WO2016165102A1 - Therapeutic peptides for cerebrovascular diseases - Google Patents
Therapeutic peptides for cerebrovascular diseases Download PDFInfo
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- WO2016165102A1 WO2016165102A1 PCT/CN2015/076747 CN2015076747W WO2016165102A1 WO 2016165102 A1 WO2016165102 A1 WO 2016165102A1 CN 2015076747 W CN2015076747 W CN 2015076747W WO 2016165102 A1 WO2016165102 A1 WO 2016165102A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/10—Peptides having 12 to 20 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
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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
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
-
- 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 present invention relates to the treatment of cerebrovascular diseases.
- it relates to a method for treating or ameliorating cerebrovascular diseases in a subject by using peptides isolated from extracts from rabbit skin inflamed by vaccinia virus.
- Cerebrovascular diseases are neural function injuries caused by abnormal blood supply of regional brain. In most countries, cerebrovascular diseases, the top three causes of all deaths, can result in a brain injury in adult. Cerebrovascular disease is a major cause for endangering the health of the middle-aged and the aged people, and a major cause of death or disability of the middle-aged and the aged people in most countries.
- Stroke one of the acute cerebrovascular diseases, is the third leading cause of death in worldwide population and induces a highest disabling rate among various diseases.
- the cerebrovascular diseases could severely affect the life quality of the elderly, bring an enormous burden to patients’ family and the society. It also tends to increase in young population.
- the cerebrovascular diseases are primarily classified into two types, hemorrhagic and ischemic, of which the latter is 60-70%, and is the most common type of cerebrovascular diseases. It is important to study the pathophysiological mechanism of ischemic cerebrovascular diseases and search for drugs which function as neuroprotection.
- drugs currently used to clinically treat cerebral ischemia mainly comprise calcium ion antagonists (nimodipine) , oxygen radical scavengers (VitE, SOD) , neurotrophic factors (nerve growth factor, neurotrophic factor) , excitatory amino acid antagonists, antioxidants and drugs which improve late-onset neuronal injury.
- These drugs function via various mechanisms of action, with uncertain therapeutical effects or less specificity or with the concomitancy of severe side-effects, and thus can not meet the clinical requirements yet.
- Research and development of novel drugs for treating ischemic cerebrovascular diseases becomes increasingly important in the field of pharmaceutics and pharmacology.
- the present invention provides a method for treating or ameliorating cerebrovascular diseases in a subject, wherein the method comprises administering to the subject an effective amount of one or more peptide comprising an amino acid sequence having at least 70%identity to DEAQETAVSSH (SEQ ID NO: 1) or variants, mutants, derivatives, or fragments thereof.
- the present invention provides the use of one or more peptide comprising an amino acid sequence having at least 70%identity to SEQ ID NO:1 or variants, mutants, derivatives, or fragments thereof in the manufacture of a medicament for treating cerebrovascular diseases in a subject.
- the cerebrovascular diseases as described herein are those which lead to damages of the neurological systems with functional deficit.
- the cerebrovascular diseases as described herein are selected from the group consisting of: ischemic brain injury or hemorrhage brain damage.
- the cerebrovascular disease is stroke.
- the expression " having at least 70%identity to SEQ ID NO: 1" is intended to mean an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 98%or 99%or more identity to SEQ ID NO: 1.
- the peptide comprises SEQ ID NO: 1 and/or DEAQETAVSSHEQD (SEQ ID NO: 2) .
- the peptide consists of SEQ ID NO: 1 and/or SEQ ID NO: 2.
- the peptide comprises at least one amino acid addition, deletion, and/or substitution, preferably 1-5, preferably 1-3 amino acid additions, deletions, and/or substitutions. In another embodiment, the amino acid addition, deletion and/or substitution are located at the C-terminal and/or N-terminal.
- the disease is treated or ameliorated by protecting nerve cells.
- the subject is human.
- the present invention relates to a polynucleotide which encodes the peptide according to the invention; a vector which comprises such polynucleotide; as well as a host cell which comprises such polynucleotide or such vector.
