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WO2016038608A1 - Peptides dérivés du récepteur de l'angiotensine et leur utilisation - Google Patents

Peptides dérivés du récepteur de l'angiotensine et leur utilisation Download PDF

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Publication number
WO2016038608A1
WO2016038608A1 PCT/IL2015/050914 IL2015050914W WO2016038608A1 WO 2016038608 A1 WO2016038608 A1 WO 2016038608A1 IL 2015050914 W IL2015050914 W IL 2015050914W WO 2016038608 A1 WO2016038608 A1 WO 2016038608A1
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Prior art keywords
cox
pain
ati
peptide
disorder
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English (en)
Inventor
Liza BARKI-HARRINGTON
Tal Sharon
Sood RAPITA
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Carmel Haifa University Economic Corp Ltd
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Carmel Haifa University Economic Corp Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/72—Receptors; Cell surface antigens; Cell surface determinants for hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates to, inter alia, peptides derived from angiotensin II type 1 receptor and methods of treating cyclooxygenase-2 associated diseases and disorders using said peptides.
  • Prostaglandins are bioactive lipids that function as major regulators of cardiovascular homeostasis. They are derived from a common H 2 prostaglandin endoperoxide (PGH 2 ), a metabolite of arachidonic acid (AA) that is formed by the rate-limiting enzyme cyclooxygenase (COX). COXs exist in two main isoforms, COX-1 and COX-2, both of which reside on the luminal surfaces of the endoplasmic reticulum and the inner and outer membranes of the nuclear envelope. Both enzymes display similar catalytic mechanisms but differ in their expression patterns.
  • PSH 2 prostaglandin endoperoxide
  • AA arachidonic acid
  • COXs cyclooxygenase
  • COXs exist in two main isoforms, COX-1 and COX-2, both of which reside on the luminal surfaces of the endoplasmic reticulum and the inner and outer membranes of the nuclear envelope. Both enzymes display similar catalytic mechanisms but differ
  • COX-1 is expressed almost ubiquitously and fulfills many housekeeping functions, while COX-2 is usually absent from most tissues but undergoes a rapid and transient increase of its expression by a broad range of pathological stimuli (Smith, W. L., and Langenbach, R., 2001, Clin Invest 107, 1491-1495). As such, inhibition of its activity by non-steroidal antiinflammatory drugs (NSAIDs) is one of the most common therapeutic targets for treatment of inflammation. However, COX-2 is also normally expressed in some tissues where it has some important physiological roles.
  • NSAIDs non-steroidal antiinflammatory drugs
  • the ATi receptor belongs to the super family of G protein coupled receptors (GPCRs) that relay signals by activating heterotrimeric G proteins, followed by second-messenger-mediated intracellular signaling.
  • GPCRs G protein coupled receptors
  • Coupling ATi to G proteins is mediated primarily through a DRY motif located in the third intracellular loop of the receptor. Mutation of this motif abrogates coupling to G proteins but ⁇ arrestin recruitment and activation of the ERK MAP kinase pathway remains intact.
  • the absence of certain phosphorylation sites in the CT of ATi prevents ⁇ arrestin-mediated signaling while preserving the G-protein pathway.
  • the present invention provides peptides derived from angiotensin II type 1 (ATi) receptor and particularly from the carboxy-tail (CT) of said ATi receptor, compositions comprising same and methods of use thereof in treatment of COX-2 associated diseases and disorders including but not limited to inflammation and pain.
  • ATi angiotensin II type 1
  • CT carboxy-tail
  • the present invention is based, in part, on the surprising finding that short amino acid sequences of the carboxy-tail of ATi down-regulate COX-2 expression, thereby being useful for treating COX-2 associated diseases and disorders.
  • the present invention provides an isolated peptide of no more than 45 amino acids comprising an amino acid sequence as set forth in SEQ ID NO: 1 (KSHSXiLSTKMSTLSYRPSDNX 2 SSSX 3 KKPAX 4 CFEVE), wherein Xi is Asn (N) or Ser (S), X 2 is Val (V) or Met (M), X 3 is Thr (T) or Ala (A) and X 4 is Pro (P) or Ser (S), or an analog, a derivative or fragment thereof.
