Analogues of diadenosine 5',5'''-P1,P4-tetraphosphate (Ap4A) as potential anti-platelet-aggregation agents.

Abstract:

:Dense granules of platelets contain a high content of diadenosine 5',5'''-P1,P4-tetraphosphate (Ap4A). We have previously demonstrated an antithrombotic effect of this compound in a live rabbit model. In the present study we find that certain synthetic Ap4A analogues are superior to Ap4A in inhibiting ADP-induced aggregation of human platelets. Analogues having a P--C--P bridge located in the P2,P3 position of Ap4A are the most potent inhibitors. These analogues are also resistant to hydrolytic enzymes. Analogues having the above characteristics exhibit competitive inhibition with ADP in the ADP-induced platelet aggregation reaction. These compounds, such as AppCHFppA, may be useful as antithrombotic agents. The analogues ApSppSpA and ApSpCHFpSpA also showed good inhibitory effects on ADP-induced platelet aggregation. In addition, this action of Ap4A and its analogues provides an example of a dinucleotide inducing an antagonistic effect by occupying an extracellular mononucleotide binding site on platelets. It calls attention to the possibility that Ap4A and its analogues may act in a similar way in whole organisms, triggering effector or inhibitory responses in any one of a variety of cells.

authors

Zamecnik PC,Kim B,Gao MJ,Taylor G,Blackburn GM

doi

10.1073/pnas.89.6.2370

keywords:

subject

Has Abstract

pub_date

1992-03-15 00:00:00

pages

2370-3

issue

6

eissn

0027-8424

issn

1091-6490

journal_volume

89

pub_type

杂志文章
  • Kinetic isotope effects in Ras-catalyzed GTP hydrolysis: evidence for a loose transition state.

    abstract::A remote labeling method has been developed to determine (18)O kinetic isotope effects (KIEs) in Ras-catalyzed GTP hydrolysis. Substrate mixtures consist of (13)C-depleted GTP and [(18)O,(13)C]GTP that contains (18)O at phosphoryl positions of mechanistic interest and (13)C at all carbon positions of the guanosine moi...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0401675101

    authors: Du X,Black GE,Lecchi P,Abramson FP,Sprang SR

    更新日期:2004-06-15 00:00:00

  • Liver uptake of chylomicron remnants with high and low apoprotein E:C ratios.

    abstract::The ability of the isolated perfused rat liver to differentiate between chylomicrons and remnants with either high or low apoprotein E:C ratios was investigated. Remnants were prepared in hepatectomized rats injected with chylomicrons double-labeled with [3H]cholesterol and 14C-labeled fatty acids. By densitometric sc...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.81.18.5863

    authors: Borensztajn J,Kotlar TJ

    更新日期:1984-09-01 00:00:00

  • Brain structure in healthy adults is related to serum transferrin and the H63D polymorphism in the HFE gene.

    abstract::Control of iron homeostasis is essential for healthy central nervous system function: iron deficiency is associated with cognitive impairment, yet iron overload is thought to promote neurodegenerative diseases. Specific genetic markers have been previously identified that influence levels of transferrin, the protein t...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1105543109

    authors: Jahanshad N,Kohannim O,Hibar DP,Stein JL,McMahon KL,de Zubicaray GI,Medland SE,Montgomery GW,Whitfield JB,Martin NG,Wright MJ,Toga AW,Thompson PM

    更新日期:2012-04-03 00:00:00

  • Escherichia coli mutS-encoded protein binds to mismatched DNA base pairs.

    abstract::The Escherichia coli mutS gene product is involved in mismatch correction in this organism. We have purified a biologically active form of the 97,000 Mr protein to near homogeneity from an overproducing strain. Enzymatic and chemical protection ("footprinting") experiments have demonstrated that mutS-encoded protein s...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.83.14.5057

    authors: Su SS,Modrich P

    更新日期:1986-07-01 00:00:00

  • The palmitoylated cysteine of the cytoplasmic tail of alpha 2A-adrenergic receptors confers subtype-specific agonist-promoted downregulation.

    abstract::Most guanine nucleotide binding protein (G protein)-coupled receptors have a conserved cysteine in the C-terminal cytoplasmic tail near the seventh transmembrane spanning region. This cysteine is known to be palmitoylated in rhodopsin, the beta 2-adrenergic receptor (beta 2AR) and the alpha 2A-adrenergic receptor (alp...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.91.23.11178

    authors: Eason MG,Jacinto MT,Theiss CT,Liggett SB

    更新日期:1994-11-08 00:00:00

  • A gene encoding the tryptophan synthase beta subunit of Arabidopsis thaliana.

    abstract::The DNA sequence of a tryptophan synthase gene and the flanking 5' and 3' regions has been determined for Arabidopsis thaliana. The sequence encodes only the beta subunit domain, indicating that alpha and beta subunits are specified by separate genes. The gene contains four introns and encodes 470 amino acid residues....