- a pharmaceutical composition comprising an effective amount of the peptide according to the invention, the polynucleotide, the vector, or the host cell as described herein, and a pharmaceutically acceptable carrier.
- the present invention also relates to the peptide, the polynucleotide, the vector, the host cell, or the pharmaceutical composition as described herein, for use as a medicament.
- the present invention relates to a peptide composition comprising or consisting of SEQ ID NO: 1 and SEQ ID NO: 2; a drug combination comprising such a composition; as well as a method of using the same.
- Fig. 1 is a schematic representation of the procedures used for screening polypeptide/small peptide-level analgesic agents from crude extracts of the inflamed rabbit skins induced by inoculation of vaccinia virus.
- Fig. 2 illustrates the identification of a functional peptide.
- the MS/MS spectrum of the doubly charged ion m/z 772.745 is shown.
- One of the amino acid sequences DEAQETAVSSHEQD (SEQ ID NO: 2) shown as an example was determined from MS differences in the y-and b-fragment ions series and matched residues 1-14 of rabbit ⁇ 1-antiproteinase F.
- Fig. 3 illustrates the stability of peptide-5 under various pH values.
- Fig. 4 shows the MALDI-TOF MS spectra of the samples
- Fig. 5 shows CD (circular dichroism) of peptide 5.
- Fig. 6 illustrates cell survival of the PC12 cells exposed to H 2 O 2 for 24h, with or without treatment by AGC 0.25, 0.5, or 1 U/ml. ** P ⁇ 0.01 compared with no treatment. Data are expressed as mean ⁇ SD from 3 experiments.
- Fig. 7 illustrates cell survival of the PC12 cells exposed to H 2 O 2 for 24h, with or without treatment by AGC 1 U/ml, or peptide 1 (10 ⁇ g/ml) , peptide 5 (10 ⁇ g/ml) or in combination of peptide 1 and 5 (10 ⁇ g/ml each) . ** P ⁇ 0.05 compared with individual use of peptide 1 or 5. Data are expressed as mean ⁇ SD from 3 experiments.
- Fig. 8 illustrates the effect of AGC on the cell survival of L-glutamic-acid treated PC12 cells.
- Fig. 9 compares the effect between AGC, peptide 1, and peptide 5 on Cell survival of L-glutamic-acid treated PC12 cells
- Fig. 10 illustrates cell survival of the PC12 cells under conditions of hypoglycemic, hypoxic or a combination of both for 24h, with or without treatment by AGC 0.25, 0.5 or 1 U/ml. ** P ⁇ 0.01 compared with no treatment. Data are expressed as mean ⁇ SD from 3 experiments.
- Fig. 11 illustrates cell survival of the PC12 cells under conditions of hypoglycemic, hypoxic or a combination of both for 24h, with or without treatment by AGC 1 U/ml, or peptide 1 (SEQ ID NO: 1) (10 ⁇ g/ml) , peptide 5 (SEQ ID NO: 2) (10 ⁇ g/ml) or in combination of peptide 1 and 5 (10 ⁇ g/ml each) . ** P ⁇ 0.01 compared with individual use of peptide 1 or 5. Data are expressed as mean ⁇ SD from 4 experiments.
- Fig. 12 shows that injection of peptide 1 and 5 resulted in high fluorescent intensity detected in the brain (shown in yellow) in 15 and 30 minutes (left and right rat) , whereas injection of control peptide did not (middle) . Data are representative of 3 experiments.
- Fig. 13 shows that injection of peptide 1 and 5 resulted in high fluorescent intensity detected in the spinal cord (shown in yellow) in 30 and 60 minutes (left and right rats) , whereas injection of control peptide did not (middle) . Data are representative of 3 experiments.
- the present inventors surprisingly found that 2 peptides isolated from extracts from rabbit skin inflamed by vaccinia virus significantly preserve the neural cell viability under hypoxic, hypoglycemia conditions or a combination of both, upon exposure to H 2 O 2 or L-glutamic acid in vitro and/or in vivo. More surprisingly, the peptide 1 and peptide 5 exhibit synergistic effects to inhibit cytotoxicity of neuronal cell (PC12) induced by hypoxic, hypoglycemia conditions or a combination of both, H 2 O 2 and L-glutamic acid, with a similar potency as seen in the use of AGC (eg, 1 U/ml) . Our data therefore successfully identify two short peptides in the AGC as active ingredients that could account, at least in part, for the neuro-protective role of AGC in the ischemic stroke.