  • SEQ ID NO: 1 KSHSXiLSTKMSTLSYRPSDNX 2 SSSX 3 KKPAX 4 CFEVE
  • Xi is Asn (N) or Ser (S)
  • X 2 is Val (V) or Met (M)
  • X 3 is Thr (T) or Ala (A)
  • X 4 is Pro (P) or Ser (S), or an analog, a derivative or fragment thereof.
  • said analog comprises the amino acid sequence as set forth in SEQ ID NO: 2 (KS HS NLS TKMS TLS YRPS DN VS S S TKKP APCFE VE) or an analog, a derivative or a fragment thereof.
  • said analog comprises the amino acid sequence as set forth in SEQ ID NO: 3 (KS HS S LS TKMS TLS YRPS DNMS S S AKKP AS CFE VE) or an analog, a derivative or a fragment thereof.
  • said analog comprises the amino acid sequence as set forth in SEQ ID NO: 4 (KS HSNLS TKMS PLS YRPS DN VS S S TKKP APCFE VE) or an analog, a derivative or a fragment thereof.
  • said analog comprises the amino acid sequence as set forth in SEQ ID NO: 5 (KS HS NLS TKMS TLS YRHS DN VS S S TKKP APCFE VE) or an analog, a derivative or a fragment thereof.
  • said fragment comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 6 (KS HS X i LS TKMS TLS YRPS ) wherein Xi is Asn (N) or Ser (S).
  • said fragment comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 7 (KSHSNLSTKMSTLSYRPS).
  • said fragment comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 8 (KS HS S LS TKMS TLS YRPS ) .
  • said fragment has a length of no more than 40 amino acids.
  • said fragment has a length of no more than 35 amino acids.
  • said fragment has a length of no more than 30 amino acids. According to another embodiment, said fragment has a length of no more than 25 amino acids. According to another embodiment, said fragment has a length of no more than 20 amino acids. According to another embodiment, said fragment has a length of no more than 15 amino acids.
  • a pharmaceutical composition comprising as an active ingredient an isolated peptide of the present invention, and a pharmaceutically acceptable carrier.
  • a method of treating, preventing or alleviating a disease in a subject, particularly a disease associated with COX-2 comprises administering to the subject in need thereof an effective amount of the peptide of the invention or the pharmaceutical composition comprising same.
  • the COX-2 associated disease or disorder is selected from the group consisting of an inflammatory associated disease or disorder, pain and stress - related pathologies.
  • said inflammatory associated disease or disorder is selected from the group consisting of: multiple sclerosis, arthritis, asthma, inflammatory bowel disease (Crohn's disease), psoriasis, and systemic lupus erythematosus (SLE).
  • said pain is selected from the group consisting of acute pain, chronic pain, cancer pain, central pain, labor pain, myocardial infarction pain, pancreatic pain, colic pain, post-operative pain, headache pain, muscle pain, pain associated with intensive care, arthritic pain, neuropathic pain, and pain associated with an oral or periodontal disease, including gingivitis and periodontitis.
  • said stress-related pathologies is selected from posttraumatic stress disorder, acute stress disorder, adjustment disorder, bereavement related disorder, general anxiety disorder, social anxiety disorder and anxiety disorder due to a medical condition.
  • a peptide of the invention or a pharmaceutical composition comprising same for use in treating, preventing or alleviating a disease in a subject, particularly a COX-2 associated disease or disorder.
  • FIGS 1A-D ATi receptor lowers COX-2 expression.
  • IB HEK 293 were transfected with YFP-COX-2 and HA-ATi as in A and levels of YFP COX-2 were analyzed by flow cytometry.
  • FIGS. 2A-E The effect of ATi on COX-2 does not require receptor activation.
  • (2B) Quantification of ERK activation (ratio of phospho to total ERK) by 1 ⁇ Angll at the indicated time points (n 3).
  • (2C) Cells were transfected with either ATi alone or in the presence of wild type COX-2 or its catalytically inactive mutant G533A COX-2. ERK activation was measured after 10 min stimulation with 1 ⁇ Angll (n 5).
