What's all the FLAP about?: 5-lipoxygenase-activating protein inhibitors for inflammatory diseases.

Abstract:

:Leukotrienes have physiological roles in innate immune responses and pathological roles in inflammatory diseases, such as asthma, allergic rhinitis and atherosclerosis. Anti-leukotriene therapy has proven benefits in the treatment of respiratory disease, either through the inhibition of leukotriene synthesis or the selective antagonism of leukotriene receptors. The first committed step in the synthesis of leukotrienes is the oxidation of arachidonic acid (AA) by 5-lipoxygenase (5-LO), and the integral membrane protein 5-lipoxygenase-activating protein (FLAP) is an essential partner of 5-LO for this process. FLAP was molecularly identified via a photoaffinity probe and an affinity gel based on MK-886, a selective leukotriene inhibitor that has no activity against broken-cell preparations of 5-LO. Several FLAP inhibitors showed efficacy in early clinical trials in asthma but were not developed commercially for unpublished reasons. Recently, the FLAP (ALOX5AP) gene has been linked to risk for myocardial infarction, stroke and restenosis, reigniting pharmaceutical interest in this target. In addition, the recent determination of the crystal structure of inhibitor-bound FLAP offers exciting potential for novel FLAP inhibitor design.

journal_name

Trends Pharmacol Sci

authors

Evans JF,Ferguson AD,Mosley RT,Hutchinson JH

doi

10.1016/j.tips.2007.11.006

subject

Has Abstract

pub_date

2008-02-01 00:00:00

pages

72-8

issue

2

eissn

0165-6147

issn

1873-3735

pii

S0165-6147(07)00287-8

journal_volume

29

pub_type

杂志文章,评审
  • Protein kinase Calpha: disease regulator and therapeutic target.

    abstract::Protein kinase Calpha (PKCalpha) is a member of the AGC (which includes PKD, PKG and PKC) family of serine/threonine protein kinases that is widely expressed in mammalian tissues. It is closely related in structure, function and regulation to other members of the protein kinase C family, but has specific functions wit...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2009.10.006

    authors: Konopatskaya O,Poole AW

    更新日期:2010-01-01 00:00:00

  • The schizophrenic faces of PICK1.

    abstract::Schizophrenia is a grave psychiatric disorder with psychotic symptoms and an enigmatic etiology. Family studies have strongly indicated that genetic risk factors have a role in this disease. Recent findings, together with previously established evidence, highlight the PDZ-domain-containing protein interacting with C-k...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2006.09.007

    authors: Dev KK,Henley JM

    更新日期:2006-11-01 00:00:00

  • Diverse functions of muscarinic acetylcholine receptor subtypes.

    abstract::Muscarinic acetylcholine receptor subtypes m1, m3 and m5 couple strongly to phosphatidylinositol turnover and hence to intracellular Ca2+ concentration via pertussis toxin (PTX) sensitive and insensitive G proteins. The m2 and m4 muscarinic receptor subtypes strongly inhibit adenylyl cyclase production via PTX sensiti...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:

    authors: Lechleiter J,Peralta E,Clapham D

    更新日期:1989-12-01 00:00:00

  • Discoidin Domains as Emerging Therapeutic Targets.

    abstract::Discoidin (DS) domains are found in eukaryotic and prokaryotic extracellular and transmembrane multidomain proteins. These small domains play different functional roles and can interact with phospholipids, glycans, and proteins, including collagens. DS domain-containing proteins are often involved in cellular adhesion...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2016.06.003

    authors: Villoutreix BO,Miteva MA

    更新日期:2016-08-01 00:00:00

  • Developing analgesics by enhancing spinal inhibition after injury: GABAA receptor subtypes as novel targets.

    abstract::The use of genetically-engineered mice has identified alpha2- and alpha3-subunit containing GABA(A) receptors as principal contributors to the spinal disinhibition that occurs after inflammation and neuropathic injury. Pharmacological comparison of subtype selective allosteric modulators such as NS11394 and L838417 wi...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2009.06.004

    authors: Munro G,Ahring PK,Mirza NR

    更新日期:2009-09-01 00:00:00

  • Heat Shock Proteins and Cancer.