- PC12 neuronal cell
- H 2 O 2 is an important reactive oxygen component which is involved in the onset of nervous system diseases such as cerebral ischemia, trauma, brain aging, Alzheimer’s disease etc. It will peroxidize the membrane lipid, decrease cell membrane fluidity, change components and activities of intracellular proteins, make chromatin concentrated and DNA broken, and finally result in cell death.
- Excitatory amino acids such as glutamic acids
- Glutamic acid can damage nerve cell line and primary nerve cell in a dose dependent manner. It is responsible for the increased intracellular calcium ion and the blocked cystine uptake, and it induces the loss of intracellular reduced glutathione (GSH) , the increased oxygen radical and nerve cell death. Therefore, H 2 O 2 or glutamic acid-induced nerve cell injury model can be used as a screening model of neuroprotective agents.
- the peptide according to the invention is used to preserve the neural cell viability upon exposure to H 2 O 2 in vitro and/or in vivo, with an unexpected synergistic effect seen in the combinatorial use of peptide 1 and 5.
- the peptide according to the invention demonstrates protective effect on the L-glutamic-acid-treated PC12 cells, with an unexpected synergistic effect seen in the combinatorial use of peptide 1 and 5
- the peptide according to the invention is used to preserve the neural cell viability under hypoglycemic and hypoxic conditions in vitro and/or in vivo, with an unexpected synergistic effect seen in the combinatorial use of peptide 1 and 5.
- the present invention relates to a method for preserving the neural cell viability upon exposure to H 2 O 2 in vitro or in vivo, comprising treating the neural cell with peptide 1 and/or 5 or administering peptide 1 and/or 5 to the subject in need thereof.
- the present invention relates to a method for preserving the neural cell viability under hypoglycemic and/or hypoxic conditions in vitro or in vivo, comprising treating the neural cell with peptide 1 and/or 5 or administering peptide 1 and/or 5 to the subject in need thereof.
- the present invention relates to a method for protecting the neural cell from glutamic acid-induced injury in vitro or in vivo, comprising treating the neural cell with peptide 1 and/or 5 or administering peptide 1 and/or 5 to the subject in need thereof.
- the lyophilized material was reconstituted with 100 ⁇ L of 0.5 M ammonia bicarbonate buffer (pH 8.5) containing 8 M urea and 0.5 M dithiothreitol (DTT) for 1 hr at 37°C, and for another 2 hr at 4°C under dark condition when 10 ⁇ L of 0.5 M iodoacetamide (IAM) was added for alkylation prior to dilution with 400 ⁇ L ammonium bicarbonate.
- 0.5 M ammonia bicarbonate buffer pH 8.5
- DTT dithiothreitol
- IAM iodoacetamide
- the resulting solutions were then digested with 0.2 ⁇ g of trypsin for 18 h at 37°C, and then the trypsin-digested solutions were acidified by 10%trifluoroacetic acid (TFA) /H 2 O to pH 3.0 value.
- the totally acidified solutions were applied onto the reverse phase C 18 column pre-equilibrated with 200 L of 0.1%TFA/H 2 O (pH 3.0) .
- the column was also washed with 200 ⁇ L of 0.1%TFA/H 2 O (pH 3.0) and then eluted with a stepwise acetonitrile gradient from 50%to 100%in 0.1%TFA at room temperature.
- the reconstituted liquid from lyophilized products was also treated by reduction, alkylation, desalting and acidified as mentioned above, except for trypsin digestion.
- the eluted fractions were collected, dried in a vacuum centrifuge, and then reconstituted in 25 ⁇ L of 80%ACN in H 2 O and analyzed by LTQ Orbitrap XL (Thermo Fisher Scientific, San Jose, CA) .