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.86.12.4604

    authors: Berlyn MB,Last RL,Fink GR

    更新日期:1989-06-01 00:00:00

  • The Usher syndrome proteins cadherin 23 and harmonin form a complex by means of PDZ-domain interactions.

    abstract::Usher syndrome type 1 (USH1) patients suffer from sensorineuronal deafness, vestibular dysfunction, and visual impairment. Several genetic loci have been linked to USH1, and four of the relevant genes have been identified. They encode the unconventional myosin VIIa, the PDZ-domain protein harmonin, and the putative ad...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.232579599

    authors: Siemens J,Kazmierczak P,Reynolds A,Sticker M,Littlewood-Evans A,Müller U

    更新日期:2002-11-12 00:00:00

  • Political complexity predicts the spread of ethnolinguistic groups.

    abstract::Human languages show a remarkable degree of variation in the area they cover. However, the factors governing the distribution of human cultural groups such as languages are not well understood. While previous studies have examined the role of a number of environmental variables the importance of cultural factors has n...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0804698106

    authors: Currie TE,Mace R

    更新日期:2009-05-05 00:00:00

  • Phosphorescence/microwave double-resonance spectra of tryptophan perturbed by methylmercury(II).

    abstract::Amplitude-modulated phosphorescence/microwave double-resonance (AM-PMDR) spectra are reported for complexes of methylmercury(II) cation, designated CH3Hg(II), with tryptophan and glyceraldehyde-3-phosphate dehydrogenase (GPDHase; from rabbit muscle). Wavelength shifts are observed in the AM-PMDR spectra of CH3Hg(II)-t...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.79.14.4313

    authors: Davis JM,Maki AH

    更新日期:1982-07-01 00:00:00

  • Proteomic and genomic signatures of repeat instability in cancer and adjacent normal tissues.

    abstract::Repetitive sequences are hotspots of evolution at multiple levels. However, due to difficulties involved in their assembly and analysis, the role of repeats in tumor evolution is poorly understood. We developed a rigorous motif-based methodology to quantify variations in the repeat content, beyond microsatellites, in ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1908790116

    authors: Persi E,Prandi D,Wolf YI,Pozniak Y,Barnabas GD,Levanon K,Barshack I,Barbieri C,Gasperini P,Beltran H,Faltas BM,Rubin MA,Geiger T,Koonin EV,Demichelis F,Horn D

    更新日期:2019-08-20 00:00:00

  • The P450-1 gene of Gibberella fujikuroi encodes a multifunctional enzyme in gibberellin biosynthesis.

    abstract::Recent studies have shown that the genes of the gibberellin (GA) biosynthesis pathway in the fungus Gibberella fujikuroi are organized in a cluster of at least seven genes. P450-1 is one of four cytochrome P450 monooxygenase genes in this cluster. Disruption of the P450-1 gene in the GA-producing wild-type strain IMI ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.091096298

    authors: Rojas MC,Hedden P,Gaskin P,Tudzynski B

    更新日期:2001-05-08 00:00:00

  • Tuning genetic control through promoter engineering.

    abstract::Gene function is typically evaluated by sampling the continuum of gene expression at only a few discrete points corresponding to gene knockout or overexpression. We argue that this characterization is incomplete and present a library of engineered promoters of varying strengths obtained through mutagenesis of a consti...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0504604102

    authors: Alper H,Fischer C,Nevoigt E,Stephanopoulos G

    更新日期:2005-09-06 00:00:00

  • Tibetan PHD2, an allele with loss-of-function properties.

    abstract::Tibetans have adapted to the chronic hypoxia of high altitude and display a distinctive suite of physiologic adaptations, including augmented hypoxic ventilatory response and resistance to pulmonary hypertension. Genome-wide studies have consistently identified compelling genetic signatures of natural selection in two...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1920546117

    authors: Song D,Navalsky BE,Guan W,Ingersoll C,Wang T,Loro E,Eeles L,Matchett KB,Percy MJ,Walsby-Tickle J,McCullagh JSO,Medina RJ,Khurana TS,Bigham AW,Lappin TR,Lee FS

    更新日期:2020-06-02 00:00:00

  • Attraction of specific thalamic input by cerebral grafts depends on the molecular identity of the implant.

    abstract::The cerebral cortex of mammals differentiates into functionally distinct areas that exhibit unique cytoarchitecture, connectivity, and molecular characteristics. Molecular specification of cells fated for limbic cortical areas, based on the expression of the limbic system-associated membrane protein (LAMP), occurs dur...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.89.9.3706

    authors: Barbe MF,Levitt P

    更新日期:1992-05-01 00:00:00

  • Involvement of wild-type p53 in pre-B-cell differentiation in vitro.

