CN109678930A - Polyethyleneglycol modified NPFF and application thereof - Google Patents
Polyethyleneglycol modified NPFF and application thereof Download PDFInfo
- Publication number
- CN109678930A CN109678930A CN201811481426.8A CN201811481426A CN109678930A CN 109678930 A CN109678930 A CN 109678930A CN 201811481426 A CN201811481426 A CN 201811481426A CN 109678930 A CN109678930 A CN 109678930A
- Authority
- CN
- China
- Prior art keywords
- npff
- dmf
- added
- peg
- phe
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 108010055752 phenylalanyl-leucyl-phenylalanyl-glutaminyl-prolyl-glutaminyl-arginyl-phenylalaninamide Proteins 0.000 title claims abstract description 40
- 229920001223 polyethylene glycol Polymers 0.000 title claims abstract description 36
- 239000002202 Polyethylene glycol Substances 0.000 title claims abstract description 21
- 102100029127 Pro-FMRFamide-related neuropeptide FF Human genes 0.000 title abstract 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 98
- 102400001095 Neuropeptide FF Human genes 0.000 claims description 37
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- 230000015572 biosynthetic process Effects 0.000 claims description 22
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 22
- 238000003786 synthesis reaction Methods 0.000 claims description 22
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 21
- 229920001184 polypeptide Polymers 0.000 claims description 20
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 16
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 239000011347 resin Substances 0.000 claims description 9
- 229920005989 resin Polymers 0.000 claims description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 8
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 8
- 238000005520 cutting process Methods 0.000 claims description 7
- 238000004090 dissolution Methods 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 150000001413 amino acids Chemical class 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- HWYCFZUSOBOBIN-AQJXLSMYSA-N (2s)-2-[[(2s)-1-[(2s)-5-amino-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-amino-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]-3-phenylpropanoyl]amino]-5-oxopentanoyl]pyrrolidine-2-carbonyl]amino]-n-[(2s)-1-[[(2s)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-(diaminome Chemical compound C([C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)C1=CC=CC=C1 HWYCFZUSOBOBIN-AQJXLSMYSA-N 0.000 claims description 5
- FEKRFYZGYUTGRY-UHFFFAOYSA-N n'-ethylmethanediimine Chemical compound CCN=C=N FEKRFYZGYUTGRY-UHFFFAOYSA-N 0.000 claims description 5
- 238000005086 pumping Methods 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- 239000003875 Wang resin Substances 0.000 claims description 4
- NERFNHBZJXXFGY-UHFFFAOYSA-N [4-[(4-methylphenyl)methoxy]phenyl]methanol Chemical compound C1=CC(C)=CC=C1COC1=CC=C(CO)C=C1 NERFNHBZJXXFGY-UHFFFAOYSA-N 0.000 claims description 4
- 238000001514 detection method Methods 0.000 claims description 4
- OKEORFXNCSRZFL-VWLOTQADSA-N (2s)-3-(4-tert-butylphenyl)-2-(9h-fluoren-9-ylmethoxycarbonylamino)propanoic acid Chemical compound C1=CC(C(C)(C)C)=CC=C1C[C@@H](C(O)=O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 OKEORFXNCSRZFL-VWLOTQADSA-N 0.000 claims description 3
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 125000000729 N-terminal amino-acid group Chemical group 0.000 claims description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 3
- 125000002619 bicyclic group Chemical group 0.000 claims description 3
- 230000000903 blocking effect Effects 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 239000006166 lysate Substances 0.000 claims description 3
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 claims description 3
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 229910021642 ultra pure water Inorganic materials 0.000 claims description 3
- 239000012498 ultrapure water Substances 0.000 claims description 3
- 238000012360 testing method Methods 0.000 claims description 2
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 claims description 2
- CMWYAOXYQATXSI-UHFFFAOYSA-N n,n-dimethylformamide;piperidine Chemical compound CN(C)C=O.C1CCNCC1 CMWYAOXYQATXSI-UHFFFAOYSA-N 0.000 claims 1
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 12
- 239000003814 drug Substances 0.000 abstract description 12
- 206010061218 Inflammation Diseases 0.000 abstract description 10
- 230000004054 inflammatory process Effects 0.000 abstract description 10
- 230000004083 survival effect Effects 0.000 abstract description 7
- 238000002474 experimental method Methods 0.000 abstract description 6