- Reverse phase nano-LC separation was performed on an Agilent 1200 series nanoflow system (Agilent Technologies, Santa Clara, CA) .
- a total of 10 ⁇ L sample from fraction was loaded onto an Agilent Zorbax XDB C18 precolumn (0.35 mm, 5 ⁇ m) , followed by separation using a C18 column (i.d. 75 ⁇ m ⁇ 25-cm, 3 ⁇ m, Micro Tech, Fontana, CA) .
- the mobile phases used were (A) 0.1%FA and (B) 0.1%FA in 100%ACN.
- a linear gradient from 5%to 35% (B) over a 90-min period at a flow rate of 300 nL/min was applied.
- the peptides were analyzed in the positive ion mode by applying a voltage of 1.8 Kv to the injection needle.
- a repeat duration of 30 s was applied to exclude the same m/z ions from the reselection for fragmentation.
- Peptides were identified by peak lists converted from the nanoLC-MS/MS spectra by searching against animal taxonomy in the Swiss-Prot databases for exact matches using the MASCOT search program (http: //www. matrixscience. com; Hirosawa et al., 1993) .
- the mass tolerance of both precursor ion and fragment ions was set to 10 ppm and 0.8 Da, respectively. Searches were performed to allow for the carbamidomethylation (C) as fixed modification, and no trypsin as variable modification.
- the amino acid sequence DEAQETAVSSHEQD (SEQ ID NO: 2) , determined from MS differences in the y-and b-fragment ions series and matched residues 1-14 of rabbit ⁇ 1-antiproteinase F, is absent in human, mouse as well as bovine ⁇ 1-antiproteinase F. Although both peptides have different length, they share the same origin from the amino acid sequence of rabbit ⁇ 1-antiproteinase F.
- Table 1 Characterization of two small peptides identified by MS/MS spectra from nano LC-MS/MS analysis
- Peptides were synthesized by using first-amino-acid-preloaded Wang resin, N-Fmoc amino acids, and PyBOP through solid phase synthesizer (PS3, Protein Technologies, Inc. ) .
- the crudes peptides were purified with RP-18 column by medium pressure liquid chromatography (MPLC) and their purities were confirmed as >95%by high performance liquid chromatography (HPLC) under UV detection at 220 nm wavelength.
- the characterizations of these peptides were proceeded by MALDI-TOF mass spectrometer (Autoflex III system, Bruker Daltonics) and Nuclear Magnetic Resonance spectroscopy (Varian 400 MHz) prior to further studies.
- Peptide-5 was also received from Mission Biotech Co. (M.B. Taipei, Taiwan) and presented same analgesic activity with our synthesized one.
- Peptide-5 was dissolved in series of solution with different pH value and stood for 3 days. Adequate amount of each resulting solution was analyzed by HPLC (Agilent 1100 series) using a Nucleodur Pyramid C18 column (250 mm ⁇ 4.6 mm, 5 ⁇ m) and gradient elution (0 min: 0.1%TFA in H2O; 10 min: 0.1%TFA in MeOH; 15 min: 0.1%TFA in MeOH) with 0.2 mL/min flow. The signals were monitored by UV detector at 220 nm wavelength. The sample collected in the stability test was also analyzed by MALDI-TOF Mass (Bruker Daltonics, Autoflex III) with 2, 5-dihydroxybenzoic acid (DHB) as matrix. Furthermore, the portion respond to the signal at 7.8 min were collected and subject to MALDI-MS analysis. Peptide-5 was also prepared 50 ⁇ M in PBS and recorded from circular dichroism (Jasco, J-810) .
- peptide-5 was stood in solution with various pH value (pH 2.0 to 8.5) for 3 day.
- the resulting solution was analyzed by HPLC and the chromatograms was recorded in UV detector. (Blue line: blank; red line: in pH 2.0; green line: in pH 4.0; pink line: in pH 7.0; black line: in pH 8.5.
- the retention time of Peptide-5 was 7.8 min. ) . This indicates that peptide 5 itself is stable, even in a very acidic environment.
- the CD of peptide 5 revealed that peptide 5 is extremely stable.