    abstract::Heat shock proteins (HSPs) constitute a large family of proteins involved in protein folding and maturation whose expression is induced by heat shock or other stressors. The major groups are classified based on their molecular weights and include HSP27, HSP40, HSP60, HSP70, HSP90, and large HSPs. HSPs play a significa...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2016.11.009

    authors: Wu J,Liu T,Rios Z,Mei Q,Lin X,Cao S

    更新日期:2017-03-01 00:00:00

  • GPCRs in NLRP3 Inflammasome Activation, Regulation, and Therapeutics.

    abstract::The NLRP3 inflammasome is an intracellular multimeric protein complex which plays an important role in the pathogenesis of various human inflammatory diseases, such as diabetes, Alzheimer's disease and atherosclerosis. Recently, various G protein-coupled receptors (GPCRs) have been reported to be involved in the activ...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2018.07.002

    authors: Tang T,Gong T,Jiang W,Zhou R

    更新日期:2018-09-01 00:00:00

  • Distribution and anchoring of molecular forms of acetylcholinesterase.

    abstract::Molecular forms of acetylcholinesterase exhibit tissue-specific distribution, and each form is anchored to the cell surface via a particular post-translational modification of the catalytic subunit. Nibaldo Inestrosa and Alejandra Perelman review evidence that heparan sulphate proteoglycans are the extracellular matri...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/0165-6147(89)90067-9

    authors: Inestrosa NC,Perelman A

    更新日期:1989-08-01 00:00:00

  • Epoxyeicosatrienoic Acid as Therapy for Diabetic and Ischemic Cardiomyopathy.

    abstract::Cardiovascular disease remains the leading cause of death worldwide. Among many potential targets for pharmacological intervention, a promising strategy involves epoxyeicosatrienoic acid (EET) and soluble epoxide hydroxylase (sEH) inhibition. sEH is the enzyme that converts EET to its less potent metabolite; therefore...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2016.08.001

    authors: Romashko M,Schragenheim J,Abraham NG,McClung JA

    更新日期:2016-11-01 00:00:00

  • New genome-wide methods bring more power to yeast as a model organism.

    abstract::Recent developments in genetic research using Saccharomyces cerevisiae have provided rapid new methods for identifying the genes that control cellular responses to treatment with a wide variety of agents, including chemicals and radiation. This significantly increases the power of yeast as a model system for studying ...

    journal_title:Trends in pharmacological sciences

    pub_type: 新闻

    doi:10.1016/s0165-6147(02)02082-5

    authors: Game JC

    更新日期:2002-10-01 00:00:00

  • Drug-lipid interaction evaluation: why a 19th century solution?

    abstract::The affinity of a drug candidate for a biological membrane (its lipophilicity) is closely related to the pharmacologically crucial events of absorption, biodistribution, metabolization and excretion. The evolution of knowledge of biological membranes during the past two decades contrasts with the rudimentary parameter...

    journal_title:Trends in pharmacological sciences

    pub_type: 历史文章,杂志文章

    doi:10.1016/j.tips.2010.06.007

    authors: Ribeiro MM,Melo MN,Serrano ID,Santos NC,Castanho MA

    更新日期:2010-10-01 00:00:00

  • Regulation of transcription factor activity by interconnected post-translational modifications.

    abstract::Transcription factors comprise just over 7% of the human proteome and serve as gatekeepers of cellular function, integrating external signal information into gene expression programs that reconfigure cellular physiology at the most basic levels. Surface-initiated cell signaling pathways converge on transcription facto...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2013.11.005

    authors: Filtz TM,Vogel WK,Leid M

    更新日期:2014-02-01 00:00:00

  • Hans Horst Meyer and the lipoid theory of narcosis.

    abstract::This year marks the 90th anniversary of the publication of Hans Horst Meyer's classic paper in which he proposed that the ability of a substance to produce narcosis or anesthesia is governed by its partition coefficient. In this article, Robert Lipnick describes the experiments carried out by Meyer and his colleagues ...

    journal_title:Trends in pharmacological sciences

    pub_type: 传,历史文章,杂志文章

    doi:10.1016/0165-6147(89)90025-4

    authors: Lipnick RL

    更新日期:1989-07-01 00:00:00

  • Of mice and flies: commonalities among 5-HT receptors.