  • (2D) Cells were transfected as above and treated with the PKC inhibitors GFX at the indicated concentrations, throughout transfection. Levels of YFP-COX-2 and CFP-ATi were analyzed by flow cytometry (n 3).
  • (2E) YFP-COX-2 was transfected with CFP-tagged wild type ATi, DRY/AAY ATi or TSTS/A ATi at ratios of 1 :5. Levels of YFP-COX-2 (black columns) and CFP-ATi (grey columns) were obtained by flow cytometry (n 5).
  • FIGS. 3A-D Inhibition of the proteasome lowers ATi and rescues COX-2.
  • Cells transfected with YFP- COX-2 and either empty vector or CFP-ATi were treated with or without 10 ⁇ MG132 for 16 h.
  • (3A) Summary graph of the effect of MG132 on YFP-COX-2 levels. (n 6).
  • (3D) Dose-dependent effect of MG132 treatment of YFP-COX-2 and CFP-ATi levels (n 3).
  • FIGS 4A-C ATi enhances proteasomal degradation of COX-2 by increasing its ubiquitination.
  • ATi co-immunoprecipitates with COX-2.
  • Cells were transfected with empty vector, COX-2, or HA-ATi and COX-2 with HA-ATi at a ratio of 1 : 1.
  • Immunoprecipitation of (4A) HA or (4B) COX-2, was performed 16 h after transfection (representative blots of n 4).
  • (4C) COX-2 ubiquitination is elevated in the presence ATi.
  • COX-2 was immunoprecipitated from cells expressing COX-2 or HA-ATi alone or together.
  • FIGS. 6A-D The tail sequence of ATi (CT) is sufficient to downregulate COX-2 expression.
  • CT ATi
  • 6A HEK 293 cells were transiently transfected with YFP-COX-2, CFP-CT or both at a ratio of 1 :5. The effect on COX-2 expression was detected by fluorescent microscopy. CFP without the CT sequence was used as control and did not lower COX-2 expression (last panel).
  • (6B) HEK 293 cells were transfected with wild type ATi or CT-Myc with or without COX-2. Representative immunoblot of n 5 experiments.
  • the present invention provides peptides derived from or corresponding to the carboxy-tail of said ATi receptor, or analogs, derivatives or fragments thereof.
  • the present invention further provides compositions comprising said peptides, and methods of use thereof in treatment of COX-2 associated diseases and disorders including but not limited to inflammation and pain.
  • ATi receptor plays an important role in facilitating COX-2 degradation, thus constituting a feedback loop that does not depend on classical signaling pathways.
  • the demonstrated regulation of ATi constitutes physiological means of controlling normal COX-2 turnover, thereby treating pathological conditions associated by COX-2.
  • short peptides derived from ATi CT downregulated COX-2 expression, thereby indicating use of said peptide in therapeutic approach for eliminating excess COX-2 protein.
  • the peptides of the invention comprise an amino acid sequence derived from or correspond to residues 325-359 of an ATi receptor such as a human ATi receptor (Uniprot accession no. P30556).
  • the present invention provides an isolated peptide comprising an amino acid sequence selected from the group consisting of: KSHSXiLSTKMSTLSYRPSDNX 2 SSSX 3 KKPAX 4 CFEVE), wherein Xi is Asn (N) or Ser (S), X 2 is Val (V) or Met (M), X is Thr (T) or Ala (A) and X 4 is Pro (P) or Ser (S) or an analog, a derivative or fragment thereof.
  • the present invention provides an isolated peptide comprising the amino acid sequence as set forth in any one of: SEQ ID NO: 2
  • KSHSNLSTKMSTLSYRPS SEQ ID NO: 8 (KSHSSLSTKMSTLSYRPS); or an analog, a derivative or fragment thereof.
  • the peptides may be between about 8 and 45 amino acids in length.
  • the peptides may comprise a sequence having between about 8 and about 45 amino acids of the carboxy-tail of an ATi receptor of a mammalian (e,g., human) variant.
  • the peptide comprises at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15 amino acids derived from, or corresponds to, the carboxy-tail of an ATi receptor and particularly to SEQ ID NO: 1.