- the CD refers to the differential absorption of left and right circularly polarized light and can be used as an indicator for the secondary structure of a peptide or protein.
- PC12 cells derived from a pheochromocytoma of the rat adrenal medulla that exhibit certain characteristics of neuro-ganglion cells, were obtained from the Chinese Academy of Medical Sciences, Beijing, China.
- PC12 cells were grown to confluence in 96 well plate and the medium was changed to serum-free medium containing 200 ⁇ M H 2 O 2 (final volume 100 ⁇ l) for 24h.
- the isolated peptide or AGC was given into wells for 1h before exposure to H 2 O 2 .
- MTT final concentration 0.5 mg/ml
- PC12 cells were obtained from the Chinese Academy of Medical Sciences, Beijing, China. To examine cell survival upon exposure to L-glutamic acid, PC12 cells were grown to confluence in 96 well plate in serum-free RPMI-1640. In cells receiving treatment, the identified peptide or AGC at a given dose was put into wells for 1h before exposure to exposure to L-glutamic acid in the medium of Mg 2+ -free Eagle’s medium containing 1mM L-glutamic acid. After 15-min incubation, medium was changed to serum-free RPMI-1640.
- MTT final concentration 0.5 mg/ml
- PC12 cells were propagated and cultured as described above.
- 125 ⁇ M Cobaltous Chloride CoCl 2 , Sigma, USA
- culture media was changed to glucose-free Eagle’s medium when PC12 grew to monolayer for additional 24h incubation.
- PC12 cells were cultured in glucose-free Eagle’s media with addition of 125 ⁇ M CoCl 2 . After 24h, cells were harvested and subject to MTT assay.
- peptide 1+5 when used in combination, peptide 1+5 was protective against the death of PC12 cells exposed to hypoxia, hypoglycemia, or the combination of hypoxia plus hypoglycemia, and the protective effect was with a similar extent when compared to the use of 1 U/ml of AGC.
- mice (6 ⁇ 8 week-old, female) were purchased from National Laboratory Animal Center, Taiwan.
- animals were anesthetized by 2%isoflurane gas mixed with oxygen and intravenous injection (i.v. ) of Cy5.5-conjugated peptide 1 or Cy5.5-conjugated peptide 5 (35 nmole/per mouse) .
- i.v. intravenous injection
- mice were placed prone or supine in a dark box and a photographic image was first acquired at low light (exposure time: 5 seconds) .
- fluorescent signals were obtained using a CCD camera thermoelectrically cooled to -70°C (Xenogen - Spectrum Imaging System, Xenogen Technology) .
- the photon integration period was 1-2 sec. Fluorescent signals were recorded as maximum photos/second/centimeter2/steradian (photon/sec/cm2/sr) and displayed in pseudocolors and superimposed on the photographic image using Xenogen’s Living Image software.
Abstract
Description
Peptide | Protein identified | pI /Mass, |
1 | DEA-X1 (DEAQETAVSSH) | 4.13 /1173.16 |
5 | DEA-X5 (DEAQETAVSSHEQD) | 3.83 /1545.49 |
Claims (23)
- A method for treating or ameliorating cerebrovascular diseases in a subject, wherein the method comprises administering to the subject an effective amount of one or more peptide comprising an amino acid sequence having at least 70% identity to DEAQETAVSSH (SEQ ID NO: 1) or variants, mutants, derivatives, or fragments thereof.
- The method of claim 1, wherein the amino acid sequence has at least 75%, 80%, 85%, 90%, 95%, 98% or 99% or more identity to SEQ ID NO: 1.
- The method of claim 1 or 2, wherein the peptide comprises SEQ ID NO: 1 and/or DEAQETAVSSHEQD (SEQ ID NO: 2) .
- The method of any one of claims 1-3, wherein the peptide substantially consists of, or consists of SEQ ID NO: 1 and/or SEQ ID NO: 2.
- The method of any one of claims 1-4, wherein the peptide comprises at least one amino acid addition, deletion, and/or substitution.
- The method of claim 5, wherein the amino acid addition, deletion and/or substitution are located at the C-terminal and/or N-terminal.