- 230000009286 beneficial effect Effects 0.000 abstract description 4
- 239000002260 anti-inflammatory agent Substances 0.000 abstract description 3
- 229940124599 anti-inflammatory drug Drugs 0.000 abstract description 3
- 230000008961 swelling Effects 0.000 abstract description 3
- 230000002035 prolonged effect Effects 0.000 abstract 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 17
- 239000000243 solution Substances 0.000 description 9
- 229940079593 drug Drugs 0.000 description 8
- 230000000638 stimulation Effects 0.000 description 8
- 230000002757 inflammatory effect Effects 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- 210000002683 foot Anatomy 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 3
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- MUDSDYNRBDKLGK-UHFFFAOYSA-N 4-methylquinoline Chemical compound C1=CC=C2C(C)=CC=NC2=C1 MUDSDYNRBDKLGK-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 101000634561 Homo sapiens Neuropeptide FF receptor 2 Proteins 0.000 description 2
- 102100029050 Neuropeptide FF receptor 2 Human genes 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229920001525 carrageenan Polymers 0.000 description 2
- 235000010418 carrageenan Nutrition 0.000 description 2
- 238000004140 cleaning Methods 0.000 description 2
- 239000003651 drinking water Substances 0.000 description 2
- 235000020188 drinking water Nutrition 0.000 description 2
- 150000002334 glycols Chemical class 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 210000003371 toe Anatomy 0.000 description 2
- CQZWLVDDIOZTJI-RYUDHWBXSA-N (2s)-2-amino-n-[(2s)-1-amino-1-oxo-3-phenylpropan-2-yl]-5-(diaminomethylideneamino)pentanamide Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@H](C(N)=O)CC1=CC=CC=C1 CQZWLVDDIOZTJI-RYUDHWBXSA-N 0.000 description 1
- 241000208340 Araliaceae Species 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 244000283207 Indigofera tinctoria Species 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 1
- 235000003140 Panax quinquefolius Nutrition 0.000 description 1
- 108010056448 RFamide peptide Proteins 0.000 description 1
- 239000012317 TBTU Substances 0.000 description 1
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 230000000146 antalgic effect Effects 0.000 description 1
- 108010083298 arginylphenylalaninamide Proteins 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 235000021050 feed intake Nutrition 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- DWYMPOCYEZONEA-UHFFFAOYSA-L fluoridophosphate Chemical compound [O-]P([O-])(F)=O DWYMPOCYEZONEA-UHFFFAOYSA-L 0.000 description 1
- 235000008434 ginseng Nutrition 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 230000008058 pain sensation Effects 0.000 description 1
- 206010033675 panniculitis Diseases 0.000 description 1
- 230000006320 pegylation Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- UIDUKLCLJMXFEO-UHFFFAOYSA-N propylsilane Chemical compound CCC[SiH3] UIDUKLCLJMXFEO-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 239000011265 semifinished product Substances 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 210000004304 subcutaneous tissue Anatomy 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Rheumatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pain & Pain Management (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Medicinal Preparation (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明公开了一种聚乙二醇修饰的NPFF。技术方案是采用聚乙二醇修饰NPFF(NPFF‑PEG)，小鼠足肿炎症模型和LPS刺激生存曲线模型检测NPFF‑PEG的抗炎活性。实验证明，NPFF‑PEG具有良好的抗炎活性。在小鼠足肿炎症模型上，NPFF‑PEG在15mg/kg和30mg/kg分别抑制炎症41.25％和50.74％(12小时)。在LPS刺激生存曲线模型上，NPFF‑PEG 1mg/kg显著延长LPS刺激组(LPS 25mg/kg)的生存时间(14天时，提高75％生存率)。本发明提供一种NPFF‑PEG作为抗炎药物的应用，为治疗相应炎症提供有益帮助，在医药领域有潜在的应用价值。
The invention discloses a polyethylene glycol modified NPFF. The technical solution is to use polyethylene glycol modified NPFF (NPFF-PEG) to detect the anti-inflammatory activity of NPFF-PEG in a mouse foot swelling inflammation model and a LPS-stimulated survival curve model. Experiments show that NPFF‑PEG has good anti-inflammatory activity. In the mouse foot swelling inflammation model, NPFF-PEG inhibited inflammation by 41.25% and 50.74% (12 hours) at 15 mg/kg and 30 mg/kg, respectively. On the LPS-stimulated survival curve model, NPFF-PEG 1 mg/kg significantly prolonged the survival time of the LPS-stimulated group (LPS 25 mg/kg) (at 14 days, increased survival by 75%). The invention provides an application of NPFF-PEG as an anti-inflammatory drug, which provides beneficial help for treating corresponding inflammation and has potential application value in the field of medicine.