    abstract::Wild-type p53 protein is a growth modulator whose inactivation has been found to be a key event in malignant transformation. Reconstitution of wild-type p53 in the p53-nonproducer, Abelson murine leukemia virus-transformed pre-B-cell line L12 gave rise to stably growing clones. Wild-type p53-producer derived cell line...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.88.20.8982

    authors: Shaulsky G,Goldfinger N,Peled A,Rotter V

    更新日期:1991-10-15 00:00:00

  • Effects of phagocytosis and colchicine on the distribution of lectin-binding sites on cell surfaces.

    abstract::The effect of phagocytosis on lectin binding to plasma membranes of polymorphonuclear leukocytes was examined. The specific activities of binding sites of concanavalin A and Ricinus communis agglutinin (defined as mug of lectin bound per 100 mug of membrane protein) were measured on isolated membranes; they decreased ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.71.2.394

    authors: Oliver JM,Ukena TE,Berlin RD

    更新日期:1974-02-01 00:00:00

  • Regulation of adenylate cyclase activity mediated by muscarinic acetylcholine receptors.

    abstract::Carbachol, an activator of muscarinic acetylcholine receptors of NG108-15 hybrid cells, inhibits adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] rapidly and reversibly and slowly evokes a 200-300% increase in adenylate cyclase activity over a period of 24-30 hr. Both the inhibition of adenylate cyc...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.75.4.1788

    authors: Nathanson NM,Klein WL,Nirenberg M

    更新日期:1978-04-01 00:00:00

  • A sonic hedgehog signaling domain in the arterial adventitia supports resident Sca1+ smooth muscle progenitor cells.

    abstract::We characterize a sonic hedgehog (Shh) signaling domain restricted to the adventitial layer of artery wall that supports resident Sca1-positive vascular progenitor cells (AdvSca1). Using patched-1 (Ptc1(lacZ)) and patched-2 (Ptc2(lacZ)) reporter mice, adventitial Shh signaling activity was first detected at embryonic ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0711382105

    authors: Passman JN,Dong XR,Wu SP,Maguire CT,Hogan KA,Bautch VL,Majesky MW

    更新日期:2008-07-08 00:00:00

  • Single-molecule FRET and linear dichroism studies of DNA breathing and helicase binding at replication fork junctions.

    abstract::DNA "breathing" is a thermally driven process in which base-paired DNA sequences transiently adopt local conformations that depart from their most stable structures. Polymerases and other proteins of genome expression require access to single-stranded DNA coding templates located in the double-stranded DNA "interior,"...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1314862110

    authors: Phelps C,Lee W,Jose D,von Hippel PH,Marcus AH

    更新日期:2013-10-22 00:00:00

  • Attention-driven discrete sampling of motion perception.

    abstract::In movies or on TV, a wheel can seem to rotate backwards, due to the temporal subsampling inherent in the recording process (the wagon wheel illusion). Surprisingly, this effect has also been reported under continuous light, suggesting that our visual system, too, might sample motion in discrete "snapshots." Recently,...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0409172102

    authors: VanRullen R,Reddy L,Koch C

    更新日期:2005-04-05 00:00:00

  • Na,K-ATPase transport from endoplasmic reticulum to Golgi requires the Golgi spectrin-ankyrin G119 skeleton in Madin Darby canine kidney cells.

    abstract::Spectrin (betaISigma*) and ankyrin (AnkG119) associate with Golgi membranes and the dynactin complex, but their role in vesicle trafficking remains uncertain. We find that the actin-binding domain and membrane-association domain 1 (MAD1) of betaI spectrin together form a constitutive Golgi targeting signal in transfec...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.94.20.10711

    authors: Devarajan P,Stabach PR,De Matteis MA,Morrow JS

    更新日期:1997-09-30 00:00:00

  • Replication of single-stranded plasmid pT181 DNA in vitro.

    abstract::Plasmid pT181 is a 4437-base-pair, multicopy plasmid of Staphylococcus aureus that encodes tetracycline resistance. The replication of the leading strand of pT181 DNA initiates by covalent extension of a site-specific nick generated by the initiator protein at the origin of replication and proceeds by an asymmetric ro...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.89.1.290

    authors: Birch P,Khan SA

    更新日期:1992-01-01 00:00:00

  • Spiperone: evidence for uptake into secretory granules.