- The method of claims 5 or 6, wherein the peptide has 1-5, preferably 1-3 amino acid additions, deletions, and/or substitutions.
- The method of any one of the preceding claims, wherein the cerebrovascular diseases are those which lead to damages of the neurological systems with functional deficit.
- The method of any one of the preceding claims, wherein the cerebrovascular diseases are selected from the group consisting of: ischemic brain injury or hemorrhage brain damage.
- The method of any one of claims 1-8, wherein the cerebrovascular disease is stroke.
- The method of any one of the preceding claims, wherein the cerebrovascular diseases are treated or ameliorated by protecting nerve cells.
- The method of any one of the preceding claims, wherein the subject is human.
- A peptide comprising an amino acid sequence having at least 70% identity to SEQ ID NO: 1, or variants, mutants, derivatives, or fragments thereof, for use in the treatment or amelioration of cerebrovascular diseases in a subject.
- The peptide of claim 13, comprising SEQ ID NO: 1 or SEQ ID NO: 2.
- The peptide of claim 13 or 14, substantially consisting of, or consisting of SEQ ID NO: 1 or SEQ ID NO: 2.
- A polynucleotide which encodes the peptide of any one of claims 13-15.
- A vector which comprises the polynucleotide of claim 16.
- A host cell which comprises the polynucleotide of claim 16 or the vector of claim 17.
- A pharmaceutical composition comprising an effective amount of the peptide of any one of claims 13-15, the polynucleotide of claim 16, the vector of claim 17, or the host cell of claim 18, and a pharmaceutically acceptable carrier.
- The peptide of any one of claims 13-15, the polynucleotide of claim 16, the vector of claim 17, the host cell of claim 18, or the pharmaceutical composition of claim 19 for use as a medicament
- Use of one or more peptide comprising an amino acid sequence having at least 70% identity to SEQ ID NO: 1 or variants, mutants, derivatives, or fragments thereof in the manufacture of a medicament for treating cerebrovascular diseases in a subject.
- The use of claim 21, wherein the peptide comprises SEQ ID NO: 1 and/or SEQ ID NO: 2.
- The use of claim 21 or 22, wherein the peptide substantially consists of, or consists of SEQ I D NO: 1 and/or SEQ ID NO: 2.
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
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KR1020177032836A KR20170137846A (en) | 2015-04-16 | 2015-04-16 | Therapeutic peptide for cerebrovascular disease |
EP15888807.3A EP3283095B1 (en) | 2015-04-16 | 2015-04-16 | Therapeutic peptides for cerebrovascular diseases |
CN202110967364.7A CN113893327A (en) | 2015-04-16 | 2015-04-16 | Therapeutic peptides for cerebrovascular diseases |
US15/566,937 US10130676B2 (en) | 2015-04-16 | 2015-04-16 | Therapeutic peptides for cerebrovascular diseases |
AU2015391458A AU2015391458A1 (en) | 2015-04-16 | 2015-04-16 | Therapeutic peptides for cerebrovascular diseases |
PCT/CN2015/076747 WO2016165102A1 (en) | 2015-04-16 | 2015-04-16 | Therapeutic peptides for cerebrovascular diseases |
CA2982387A CA2982387A1 (en) | 2015-04-16 | 2015-04-16 | Therapeutic peptides for cerebrovascular diseases |
CN201580078903.4A CN107847550B (en) | 2015-04-16 | 2015-04-16 | Therapeutic peptides for cerebrovascular diseases |
JP2018505510A JP6703595B2 (en) | 2015-04-16 | 2015-04-16 | Therapeutic peptide for cerebrovascular disease |
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PCT/CN2015/076747 WO2016165102A1 (en) | 2015-04-16 | 2015-04-16 | Therapeutic peptides for cerebrovascular diseases |
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US (1) | US10130676B2 (en) |
EP (1) | EP3283095B1 (en) |
JP (1) | JP6703595B2 (en) |