Description
Technical field
The invention belongs to medical usage technical fields, and in particular to a kind of polyethyleneglycol modified NPFF.
Background technique
Neuropeptide FF (Neuropeptide FF, NPFF) is a kind of endogenous neural octapeptide in the mammalian body
(FLFQPQRFamide), endogenous receptor NPFFR2 (NPFF receptor2, NPFFR2) belongs to g protein coupled receptor (G
Protein-Coupled Receptor, GPCR) family.NPFF belongs to RFamide peptide family, and (common trait of the peptide family is
Its C latter end all has RFamide).NPFF has multiple biological function, including participates in pain sensation conduction, blood pressure, ingests, interior point
It secretes, body temperature etc..Since NPFF is distributed widely in various biological process in internal and wide participation body, NPFF's grinds
Study carefully and is of great significance.
It the advantages that strong, high specificity active as the protein drug of representative using polypeptide, is widely used at present, still
Since protein drug ginseng is the problems such as water-soluble, stability is poor, and plasma half-life is short, it is limited to a certain extent and is answered
With.Polyethylene glycol (PEG) refers to ethylene oxide polymer, has stronger hydrogen bonding capability, PEG and drug covalent coupling
Afterwards, immunogenicity can be reduced, drug half-life is improved, improves biological stability and internal physicochemical property
(Biomacromolecules.2014；15(5):1543-59).There are many pharmaceutical grade proteins of PEG modification to be examined by FDA
Batch, it is used for clinical treatment.PEG modification is one of improved most effective strategy of current polypeptide drugs.Currently, resisting although NPFF has
Scorching activity (Peptides.2013；47 (1): 124-32.), due to it because the problems such as being easy degradation, half-life short, limits
Its development and application as drug.Currently, there is not yet using polyethyleneglycol modified NPFF report.
Summary of the invention
The present invention provides a kind of polyethyleneglycol modified NPFF, using polyethyleneglycol modified NPFF (NPFF-PEG), mouse
The anti-inflammatory activity of the swollen inflammatory model of foot and LPS stimulation survivorship curve model inspection NPFF-PEG.It is demonstrated experimentally that NPFF-PEG has
Good anti-inflammatory activity.On mouse enough swollen inflammatory model, NPFF-PEG inhibits inflammation in 15mg/kg and 30mg/kg respectively
41.25% and 50.74% (12 hours).On LPS stimulation survivorship curve model, NPFF-PEG 1mg/kg significantly extends LPS thorn
Swash the life span (at 14 days, improving 75% survival rate) of group (LPS 25mg/kg).The present invention provides a kind of NPFF-PEG conduct
The application of anti-inflammatory drug provides beneficial to help to treat corresponding inflammation, has potential application value in field of medicaments.
The technical solution adopted by the present invention to solve the technical problems: a kind of polyethyleneglycol modified NPFF, using poly- second
Glycol modifies the N-terminal of NPFF, and molecular formula is C60H87N15O13, molecular weight is 1226.30, and molecular structural formula is:
A kind of above-mentioned polyethyleneglycol modified NPFF preparation method, its main feature is that the following steps are included:
Step 1: in the reaction vessel, N is added, N- dimethylformamide adds wang resin, vibrates 25min；
Solvent is taken out Step 2: filtering, addition is equivalent to 4 times moles of synthesis polypeptide of fmoc-protected Phe (Fmoc-L-
Phe (4-tBu)-OH), add the bicyclic ethyl carbodiimide (DCC) and 4- diformazan ammonia for being equivalent to 12 times of synthesis polypeptides mole
Yl pyridines (DMAP) add DMF dissolution, vibrate 35min, closed with acetic anhydride；
Step 3: pumping DMF, the Piperidine/DMF solution of volume fraction 20% is added, after draining 10min, adds volume point
The Piperidine/DMF solution of number 20% reacts 20min；
Step 4: pumping Piperidine/DMF solution, ten grainy resins are taken out from reaction vessel with sterile pipette tip, are put into
Each drop of potassium cyanide, ninhydrin, phenol solution is added in blank cuvette, and 106-111 DEG C of heating 6min, deepening blue is the positive
Reaction.
