan YJ,Zhang Y,Shao H,Bryant-Thomas T,Vidal R,Frangione B,Ghiso J,Pappolla MA

    更新日期：2001-12-11 00:00:00

  • Chemical and enzymatic oxidation of benzimidazoline-2-thiones: a dichotomy in the mechanism of peroxidase inhibition.

    abstract：:Derivatives of imidazole-2-thiones block reactions catalyzed by thyroid peroxidase (TPX) and the closely related lactoperoxidase (LPX), and this property is used therapeutically to treat hyperthyroidism. The reactions of a series of benzimidazoline-2-thiones with chemical and enzymatic oxidants were investigated to pr...

    journal_title：Biochemistry

    pub_type： 杂志文章

    doi：10.1021/bi00052a009

    authors： Doerge DR,Decker CJ,Takazawa RS

    更新日期：1993-01-12 00:00:00