  • said fragment has a length of no more than 35 amino acids, no more than 34 amino acids, no more than 33 amino acids, no more than 32 amino acids, no more than 31 amino acids, no more than 30 amino acids, no more than 29 amino acids, no more than 28 amino acids, no more than 27 amino acids, no more than 26 amino acids, no more than 25 amino acids, no more than 24 amino acids, no more than 23 amino acids, no more than 22 amino acids, no more than 21 amino acids, no more than 20 amino acids, no more than 19 amino acids, no more than 18 amino acids, no more than 17 amino acids, no more than 16 amino acids, no more than 15 amino acids, no more than 14 amino acids, no more than 13 amino acids, no more than 12 amino acids, no more than 11 amino acids or no more than 10 amino acids, wherein each possibility represents a separate embodiment of the invention.
  • peptide encompasses native peptides (degradation products, synthetic peptides or recombinant peptides), pep tidomime tics (typically including non-peptide bonds or other synthetic modifications) and the peptide analogues peptoids and semipeptoids, and may have, for example, modifications rendering the peptides more stable while in the body or more capable of penetrating into cells.
  • polypeptide and “protein” are used interchangeably herein to refer to a polymer of amino acid residues.
  • the terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical analogue of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers.
  • the peptide of the invention comprises a sequence derived from residues 325-359 of an ATi receptor, with a conservative substitution.
  • a conservative substitution is recognized in the art as a substitution of one amino acid for another amino acid that has a similar property.
  • Free hydroxyl groups may be derivatized to form O-acyl or O-alkyl derivatives.
  • the imidazole nitrogen of histidine may be derivatized to form N-im-benzylhistidine.
  • chemical derivatives are those peptides, which contain one or more naturally occurring amino acid derivatives of the twenty standard amino acid residues. For example: 4-hydroxyproline may be substituted for proline; 5-hydroxylysine may be substituted for lysine; 3-methylhistidine may be substituted for histidine; homoserine may be substituted or serine; and ornithine may be substituted for lysine.
  • Essential fatty acids may refer to certain fatty acids, in particular polyunsaturated fatty acids that an organism must ingest in order to survive, being unable to synthesize the particular essential fatty acid de novo. Examples include the essential fatty acid C9, C12-linoleic acid and their structural variants. Essential fatty acids may be found in nature or produced synthetically.
  • the peptides of the invention may alternatively be synthesized such that one or more of the bonds, which link the amino acid residues of the peptides are non-peptide bonds.
  • bonds include, but are not limited to, imino, ester, hydrazide, semicarbazide, and azo bonds, which can be formed by reactions well known to skilled in the art.
  • the peptide disclosed herein is useful in treating affective disorders including but not limited to anxiety disorders (e.g., generalized anxiety disorder (GAD), social anxiety disorder (SAD; alternatively known as social phobia), panic disorder (with or without agoraphobia), posttraumatic stress disorder (PTSD), obsessive- compulsive disorder (OCD), separation anxiety disorder), mood disorders (e.g., depressive disorder, bipolar disorder) and psychotic disorders (e.g., schizophrenia, schizoaffective disorder, delusional disorder), substance-related disorders (e.g., substance abuse, substance-induced disorder, substance withdrawal).
  • GAD generalized anxiety disorder
  • SAD social anxiety disorder
  • PTSD posttraumatic stress disorder
  • OCD obsessive- compulsive disorder
  • separation anxiety disorders e.g., depression disorder, bipolar disorder
  • mood disorders e.g., depressive disorder, bipolar disorder
  • psychotic disorders e.g., schizophrenia, schizoaffective disorder, delusional disorder
  • substance-related disorders e
  • a “therapeutically effective amount” of the peptide is that amount of peptide which is sufficient to provide a beneficial effect to the subject to which the peptide is administered. More specifically, a therapeutically effective amount means an amount of the peptide effective to prevent, alleviate or ameliorate tissue damage or symptoms of a disease of the subject being treated.
  • Alexa Fluor 647 (Cy5) donkey anti-goat IgG for microscopy imaging experiments was obtained from Life Technologies (Carlsbad, CA).