Step 5: successively being cleaned three times with DMF, methanol, DMF；
Step 6: by 3 times moles of synthesis polypeptide of protected amino acid, o- benzotriazole-tetramethylurea hexafluorophosphate
It after being dissolved with DMF, is added in reaction vessel, then is rapidly added 12 times moles of synthesis polypeptide of 4- methyl morpholine, react 35min；
Step 7: the DMF for sequentially adding 10ml/g is washed 2 times, the methanol of 10ml/g is washed 4 times, and the DMF of 10ml/g is washed 2 times；
Step 8: repeating step 2 to step 7, following sequence ammonia is successively condensed to N-terminal residue sequence according to sequence C section
Base acid: Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2。
Step 9: Mass Spectrometer Method NPFF is main peak, the NH for being equivalent to 3 times moles of NPFF of synthesis is added2-(CH2CH2O)8-
CH2CH2COOH is equivalent to 6 times moles of synthesis polypeptide of HBTU, after DMF dissolution, is added and is equivalent to 20 times moles of NPFF synthesis
NMM reacts 40min；It is colourless to be shown after the method detection of step 4, take out Fmoc blocking group；
Step 10: DMF3 times of 10ml/g is added, and the methanol of 10ml/g 3 times, DMF3 times of 10ml/g, the DCM3 of 10ml/g
It is secondary, drain 30min；
Step 11: preparing trifluoroacetic acid 95% (V/V), the cutting liquid of 10ml/g is added；Ultrapure water 2% (V/V)；Three is different
Propyl silane 1% (V/V)；1,2- dithioglycol 2% (V/V).Cutting resin 150min；
Step 12: chlorine protection is lower to dry up lysate, ether volatilizees dry at washing 8 times, 24 DEG C；
Step 13: high performance liquid chromatography purifies, mobile phase: volume fraction is 0.1% trifluoroacetic acid and acetonitrile with 50:
50 volume ratios mix, and obtain polyethyleneglycol modified NPFF sterling.
The beneficial effects of the present invention are: the present invention uses polyethyleneglycol modified NPFF (NPFF-PEG), the swollen inflammation of mouse foot
The anti-inflammatory activity of model and LPS stimulation survivorship curve model inspection NPFF-PEG.It is demonstrated experimentally that NPFF-PEG has good resist
Scorching activity.On mouse enough swollen inflammatory model, NPFF-PEG inhibits 41.25% He of inflammation in 15mg/kg and 30mg/kg respectively
50.74% (12 hours).On LPS stimulation survivorship curve model, NPFF-PEG1mg/kg significantly extends LPS stimulation group (LPS
Life span (at 14 days, improving 75% survival rate) 25mg/kg).The present invention provides a kind of NPFF-PEG as anti-inflammatory drug
Application, provide to treat corresponding inflammation beneficial to help, have potential application value in field of medicaments.
It elaborates with reference to the accompanying drawings and detailed description to the present invention.
Detailed description of the invention
Fig. 1 is mouse swollen inflammatory model evaluation NPFF-PEG anti-inflammatory activity enough.V.S.Control,*P<0.05,**P<
0.01,***P<0.001,****P<0.0001.NPFF-PEG has significant anti-inflammatory activity.
Fig. 2 is LPS stimulation survivorship curve experimental evaluation NPFF-PEG anti-inflammatory activity.NPFF-PEG has significant anti-inflammatory work
Property.
Fig. 3 is the polyethyleneglycol modified NPFF Mass Spectrometric Identification figure of the present invention.
Specific embodiment
Following embodiment referring to Fig.1-3.
Embodiment 1.The preparation of Pegylation NPFF (NPFF-PEG).
Synthetic method: TBTU+DIEA+ protected amino acid, whole three times feed intake, and modify on the amino of N-terminal Phe.
Below in conjunction with attached drawing, the embodiment of the present invention is described.Specific experiment condition is not specified in embodiment
Method, usually according to manufacturer or normal condition.