    abstract::Pharmacological studies as well as molecular cloning of 5-HT receptors have revealed a multiplicity of receptor subtypes, not only in mammals but, as discussed in this review by René Hen, also in molluscs and arthropods. Most of these receptors belong to the G protein-coupled receptor family, and their mechanism of ac...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/0165-6147(92)90054-a

    authors: Hen R

    更新日期:1992-04-01 00:00:00

  • Characterization of the action of antipsychotic subtypes on valproate-induced chromatin remodeling.

    abstract::Recent advances in schizophrenia (SZ) research indicate that the telencephalic gamma-aminobutyric acid (GABA)ergic neurotransmission deficit associated with this psychiatric disorder probably is mediated by the hypermethylation of the glutamic acid decarboxylase 67 (GAD(67)), reelin and other GABAergic promoters. A ph...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章

    doi:10.1016/j.tips.2008.10.010

    authors: Guidotti A,Dong E,Kundakovic M,Satta R,Grayson DR,Costa E

    更新日期:2009-02-01 00:00:00

  • How important is intestinal cytochrome P450 3A metabolism?

    abstract::Cytochrome P450 3A (CYP3A) enzymes metabolize a wide variety of xenobiotics including many drugs. Because CYP3A is localized in both the liver and intestine, it can make a major contribution to the presystemic elimination of substrate drugs after oral administration ('first-pass metabolism'). However, assessments of t...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章

    doi:10.1016/j.tips.2009.02.003

    authors: van Herwaarden AE,van Waterschoot RA,Schinkel AH

    更新日期:2009-05-01 00:00:00

  • A Coordinated Attack: Rett Syndrome Therapeutic Development.

    abstract::Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the Methyl CpG binding protein 2 (MeCP2) gene. This Science & Society article focuses on pharmacological strategies that attack RTT treatment from multiple angles, including drug repurposing and de novo discovery efforts, and discusses the imp...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2019.02.007

    authors: Gogliotti RG,Niswender CM

    更新日期:2019-04-01 00:00:00

  • Novel anxiolytics that act as partial agonists at benzodiazepine receptors.

    abstract::Benzodiazepines in clinical use have a range of pharmacological activities. Some, e.g. sedation, tolerance and addiction, are not welcome. Undesirable side-effects of drugs are often controlled by developing compounds that bind more selectively to one particular receptor subtype. An alternative approach, discussed her...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/0165-6147(90)90126-s

    authors: Haefely W,Martin JR,Schoch P

    更新日期:1990-11-01 00:00:00

  • Deep Learning to Therapeutically Target Unreported Complexes.

    abstract::The disruption of large protein-protein (PP) interfaces remains a challenge in targeted therapy. Designing drugs that compete with binding partners is daunting, especially when the structure of the protein complex is unknown. To address the problem we propose a deep protein databank (PDB) learning platform to discover...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章

    doi:10.1016/j.tips.2019.04.009

    authors: Fernández A

    更新日期:2019-08-01 00:00:00

  • Protein engineering and the study of structure--function relationships in receptors.

    abstract::Protein engineering is a powerful tool for studying relationships between receptor structure and function--providing that it is used and interpreted appropriately. Site-directed mutagenesis, deletion mutagenesis and construction of chimaeric proteins have all been used to characterize receptors. In this review, Walter...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/0165-6147(90)90009-w

    authors: Ward WH,Timms D,Fersht AR

    更新日期:1990-07-01 00:00:00

  • Sphingosine Kinase 2 in Autoimmune/Inflammatory Disease and the Development of Sphingosine Kinase 2 Inhibitors.

    abstract::The purpose of this Opinion is to present a case for targeting sphingosine kinase 2 (SK2) in autoimmune/inflammatory disease. Data obtained using Sphk2-/- mice suggest that SK2 is an anti-inflammatory enzyme, although this might be misleading because of a compensatory increase in the expression of a second isoform, sp...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2017.04.003

    authors: Pyne NJ,Adams DR,Pyne S

    更新日期:2017-07-01 00:00:00

  • Inflammation and neurodegeneration: the story 'retolled'.