KR (1) | KR20170137846A (en) |
CN (2) | CN113893327A (en) |
AU (1) | AU2015391458A1 (en) |
CA (1) | CA2982387A1 (en) |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2020024142A1 (en) * | 2018-08-01 | 2020-02-06 | Vanford Bio-Drug Development Limited | Novel peptides and its derivatives capable of stimulating cytokine release |
WO2020248240A1 (en) * | 2019-06-14 | 2020-12-17 | 俊熙有限公司 | Use of extract from rabbit skin inflamed by vaccinia virus in treatment of cancer |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA3128060A1 (en) * | 2019-01-30 | 2020-08-06 | Nippon Zoki Pharmaceutical Co., Ltd. | Inhibiting or alleviating agent for inflammation in the brain |
CN112759625B (en) * | 2019-10-18 | 2023-05-05 | 沛尔生技医药股份有限公司 | Use of peptides for the preparation of a medicament for the treatment of inflammatory diseases and pain |
AU2019470693B2 (en) * | 2019-10-18 | 2022-07-14 | Pell Bio-Med Technology Co., Ltd | Peptide and use thereof in preparation of drug for treating inflammatory diseases and pain |
JP2020063311A (en) * | 2020-01-31 | 2020-04-23 | プライム・バイオ‐ドラッグ・ディヴェロップメント・リミテッドPrime Bio‐Drug Development Limited | Therapeutic peptides for cerebrovascular diseases |
WO2023184473A1 (en) * | 2022-04-01 | 2023-10-05 | 首创生物技术有限公司 | Use of peptide in treating neurodegenerative diseases or improving cognitive function |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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US20030077266A1 (en) * | 2001-10-19 | 2003-04-24 | John Lezdey | Anti-cancer compositions |
CN104321337A (en) * | 2012-05-25 | 2015-01-28 | 永林有限公司 | Peptide and the use thereof |
Family Cites Families (2)
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WO2000051624A2 (en) * | 1999-03-05 | 2000-09-08 | The Trustees Of University Technology Corporation | Methods and compositions useful in inhibiting apoptosis |
US20130203650A1 (en) * | 2010-08-31 | 2013-08-08 | Yissum Research Development Company Of The Hebrew Uviversity Of Jerusalem | Polypeptides derived from alpha-1 antitrypsin and methods of use thereof |
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2015
- 2015-04-16 EP EP15888807.3A patent/EP3283095B1/en active Active
- 2015-04-16 US US15/566,937 patent/US10130676B2/en active Active
- 2015-04-16 AU AU2015391458A patent/AU2015391458A1/en not_active Abandoned
- 2015-04-16 WO PCT/CN2015/076747 patent/WO2016165102A1/en active Application Filing
- 2015-04-16 JP JP2018505510A patent/JP6703595B2/en active Active
- 2015-04-16 CN CN202110967364.7A patent/CN113893327A/en active Pending
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US20030077266A1 (en) * | 2001-10-19 | 2003-04-24 | John Lezdey | Anti-cancer compositions |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2020024142A1 (en) * | 2018-08-01 | 2020-02-06 | Vanford Bio-Drug Development Limited | Novel peptides and its derivatives capable of stimulating cytokine release |
WO2020248240A1 (en) * | 2019-06-14 | 2020-12-17 | 俊熙有限公司 | Use of extract from rabbit skin inflamed by vaccinia virus in treatment of cancer |
CN114340645A (en) * | 2019-06-14 | 2022-04-12 | 俊熙有限公司 | Use of extract of rabbit fur with inflammation caused by vaccinia virus for treating cancer |
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KR20170137846A (en) | 2017-12-13 |
JP6703595B2 (en) | 2020-06-03 |
CN113893327A (en) | 2022-01-07 |
AU2015391458A1 (en) | 2017-11-02 |
US20180125923A1 (en) | 2018-05-10 |
US10130676B2 (en) | 2018-11-20 |
CN107847550B (en) | 2021-07-30 |
CA2982387A1 (en) | 2016-10-20 |
EP3283095B1 (en) | 2020-11-11 |
CN107847550A (en) | 2018-03-27 |
JP2018516273A (en) | 2018-06-21 |
EP3283095A4 (en) | 2018-12-05 |
EP3283095A1 (en) | 2018-02-21 |
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