Solid phase polypeptide synthesis prepares the polyethylene glycol derivative of NPFF, and steps are as follows:
Step 1: swellable resins: in the reaction vessel, N is added, N- dimethylformamide (DMF) adds wang resin
(wang resin) vibrates 25min；
Step 2: connecing amino acid: filtering and take out solvent, addition is equivalent to 4 times moles of synthesis polypeptide of fmoc-protected Phe
(Fmoc-L-Phe (4-tBu)-OH), add the bicyclic ethyl carbodiimide (DCC) for being equivalent to 12 times of synthesis polypeptides mole and
4-dimethylaminopyridine (DMAP) adds DMF dissolution, vibrates 35min, closed with acetic anhydride；
Step 3: deprotection: DMF is pumped, is added Piperidine/DMF solution (volume fraction 20%), after draining 10min, then plus
Enter Piperidine/DMF solution (volume fraction 20%), reacts 20min；
Step 4: detection: pumping Piperidine/DMF solution, carefully take out more than ten from reaction vessel with sterile pipette tip
Grainy resin is put into blank cuvette, and each drop of potassium cyanide, ninhydrin, phenol solution is added, and 106-111 DEG C of heating 6min deepens indigo plant
Color is positive reaction.
Step 5: washing: successively being cleaned three times with DMF, methanol, DMF；
Step 6: condensation reaction: by 3 times moles of synthesis polypeptide of protected amino acid, o- benzotriazole-tetramethylurea six
It after fluorophosphate (HBTU) is dissolved with DMF, is added in reaction vessel, then is rapidly added 12 times moles of synthesis polypeptide of 4- methyl
Quinoline (NMM) reacts 35min；
Step 7: washing: sequentially adding DMF (10ml/g) and wash 2 times, methanol (10ml/g) is washed 4 times, and DMF (10ml/g) washes 2
It is secondary；
Step 8: repeating step 2 to step 7, following sequence ammonia is successively condensed to N-terminal residue sequence according to sequence C section
Base acid
Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2
Step 9: Mass Spectrometer Method NPFF is main peak, the NH for being equivalent to 3 times moles of NPFF of synthesis is added2-(CH2CH2O)8-
CH2CH2COOH is equivalent to 6 times moles of synthesis polypeptide of HBTU, after DMF dissolution, is added and is equivalent to 20 times moles of NPFF synthesis
NMM reacts 40min；It is colourless to be shown after the method detection of step 4, take out Fmoc blocking group；
Step 10: draining, resin is washed: DMF (10ml/g) 3 times, methanol (10ml/g) 3 times, DMF (10ml/g) 3 times, DCM
(10ml/g) 3 times, drains 30min；
Step 11: the polypeptide on cutting resin: preparing trifluoroacetic acid 95% (V/V), cutting liquid (10ml/g)；Ultrapure water
2% (V/V)；Tri isopropyl silane 1% (V/V)；1,2- dithioglycol 2% (V/V).Cutting resin 150min；
Step 12: drying up and washing: chlorine protection is lower to dry up lysate, and ether washs 8 times, volatilizees under room temperature (24 DEG C)
It is dry；
Step 13: preparing dry powder dress polypeptide semifinished product: (mobile phase: volume fraction is for high performance liquid chromatography purifying
0.1% trifluoroacetic acid and acetonitrile are mixed with 50:50 volume ratio), that is, obtain the polyethylene glycol derivative sterling of NPFF, knot
Structure formula is as follows:
Referring to Fig. 3, NPFF-PEG mass spectroscopy molecular amount is 1226.30, consistent with the molecular weight of theoretical calculation, illustrates NPFF-
PEG identification is errorless.
Embodiment 2.Swollen inflammatory model evaluates NPFF-PEG anti-inflammatory activity to mouse enough.
1) experimental animal: experiment mice feeding environment is cleaning grade, 22 ± 2 DEG C of environment temperature, humidity 50%-55%, 08:
00-20:00 illumination.The every cage 6-8 of mouse is only raised, and can freely ingest drinking-water.
2) experimental group: experiment is divided into blank control group (Vehicle), positive controls (DEX 5mg/kg), NPFFR2-
PEG (15mg/kg), NPFFR2-PEG (30mg/kg), totally 4 groups.Each group mouse quantity is consistent (8/group).