    abstract::Toll-like receptors (TLRs) play a crucial role in innate immunity by recognizing conserved motifs predominantly found in microorganisms. Increasing evidence supports a role for TLRs in sterile inflammation as observed in neurodegenerative disorders. This includes work suggesting a contribution for these receptors to t...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2012.07.002

    authors: Drouin-Ouellet J,Cicchetti F

    更新日期:2012-10-01 00:00:00

  • Roles of CRAC and Cav-like channels in T cells: more than one gatekeeper?

    abstract::Ca2+ channels in the plasma membrane of T cells vitally influence Ca2+-dependent signals that lead ultimately to cytokine secretion, cellular proliferation and apoptosis. Conventional models depict the Ca2+ inrush across the T-cell membrane following T-cell receptor engagement as being due to Ca2+-release-activated Ca...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2006.05.007

    authors: Kotturi MF,Hunt SV,Jefferies WA

    更新日期:2006-07-01 00:00:00

  • 5-HT3 receptors in the CNS: 3B or not 3B?

    abstract::5-HT(3) receptors are widely distributed in the CNS and PNS where they participate in a variety of physiological processes. Native 5-HT(3) receptors in the CNS display functional and pharmacological heterogeneity, suggesting the existence of multiple receptor subunits. However, recent evidence suggests that of the two...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/S0165-6147(03)00051-8

    authors: van Hooft JA,Yakel JL

    更新日期:2003-04-01 00:00:00

  • Muscarinic activation of potassium channels in cardiac myocytes: kinetic aspects of G protein function in vivo.

    abstract::Muscarinic agonists open potassium-selective K(ACh) channels in cardiac myocytes of pacemaker or atrial origin. Receptor activation is coupled to channel opening by a membrane bound guanine nucleotide-binding protein (GK) through a process that does not require cytoplasmic intermediates. We have used the muscarinic po...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:

    authors: Szabo G,Otero AS

    更新日期:1989-12-01 00:00:00

  • Excitatory amino acid receptors, second messengers and regulation of intracellular Ca2+ in mammalian neurons.

    abstract::As we have learnt from earlier articles in our series on the pharmacology of excitatory amino acids, neurons and glia express several subtypes of excitatory amino acid receptor, the activation of which increases intracellular free calcium ion concentration. In this sixth article, Mark Mayer and Richard Miller detail t...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/0165-6147(90)90254-6

    authors: Mayer ML,Miller RJ

    更新日期:1990-06-01 00:00:00

  • Nicotine addiction: the possible role of functional upregulation.

    abstract::Upregulation of binding to nicotinic acetylcholine receptors (nAChRs) is observed in the brains of both smokers and animals chronically exposed to nicotine, although whether this in vivo change is accompanied by an increase in receptor function is unknown. In vitro recordings indicate that alpha4beta2- and alpha7-subt...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/S0165-6147(00)01979-9

    authors: Buisson B,Bertrand D

    更新日期:2002-03-01 00:00:00

  • Structural insights into adrenergic receptor function and pharmacology.

    abstract::It has been over 50years since Sir James Black developed the first beta adrenergic receptor (βAR) blocker to treat heart disease. At that time, the concept of cell surface receptors was relatively new and not widely accepted, and most of the tools currently used to characterize plasma membrane receptors had not been d...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2011.02.005

    authors: Kobilka BK

    更新日期:2011-04-01 00:00:00

  • Beyond vasodilatation: non-vasomotor roles of epoxyeicosatrienoic acids in the cardiovascular system.

    abstract::Epoxyeicosatrienoic acids (EETs), derived from arachidonic acid by cytochrome P450 epoxygenases, are potent vasodilators that function as endothelium-derived hyperpolarizing factors in some vascular beds. EETs are rapidly metabolized by soluble epoxide hydrolase to form dihydroxyeicosatrienoic acids (DHETs). Recent re...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2006.11.002

    authors: Larsen BT,Campbell WB,Gutterman DD

    更新日期:2007-01-01 00:00:00

  • Molecular biology of 5-HT receptors.

    abstract::Within the past six months, isolation of cDNA or genomic clones has been reported for three 5-HT receptors, the 5-HT1C, 5-HT1A and 5-HT2 subtypes. As members of the G protein receptor superfamily, all three 5-HT receptor clones encode single-subunit proteins containing approximately 450 amino acids arrayed as seven in...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/0165-6147(89)90080-1

    authors: Hartig PR

    更新日期:1989-02-01 00:00:00