  • PGE2 Rabbit antisera for radioimmunoassays and 1-Oleoyl- 2-acetyl-sn-glycerol (OAG) were purchased from Sigma Aldrich (Rehovoth, Israel).
  • Tritium- labeled PGE2 (190 Ci/mmol) was obtained from Perkin Elmer (Waltham, MA).
  • (s)-MG132 was from Cayman Chemical (Ann Arbor, MI).
  • GF109203X (GFX) was from Tocris Bioscience (Bristol, UK). All other reagents were standard laboratory grade.
  • COX2-YFP Forward 5'- ATTAAGCTTATGCTCGCCCGCGCCCTG-3' and reverse a 5'- ATTGGATCCTTCAGTTCAGTCGAACGTTC-3' and inserted into pEYFP-Nl vector (Clontech) between BamHI and Hindlll sites.
  • CFP- ATI forward primer 5'- ATACTCGAGATGGCCCTTGACTCTTCT-3' and reverse primer 5'- ATAGGATCCCGCTCC ACCTC AAAAC-3 '
  • CFP- TSTS/A ATi forward primer 5'- ATACTCGAGATGGCCCTTGACTCTTCT-3' and the reverse primer 5'- ATAGGATCCC GCTCCACCTCAAAAC-3'
  • CFP-DRY/AAY ATi forward p5'- ATACTCGAGA TGGCCCTTGACTCTTCT-3' and the reverse primer 5'- ATAGGATCCCGCT CCACCTCAAAAC-3'.
  • CFP- ATi carboxyl-tail (CT; amino acids 325-359) was cloned using the oligo overlap cloning method into pECFP-Nl vector (Clontech) between EcoRI and BamHI sites using the overlapping primers: 5'-
  • Radioimmunoassay- 140,000 cells were plated in 12- well dishes and transfected with COX-2, with either pcDNA or ATi, as indicated above. Radioimmunoassays were performed as describe in Haddad 2012, ibid. Flow cytometry- Cells were washed twice with PBS, and resuspended in 150-200 ⁇ PBS for cytometric analysis. All experiments were performed in triplicates. The samples were analyzed using BD FACSCanto II flow cytometer with DACSDiva software (BD Biosciences, San Jose, CA).
  • HEK293 cells were co- transfected with COX-2 together with either empty plasmid or the receptor, and analyzed for the ability of COX-2 to generate PGE 2 . Since HEK 293 cells do not express detectable amounts of either COX isoform, the data reflects only the activity of transfected COX-2 (Haddad 2012, ibid.). As depicted in Fig. 1A, co-transfection of COX-2 with ATi at a ratio of 1:5 reduced PGE 2 secretion by nearly half. To find out whether this decrease is due to diminished COX-2 levels, flow cytometry was used to analyze the levels of YFP-tagged COX-2 in the absence or presence of ATi.
  • the inventors next sought to determine whether the effect of ATi on COX-2 is mediated via its classical signaling pathways (Wei et al., 2003, Proc Natl Acad Sci U S A 100, 10782- 10787).
  • the inventors expressed COX-2, ATi, or both in HEK 293 cells, stimulated them with the ATi ligand Angll and measured COX-2 levels and phosphorylation of the ERK MAP kinase as an indication for receptor activation.
  • Cells transfected with COX-2 alone did not show a response to Angll, indicating that they do not express significant amount of endogenous ATi (Fig. 2A, first two lanes).
  • the inventors next tested whether COX-2 and ATI interact with each other. For this, cells were transfected with each protein alone or together, and samples were subject to immunoprecipitation. To enable detection of a possible interaction, a transfection ratio of 1: 1 COX-2: ATI that was found in dose-titration experiments to have a minimal effect on COX-2 expression (Fig. ID), was used. As shown in Fig. 4A and 4B, only cells that expressed both proteins showed the reciprocal protein in co- precipitates.
  • COX-2 was immunoprecipitated from all samples and membranes were probed first for ubiquitination levels and then for the presence of COX-2 and ATI. Under conditions of 1: 1 co- expression ATI did not cause a significant reduction in COX-2 but the levels of its ubiquitination were elevated compared to those of COX-2 alone (Fig. 4C).