3) the swollen inflammatory model of mouse foot: taking 6-8 week old healthy mice to be grouped at random, and every group 10~12.Abdominal cavity note respectively
Various kinds of drug is penetrated, gives 25 μ l, 1% (W/V) carrageenin injection as control in the right toes subcutaneous tissue of mouse after 30 minutes
It gives 25 μ l, 0.9% physiological saline to be subcutaneously injected in left foot toe, records 1,2,3,4 after injecting pro-inflammatory cytokine carrageenan respectively,
The thickness of 5,6,24,48 hours mouse or so foot, is measured with vernier caliper.Swelling thickness (mm)=right sufficient thickness (mm)-
Left foot thickness (mm).
Referring to Fig. 1, on mouse enough swollen inflammatory model, NPFF-PEG2 inhibits inflammation in 15mg/kg and 30mg/kg respectively
41.25% and 50.74% (12 hours).
Embodiment 3.LPS stimulates survivorship curve experimental evaluation NPFF-PEG anti-inflammatory activity.
1) experimental animal: experiment mice feeding environment is cleaning grade, 22 ± 2 DEG C of environment temperature, humidity 50%-55%, 08:
00-20:00 illumination.The every cage 6-8 of mouse is only raised, and can freely ingest drinking-water.
2) experimental group: experiment is divided into positive controls (LPS 25mg/kg), medicine group (LPS 25mg/kg+NPFFR2-
PEG 1mg/kg), totally 2 groups.Each group mouse quantity is consistent (11/group).
3) LPS stimulates survivorship curve to test: 6-8 week old healthy mice is selected, it is random to be grouped, and every group 15.It gives respectively
Different drug-treateds (different according to experimental group) observes the variations such as activity, behavior of the mouse in 0-14d and (contains daily body
Weight), mouse is put to death after the completion, and the physiological indexes such as record mouse general activity, the state of mind, every daily weight are kept records of
And analyze survivorship curve.
Referring to fig. 2, on LPS stimulation survivorship curve model, NPFF-PEG2 1mg/kg significantly extends LPS stimulation group (LPS
Life span (at 14 days, improving 75% survival rate) 25mg/kg).
Specific embodiment is active constituent to polyethyleneglycol modified NPFF (NPFF-PEG) below, is preparing anti-inflammatory and antalgic
Application in drug is described further.
Embodiment 4.The preparation of tablet.
Technique: 1000, tablet are made by the common process for preparing tablet, every 40mg containing NPFF-PEG.
Usage and dosage: twice a day, 2~3 every time.
Embodiment 5.The preparation of soft capsule.
Technique: 1000 are made by the common process for preparing capsule, every capsule 80mg containing NPFF-PEG.
Usage and dosage: twice a day, 2~3 every time.
Embodiment 6.The preparation of injection.
Technique: being operated by the common process for preparing injection, and injection 1000 of 2ml are made altogether, and every contains NPFF-
PEG 120mg。
Usage and dosage: twice a day, 1~2 every time.
The auxiliary materials such as filler, disintegrating agent, binder, lubricant in the various embodiments described above are most conventional in pharmacy
Auxiliary material.