    abstract::Spiperone, a dopamine antagonist widely used as a specific ligand for dopamine and serotonin receptors, is actively accumulated into the F4C1 strain of rat pituitary tumor cells. The accumulation of 10 nM [3H]spiperone was linear for 3 min and reached a steady state after 10 min. Spiperone accumulation was reduced 50%...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.81.6.1867

    authors: Dannies PS,Rudnick MS,Fishkes H,Rudnick G

    更新日期:1984-03-01 00:00:00

  • VHL loss in renal cell carcinoma leads to up-regulation of CUB domain-containing protein 1 to stimulate PKC{delta}-driven migration.

    abstract::A common genetic mutation found in clear cell renal cell carcinoma (CC-RCC) is the loss of the von Hippel-Lindau (VHL) gene, which results in stabilization of hypoxia-inducible factors (HIFs), and contributes to cancer progression and metastasis. CUB-domain-containing protein 1 (CDCP1) was shown to promote metastasis ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1011777108

    authors: Razorenova OV,Finger EC,Colavitti R,Chernikova SB,Boiko AD,Chan CK,Krieg A,Bedogni B,LaGory E,Weissman IL,Broome-Powell M,Giaccia AJ

    更新日期:2011-02-01 00:00:00

  • At least two mutant alleles of ornithine delta-aminotransferase cause gyrate atrophy of the choroid and retina in Finns.

    abstract::Gyrate atrophy of the choroid and retina (GA) is an inherited chorioretinal degeneration caused by deficiency of ornithine delta-aminotransferase (OAT; L-ornithine: 2-oxo-acid aminotransferase; EC 2.6.1.13). GA is one of the "Finnish genetic diseases," a group of several rare monogenic disorders that occur with increa...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.86.1.197

    authors: Mitchell GA,Brody LC,Sipila I,Looney JE,Wong C,Engelhardt JF,Patel AS,Steel G,Obie C,Kaiser-Kupfer M

    更新日期:1989-01-01 00:00:00

  • In vitro trimerization of OmpF porin secreted by spheroplasts of Escherichia coli.

    abstract::It is not yet clear how bacterial outer membrane proteins reach their correct destination after they are secreted across the cytoplasmic membrane. We show here that porin OmpF is secreted into the medium as a water-soluble monomeric protein by spheroplasts of Escherichia coli. Furthermore, this monomeric porin is take...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.87.2.743

    authors: Sen K,Nikaido H

    更新日期:1990-01-01 00:00:00

  • Stereospecific gating of functional motions in Pin1.

    abstract::Pin1 is a modular enzyme that accelerates the cis-trans isomerization of phosphorylated-Ser/Thr-Pro (pS/T-P) motifs found in numerous signaling proteins regulating cell growth and neuronal survival. We have used NMR to investigate the interaction of Pin1 with three related ligands that include a pS-P substrate peptide...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1019382108

    authors: Namanja AT,Wang XJ,Xu B,Mercedes-Camacho AY,Wilson KA,Etzkorn FA,Peng JW

    更新日期:2011-07-26 00:00:00

  • Rapid typing of tandemly repeated hypervariable loci by the polymerase chain reaction: application to the apolipoprotein B 3' hypervariable region.

    abstract::The 3' flanking region of the apolipoprotein B (apoB) gene contains a hypervariable region consisting of a variable number of tandemly repeated short A + T-rich DNA sequences (VNTRs). We present a general method that utilizes the polymerase chain reaction to rapidly and accurately type this and other VNTR loci. We use...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.86.1.212

    authors: Boerwinkle E,Xiong WJ,Fourest E,Chan L

    更新日期:1989-01-01 00:00:00

  • MAPK-directed activation of the whitefly transcription factor CREB leads to P450-mediated imidacloprid resistance.

    abstract::The evolution of insect resistance to pesticides poses a continuing threat to agriculture and human health. While much is known about the proximate molecular and biochemical mechanisms that confer resistance, far less is known about the regulation of the specific genes/gene families involved, particularly by trans-act...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1913603117

    authors: Yang X,Deng S,Wei X,Yang J,Zhao Q,Yin C,Du T,Guo Z,Xia J,Yang Z,Xie W,Wang S,Wu Q,Yang F,Zhou X,Nauen R,Bass C,Zhang Y

    更新日期:2020-05-12 00:00:00

  • A global suppressor motif for p53 cancer mutants.

    abstract::The transcription factor and tumor suppressor protein p53 is frequently inactivated in human cancers. In many cases, p53 gene mutations result in high levels of inactive, full-length p53 protein with one amino acid change in the core domain that recognizes p53 DNA-binding sites. The ability to endow function to mutate...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0401162101

    authors: Baroni TE,Wang T,Qian H,Dearth LR,Truong LN,Zeng J,Denes AE,Chen SW,Brachmann RK

    更新日期:2004-04-06 00:00:00