  • G protein-coupled receptor kinases G protein-coupled receptor kinases
  • GRKs G protein-coupled receptor kinases
  • the data presented herein show that Angll- mediated activation of the receptor, or inhibition of PKC activity, do not reverse its effect on COX-2 expression.
  • ATi mutants that are defective in their ability to engage with G proteins DRY/AAY
  • TSTS/A ⁇ arrestin
  • the CT of ATi harbors specific motifs that interact with many different molecules involved in downstream signaling such as G proteins and ⁇ arrestin, proteins of the JAK/STAT pathway and others. While not yet identified in ATi, other receptors such as rhodopsin contain a sorting signal that binds to the GTPase ARF4, a regulator of protein sorting. In terms of ubiquitination, the ⁇ 2 adrenergic receptor was shown to recruit the E3 ubiquitin ligase Nedd4 and to undergo ubiquitination prior to its degradation.
  • COX-2 is constitutively expressed in the cortex of the mammalian kidney (macula densa and the thick ascending limb of Henle), where it generates prostaglandins that raise the levels of renin. Elevated renin (e.g. due to salt depletion or inhibition of the angiotensin converting enzyme (ACE) cause a significant increase in COX-2 expression thus constituting positive feedback loop between renin and COX- 2. In contrast, the end product of renin, Angll, negatively regulates the expression of COX-2.
  • ACE angiotensin converting enzyme
  • mice with a genetic depletion of ATi also display significantly higher levels of COX-2 in their macula densa thus providing support that the actual presence of the ATi receptor is required to keep COX-2 expression at bay.

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Abstract

L'invention concerne des peptides dérivés de l'extrémité carboxy du récepteur de l'angiotensine II de type 1 ou correspondant à celle-ci. En outre, l'invention concerne des compositions pharmaceutiques comprenant lesdits peptides et leur utilisation dans le traitement, l'atténuation ou la prévention d'une maladie associée à la COX-2, telle que, entre autres, des maladies et une douleur inflammatoires.
PCT/IL2015/050914 2014-09-08 2015-09-08 Peptides dérivés du récepteur de l'angiotensine et leur utilisation Ceased WO2016038608A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4032914A4 (fr) * 2019-09-20 2023-10-18 Kyungpook National University Industry-Academic Cooperation Foundation Anticorps pour la détection d'acétylation de la protéine cox2, et ses utilisations

Citations (1)

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Publication number Priority date Publication date Assignee Title
WO2005114221A2 (fr) * 2004-05-21 2005-12-01 The Institute For Systems Biology Compositions et methodes de quantification de glycoproteines du serum

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Publication number Priority date Publication date Assignee Title
WO2005114221A2 (fr) * 2004-05-21 2005-12-01 The Institute For Systems Biology Compositions et methodes de quantification de glycoproteines du serum

Non-Patent Citations (3)

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Title
CHENG, HUI-FANG ET AL.: "Angiotensin II attenuates renal cortical cyclooxygenase-2 expression.", JOURNAL OF CLINICAL INVESTIGATION, vol. 103, no. 7, 1999, Retrieved from the Internet <URL:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC408259> [retrieved on 19990430] *
GROSS, GIL ET AL.: "Inhibition of cyclooxygenase-2 prevents inflammation-mediated preterm labor in the mouse.", AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY, INTEGRATIVE AND COMPARATIVE PHYSIOLOGY, vol. 278, no. 6, 2000, Retrieved from the Internet <URL:http://ajpregu.physiology.org/content/278/6/R1415.short> [retrieved on 20000601] *
SOOD, RAPITA ET AL.: "Down-regulation of Cyclooxygenase-2 by the Carboxyl Tail of the Angiotensin II Type 1 Receptor.", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 289, no. 45, 2014, pages 31473 - 31479, Retrieved from the Internet <URL:http://www.jbc.org/content/289/45/31473.full> [retrieved on 20140917] *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4032914A4 (fr) * 2019-09-20 2023-10-18 Kyungpook National University Industry-Academic Cooperation Foundation Anticorps pour la détection d'acétylation de la protéine cox2, et ses utilisations

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