Claims (2)
1. a kind of polyethyleneglycol modified NPFF, using the N-terminal of polyethyleneglycol modified NPFF, molecular formula is C60H87N15O13, point
Son amount is 1226.30, and molecular structural formula is:
2. a kind of polyethyleneglycol modified NPFF preparation method described in claim 1, its main feature is that the following steps are included:
Step 1: in the reaction vessel, N is added, N- dimethylformamide adds wang resin, vibrates 25min；
Solvent is taken out Step 2: filtering, addition is equivalent to 4 times moles of synthesis polypeptide of fmoc-protected Phe (Fmoc-L-Phe
(4-tBu)-OH), the bicyclic ethyl carbodiimide and 4-dimethylaminopyridine for being equivalent to 12 times of synthesis polypeptides mole are added, then
DMF dissolution is added, vibrates 35min, is closed with acetic anhydride；
Step 3: pumping DMF, the Piperidine/DMF solution of volume fraction 20% is added, after draining 10min, adds volume fraction
20% Piperidine/DMF solution reacts 20min；
Step 4: pumping Piperidine/DMF solution, ten grainy resins are taken out from reaction vessel with sterile pipette tip, are put into blank
Each drop of potassium cyanide, ninhydrin, phenol solution is added in test tube, and 106-111 DEG C of heating 6min, deepening blue is positive reaction；
Step 5: successively being cleaned three times with DMF, methanol, DMF；
Step 6: by 3 times moles of synthesis polypeptide of protected amino acid, o- benzotriazole-tetramethylurea hexafluorophosphate DMF
It after dissolution, is added in reaction vessel, then is rapidly added 12 times moles of synthesis polypeptide of 4- methyl morpholine, react 35min；
Step 7: the DMF for sequentially adding 10ml/g is washed 2 times, the methanol of 10ml/g is washed 4 times, and the DMF of 10ml/g is washed 2 times；
Step 8: repeating step 2 to step 7, following sequence amino acid is successively condensed to N-terminal residue sequence according to sequence C section:
Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2；
Step 9: Mass Spectrometer Method NPFF is main peak, the NH for being equivalent to 3 times moles of NPFF of synthesis is added2-(CH2CH2O)8-
CH2CH2COOH is equivalent to 6 times moles of synthesis polypeptide of HBTU, after DMF dissolution, is added and is equivalent to 20 times moles of NPFF synthesis
NMM reacts 40min；It is colourless to be shown after the method detection of step 4, take out Fmoc blocking group；
Step 10: DMF3 times of 10ml/g is added, and the methanol of 10ml/g 3 times, DMF3 times of 10ml/g, DCM3 times of 10ml/g,
Drain 30min；
Step 11: preparing trifluoroacetic acid 95% (V/V), the cutting liquid of 10ml/g is added；Ultrapure water 2% (V/V)；Triisopropyl
Silane 1% (V/V)；1,2- dithioglycol 2% (V/V)；Cutting resin 150min；
Step 12: chlorine protection is lower to dry up lysate, ether volatilizees dry at washing 8 times, 24 DEG C；
Step 13: high performance liquid chromatography purifies, mobile phase: volume fraction is 0.1% trifluoroacetic acid and acetonitrile with 50:50 body
Product ratio mixes, and obtains polyethyleneglycol modified NPFF sterling.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811481426.8A CN109678930B (en) | 2018-12-05 | 2018-12-05 | NPFF modified by polyethylene glycol and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811481426.8A CN109678930B (en) | 2018-12-05 | 2018-12-05 | NPFF modified by polyethylene glycol and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109678930A true CN109678930A (en) | 2019-04-26 |
| CN109678930B CN109678930B (en) | 2022-04-29 |
Family
ID=66186462
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811481426.8A Active CN109678930B (en) | 2018-12-05 | 2018-12-05 | NPFF modified by polyethylene glycol and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109678930B (en) |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070140966A1 (en) * | 2005-10-19 | 2007-06-21 | Ibc Pharmaceuticals, Inc. | Multivalent immunoglobulin-based bioactive assemblies |
| CN101316625A (en) * | 2005-12-07 | 2008-12-03 | 霍夫曼-拉罗奇有限公司 | Neuropeptide-2 receptor-agonists |
| CN102369209A (en) * | 2009-03-20 | 2012-03-07 | 韩美控股株式会社 | Method for preparing a site-specific physiologically active polypeptide conjugate |
| CN102596228A (en) * | 2009-10-13 | 2012-07-18 | 霍夫曼-拉罗奇有限公司 | Neuropeptide-2 receptor (Y-2R) agonists |
| CN102850431A (en) * | 2012-04-06 | 2013-01-02 | 兰州大学 | Chimeric peptide based on opioid peptide Biphalin and neuropeptide FF, its synthesis and application |
| CN103517712A (en) * | 2010-12-15 | 2014-01-15 | 神经佐剂股份有限公司 | Neuropeptide analogs, compositions, and methods for treating pain |
| CN106084001A (en) * | 2016-04-21 | 2016-11-09 | 兰州大学 | The Mutiple Targets peptide quasi-molecule of one OPIOIDS and neuropeptide FF receptor and preparation thereof and application |
-
2018
- 2018-12-05 CN CN201811481426.8A patent/CN109678930B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070140966A1 (en) * | 2005-10-19 | 2007-06-21 | Ibc Pharmaceuticals, Inc. | Multivalent immunoglobulin-based bioactive assemblies |
| CN101316625A (en) * | 2005-12-07 | 2008-12-03 | 霍夫曼-拉罗奇有限公司 | Neuropeptide-2 receptor-agonists |
| CN102369209A (en) * | 2009-03-20 | 2012-03-07 | 韩美控股株式会社 | Method for preparing a site-specific physiologically active polypeptide conjugate |
| CN102596228A (en) * | 2009-10-13 | 2012-07-18 | 霍夫曼-拉罗奇有限公司 | Neuropeptide-2 receptor (Y-2R) agonists |
| CN103517712A (en) * | 2010-12-15 | 2014-01-15 | 神经佐剂股份有限公司 | Neuropeptide analogs, compositions, and methods for treating pain |
| CN102850431A (en) * | 2012-04-06 | 2013-01-02 | 兰州大学 | Chimeric peptide based on opioid peptide Biphalin and neuropeptide FF, its synthesis and application |
| CN106084001A (en) * | 2016-04-21 | 2016-11-09 | 兰州大学 | The Mutiple Targets peptide quasi-molecule of one OPIOIDS and neuropeptide FF receptor and preparation thereof and application |
Non-Patent Citations (3)
| Title |
|---|
| YORAM SHECHTER等: "Reversible PEGylation of peptide YY3-36 prolongs its inhibition of food intake in mice", 《FEBS LETTERS》 * |
| YU-LONG SUN等: "The anti-inflammatory potential of neuropeptide FF in vitro and in vivo", 《PEPTIDES》 * |
| 孙瑜隆: "神经肽FF的生物活性研究进展", 《现代生物医学进展》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109678930B (en) | 2022-04-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102850431B (en) | Chimeric Peptide Based on Opioid Peptide Biphalin and Neuropeptide FF and Its Synthesis and Application | |
| TWI672315B (en) | Acylated insulin compound | |
| CN106632603B (en) | One group of peptide and its pharmaceutical composition and application | |
| CN101041693B (en) | Novel blood sugar lowing polypeptide and uses thereof | |
| CN109718363A (en) | Prevention, the peptide for alleviating or treating Alzheimer disease and its application | |
| PT1133522E (en) | Antagonistic analogs of gh-rh inhibiting igf-i and -ii | |
| CN104072587B (en) | Protamine mimetic peptide and pharmaceutical salt and application thereof | |
| EP0585444B1 (en) | Hepatoma treatment with somatostatin analogs | |
| Lalani et al. | Review on therapeutic potential of peptides: Advancements in synthesis methods, linear and cyclic peptides, and strategies for overcoming challenges | |
| CN109678930A (en) | Polyethyleneglycol modified NPFF and application thereof | |
| EP0588873B1 (en) | Treatment of liver cancer | |
| TW200944236A (en) | G-CSF conjugates modified by water-soluble polymers | |
| CN112608367B (en) | Non-natural amino acid short peptide and application thereof in anti-tumor | |
| CN103012596A (en) | Endomorphin-derived peptide with blood-brain barrier permeability as well as synthesis and application of endomorphin-derived peptide | |
| WO2022257831A1 (en) | Polypeptide compounds using pd-1 receptors as targets, preparation method therefor and use thereof | |
| CN114195858A (en) | Polypeptide and its modified body and application in preparing anti-inflammatory and bactericidal medicine | |
| JPS61130236A (en) | Medicine containing fully synthetic alpha-peptide promoting exhaustion of sodium from human pericardium | |
| CN110437310B (en) | Fatty acid modified neuropeptide S analogue and synthesis and application thereof | |
| CN119285697A (en) | N-terminal 1-bit phosphorylation modified derivative of NPFF, and preparation method and application thereof | |
| CN117531021B (en) | Acanthopanax senticosus glycoside E-targeting peptide conjugate and application thereof | |
| CN109232747B (en) | Cyclized hybrid peptide of dynorphin A (1-8) coupled with neurotensin (8-13) and its synthesis method and application | |
| CN109721653A (en) | A kind of glucagon-like-peptide-1 fragment analogue and its application | |
| CN100546658C (en) | Polyoxyethylene ligand containing liver cancer targeting peptide and its synthesis method | |
| CN101385858B (en) | Purified PEG human growth hormone conjugates and preparation thereof | |
| CN101128482A (en) | Potent full and partial agonists and antagonists of the orphanin receptor |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |