CN114159461A - 青霉素修饰的ε-聚赖氨酸类抗菌肽及其制备方法 - Google Patents
青霉素修饰的ε-聚赖氨酸类抗菌肽及其制备方法 Download PDFInfo
- Publication number
- CN114159461A CN114159461A CN202111393635.9A CN202111393635A CN114159461A CN 114159461 A CN114159461 A CN 114159461A CN 202111393635 A CN202111393635 A CN 202111393635A CN 114159461 A CN114159461 A CN 114159461A
- Authority
- CN
- China
- Prior art keywords
- penicillin
- polylysine
- epsilon
- antibiotics
- modified
- 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.)
- Pending
Links
- 108010039918 Polylysine Proteins 0.000 title claims abstract description 70
- 239000003910 polypeptide antibiotic agent Substances 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title abstract description 13
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims abstract description 80
- 229940049954 penicillin Drugs 0.000 claims abstract description 76
- 229930182555 Penicillin Natural products 0.000 claims abstract description 75
- 239000003242 anti bacterial agent Substances 0.000 claims abstract description 29
- 229940088710 antibiotic agent Drugs 0.000 claims abstract description 28
- 230000000844 anti-bacterial effect Effects 0.000 claims abstract description 16
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- 230000003115 biocidal effect Effects 0.000 claims description 24
- 150000002148 esters Chemical class 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 239000007864 aqueous solution Substances 0.000 claims description 10
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- 239000012752 auxiliary agent Substances 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 5
- 239000000178 monomer Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 claims description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 3
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 3
- 229930195708 Penicillin V Natural products 0.000 claims description 3
- 229960003669 carbenicillin Drugs 0.000 claims description 3
- FPPNZSSZRUTDAP-UWFZAAFLSA-N carbenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)C(C(O)=O)C1=CC=CC=C1 FPPNZSSZRUTDAP-UWFZAAFLSA-N 0.000 claims description 3
- 239000003638 chemical reducing agent Substances 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 3
- 235000019371 penicillin G benzathine Nutrition 0.000 claims description 3
- 229940056360 penicillin g Drugs 0.000 claims description 3
- 229940056367 penicillin v Drugs 0.000 claims description 3
- BPLBGHOLXOTWMN-MBNYWOFBSA-N phenoxymethylpenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)COC1=CC=CC=C1 BPLBGHOLXOTWMN-MBNYWOFBSA-N 0.000 claims description 3
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 3
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 3
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 claims description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Substances CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 2
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 claims description 2
- BGNGWHSBYQYVRX-UHFFFAOYSA-N 4-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=C(C=O)C=C1 BGNGWHSBYQYVRX-UHFFFAOYSA-N 0.000 claims description 2
- RGUKYNXWOWSRET-UHFFFAOYSA-N 4-pyrrolidin-1-ylpyridine Chemical compound C1CCCN1C1=CC=NC=C1 RGUKYNXWOWSRET-UHFFFAOYSA-N 0.000 claims description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 17
- 239000003814 drug Substances 0.000 abstract description 17
- 239000002994 raw material Substances 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 4
- 125000003277 amino group Chemical group 0.000 abstract description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract description 3
- 230000008878 coupling Effects 0.000 abstract description 3
- 238000010168 coupling process Methods 0.000 abstract description 3
- 238000005859 coupling reaction Methods 0.000 abstract description 3
- 230000002195 synergetic effect Effects 0.000 abstract description 3
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 229960003324 clavulanic acid Drugs 0.000 abstract description 2
- HZZVJAQRINQKSD-PBFISZAISA-N clavulanic acid Chemical compound OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 abstract description 2
- 230000000857 drug effect Effects 0.000 abstract description 2
- 125000000524 functional group Chemical group 0.000 abstract description 2
- 229960000210 nalidixic acid Drugs 0.000 abstract description 2
- MHWLWQUZZRMNGJ-UHFFFAOYSA-N nalidixic acid Chemical compound C1=C(C)N=C2N(CC)C=C(C(O)=O)C(=O)C2=C1 MHWLWQUZZRMNGJ-UHFFFAOYSA-N 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 230000002209 hydrophobic effect Effects 0.000 abstract 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 229920000656 polylysine Polymers 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 230000035484 reaction time Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 230000002949 hemolytic effect Effects 0.000 description 5
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 5
- 239000000523 sample Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 206010018910 Haemolysis Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 210000000601 blood cell Anatomy 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000008588 hemolysis Effects 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 108700024478 penicilloyl polylysine Proteins 0.000 description 2
- 229920000729 poly(L-lysine) polymer Polymers 0.000 description 2
- 238000006116 polymerization reaction Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 231100000820 toxicity test Toxicity 0.000 description 2
- 241000222122 Candida albicans Species 0.000 description 1
- 206010013700 Drug hypersensitivity Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000006137 Luria-Bertani broth Substances 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 241000228143 Penicillium Species 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 239000000022 bacteriostatic agent Substances 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- IYNDLOXRXUOGIU-LQDWTQKMSA-M benzylpenicillin potassium Chemical group [K+].N([C@H]1[C@H]2SC([C@@H](N2C1=O)C([O-])=O)(C)C)C(=O)CC1=CC=CC=C1 IYNDLOXRXUOGIU-LQDWTQKMSA-M 0.000 description 1
- FCPVYOBCFFNJFS-LQDWTQKMSA-M benzylpenicillin sodium Chemical compound [Na+].N([C@H]1[C@H]2SC([C@@H](N2C1=O)C([O-])=O)(C)C)C(=O)CC1=CC=CC=C1 FCPVYOBCFFNJFS-LQDWTQKMSA-M 0.000 description 1
- 125000003460 beta-lactamyl group Chemical group 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 229940095731 candida albicans Drugs 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000005142 microbroth dilution method Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 201000005354 penicillin allergy Diseases 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010267 two-fold dilution method Methods 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/74—Synthetic polymeric materials
- A61K31/785—Polymers containing nitrogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- 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
- A61K47/54—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 compound
- A61K47/55—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 compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
- A61K47/552—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 compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds one of the codrug's components being an antibiotic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
青霉素修饰的ε‑聚赖氨酸类抗菌肽及其制备方法,通过ε‑聚赖氨酸上的氨基与青霉素类抗生素的羧基结合,分别制备连接不同数量小分子青霉素类抗生素的青霉素修饰的ε‑聚赖氨酸类抗菌肽,且ε‑聚赖氨酸经过部分偶合后仍具有较多侧链官能团,可通过结合不同的药物,如克拉维酸、萘啶酸等,实现协同用药效果,具有较广的适用范围;本发明通过ε‑聚赖氨酸良好的亲水性及生物相容性与疏水性青霉素类药物偶合,在提升疏水性药物溶解度的同时,结合两类物质的抑菌特性,在保有青霉素类抗生素对一般菌种较强抑菌效果的同时,协同发挥ε‑聚赖氨酸广谱抗菌效果,拓展药物有效抗菌范围;本发明合成路径简单,原料易得,制造成本低廉。
Description
技术领域
本发明属于生物医用高分子技术领域,具体涉及一种青霉素修饰的ε-聚赖氨酸类抗菌肽及其制备方法。
背景技术
青霉素类抗生素是一类化学结构中含有β-内酰胺环并五元噻唑环的抗生素,最早由英国生物化学家弗莱明于1928年发现。通过改变侧链基团的化学结构,青霉素类抗生素具有多种不同抗菌谱和抗菌效果,在临床治疗中被广泛使用。但由于早期对其认知的限制,错用、滥用该类抗生素,导致相应耐药菌不断被诱发积累,最终导致其药效逐渐下降。
而ε-聚赖氨酸最早由两位日本化学家Shoji Shima和Heiichi Sakai于20世纪70年代在研究一类链霉菌的分泌物中发现,并在21世纪初作为抑菌物质,被广泛应用于食品添加剂中。ε-聚赖氨酸是由一个赖氨酸残基上的羧基与另一个赖氨酸残基上的ε-氨基依次连接形成的线性多肽,具有良好的水溶性、生物相容性、广谱抗菌效果以及不易产生耐药性等特点,被广泛用于药物改性、抗体研究等生物医学领域中。但由于其自身抗菌效果有限,难以作为临床抗菌药物单独使用。而现有的ε-聚赖氨酸衍生药物合成相对复杂,大多作为药物载体、基因治疗的辅助剂或药物的联接片段使用,而鲜少发挥其自身的抗菌特性。
发明内容
基于上述研究背景,本发明针对现有技术的不足,首要目的是提供一种青霉素修饰的ε-聚赖氨酸类抗菌肽。
本发明的第二个目的在于提供一种青霉素修饰的ε-聚赖氨酸类抗菌肽的制备方法。
为达到上述目的,本发明的解决方案是:
一种青霉素修饰的ε-聚赖氨酸类抗菌肽,其结构式如下:
其中,x选自0-20中的整数,x代表ε-聚赖氨酸侧链偶合的青霉素类抗生素的个数,A表示青霉素类抗生素,R表示ε-聚赖氨酸单体。
优选地,青霉素类抗生素选自苄青霉素、苯氧甲基青霉素、羧苄青霉素以及其他不含游离氨基的青霉素类抗生素中的一种以上。
一种如上述的青霉素修饰的ε-聚赖氨酸类抗菌肽的制备方法,其包括如下步骤:
(1)青霉素类抗生素盐、缩水剂和助剂在水溶液或水与有机溶剂混合溶液内反应,得到青霉素类抗生素活化酯,其结构式为:
(2)将步骤(1)所述青霉素类抗生素活化酯加入有机溶剂溶解,加入预先溶解的ε-聚赖氨酸水溶液反应,经透析得到所述青霉素修饰的ε-聚赖氨酸类抗菌肽,其结构式为:
其中,x选自1-20中的整数,x代表ε-聚赖氨酸侧链偶合的青霉素类抗生素的个数,A表示青霉素类抗生素,R表示ε-聚赖氨酸单体。
优选地,步骤(1)中,水溶液的pH在3.0-10.0之间。
优选地,步骤(1)中,青霉素类抗生素盐选自苄青霉素、苯氧甲基青霉素、羧苄青霉素以及其他不含游离氨基的青霉素类抗生素的钾盐、钠盐、钙盐中的一种以上。
优选地,步骤(1)中,缩水剂选自N,N’-二异丙基碳二亚胺、N,N’-二环己基碳二亚胺、N,N'-二(2,6-二异丙基苯基)碳二亚胺、N,N'-二苯基碳二亚胺、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐中的一种以上。
优选地,步骤(1)中,助剂选自N-羟基邻苯二甲酰亚胺、N-羟基琥珀酰亚胺、1-羟基苯并三氮唑、N-羟基-7-氮杂苯并三氮唑、4-N,N-二甲基吡啶、4-吡咯烷基吡啶、N,N-二异丙基乙胺、N-甲基吗啉中的一种以上。
优选地,步骤(2)中,ε-聚赖氨酸的聚合度为10-40。
优选地,步骤(2)中,ε-聚赖氨酸水溶液pH在6.0-12.0之间。
优选地,步骤(1)(2)中,有机溶剂或混合溶剂中的有机溶剂选自四氢呋喃、N,N-二甲基甲酰胺、二氯甲烷、甲苯、丙酮和二甲基亚砜中的一种以上。
优选的,步骤(2)中,预先溶解的ε-聚赖氨酸与所述步骤(1)中制备的青霉素类抗生素活化酯投料摩尔比为1-20。
优选地,步骤(1)的反应的温度为0-30℃,反应的时间为0.5-6h。
优选地,步骤(2)的反应的温度为0-30℃,反应的时间为8-24h。
由于采用上述方案,本发明的有益效果是:
第一、本发明通过将青霉素类抗生素制备为活化酯,与ε-聚赖氨酸反应,制备了一系列侧链连接不同数目的小分子青霉素类抗生素的青霉素修饰的ε-聚赖氨酸类抗菌肽,且ε-聚赖氨酸经过部分偶合后仍具有较多侧链官能团,可通过结合多种的药物,如克拉维酸、萘啶酸等,实现协同用药效果。
第二、本发明的相对未成盐的青霉素类抗生素而言,水溶性提升,能较好的被输送进入人体;另外,利用ε-聚赖氨酸广谱抗菌性,结合青霉素类抗生素对于一般菌种较强的抗菌果,在保有青霉素类抗生素对革兰阳性细菌较强抑菌效果的同时,减少白色念珠菌等真菌以及铜绿假单胞菌等革兰阴性菌对于青霉素类抗生素使用效果的限制。同时,经过溶血毒性测试,可以得出,样品结合了青霉素盐以及ε-聚赖氨酸良好的生物相容性,溶血率在>4×MIC(4mg/mL)时,仍小于20%。
第三、本发明的青霉素修饰的ε-聚赖氨酸类抗菌肽的合成方法简单,制造成本低廉。
附图说明
图1为本发明的青霉素修饰的ε-聚赖氨酸类抗菌肽的制备过程示意图
图2为ε-聚赖氨酸-双青霉素核磁共振氢谱(“×”对应为溶剂等其他杂质)
图3为ε-聚赖氨酸-双青霉素及其原料抑菌效果测试(浓度c=2μg/mL)
图4为ε-聚赖氨酸-双青霉素及其原料溶血毒性结果图
图5为青霉噻唑酰多聚赖氨酸典型结构(PLL代表多聚赖氨酸)
图6.发明人参考文献1方法所制备的ε-聚赖氨酸-青霉素核磁共振氢谱。
参考文献1:CANEVA E.,DI G.P.,FARINA F.,ORLANDI M.,RINDONE B.,FALAGIANIP..Synthesis and Characterization of a Penicillin-Poly(L-Lysine)WhichRecognizes Human IgE Anti-Penicillin Antibodies[J].Bioconjugate Chem.,1993,4(5):309-313.
图7.实施例5中ε-聚赖氨酸-双青霉素核磁共振氢谱
图8实施例6中ε-聚赖氨酸-单青霉素核磁共振氢谱
图9.实施例7中ε-聚赖氨酸-四青霉素核磁共振氢谱
具体实施方式
本发明提供了一种青霉素修饰的ε-聚赖氨酸类抗菌肽及其制备方法。
以下结合实施例对本发明作进一步的说明。
实施例中原料中ε-聚赖氨酸购自于郑州拜纳佛生物工程股份有限公司,ε-聚赖氨酸的聚合度为25~35。
实施例1:
本实施例的ε-聚赖氨酸-双青霉素的制备方法包括如下步骤:
(1)将3.72g(0.01mol)青霉素钾、3.09g N,N’-二环己基碳二亚胺和3.46g N-羟基琥珀酰亚胺溶解在15ml pH=5盐酸稀溶液与四氢呋喃混合溶剂(pH=5盐酸稀溶液:四氢呋喃=2:1;v/v)中,在4℃下反应3h,得到青霉素活化酯单体,如下;
(2)向青霉素活化酯中加入5mL四氢呋喃溶解,加入预先溶解的含16.115gε-聚赖氨酸的去离子水溶液30mL混合反应12h,得到所述ε-聚赖氨酸-双青霉素。
通过1H-NMR对产品结构进行验证,可以得到ε-聚赖氨酸-双青霉素相应特征峰如图2所示:其中b-f与k-m的峰面积比(66:5)与投料比相符,进而,可以验证得出,已成功合成ε-聚赖氨酸-双青霉素。
实施例2:ε-聚赖氨酸-双青霉素最小抑菌浓度IC50值的测定
实验方法:
ε-聚赖氨酸-双青霉素来源:实施例1
采用微量肉汤稀释法测定,首先将适宜的LB肉汤(高压蒸汽灭菌)加入96孔板内,然后将将冻干得到的待测样品(2mg/mL)和对照药品(青霉素、ε-聚赖氨酸)的溶液(等质量浓度)分别加到96孔板各行第1孔内,采用二倍稀释法稀释,最后将等体积的菌液接种进入各孔板中,得到各测试组的最终药物浓度分别为500μg/mL,250μg/mL,125μg/mL,62.5μg/mL,31.25μg/mL,16μg/mL,8μg/mL。测试同时设置两个平行空白对照组(即无样品加入),37℃恒温培养12h,通过测试样液吸光度OD值的变化测试细菌的生长情况,读取样品的IC50值。本实验以OD值增量为空白对照组一半对应的浓度作为该药物的IC50值。
实验结果:
ε-聚赖氨酸-双青霉素与等质量浓度的青霉素、ε-聚赖氨酸相比,表现出了更为优异的抗菌活性,具有显著的抑菌效果(见图3,浓度为2μg/mL时,各实验组在630nm下,吸光度随时间的变化)。对应12h时,ε-聚赖氨酸-双青霉素、青霉素、ε-聚赖氨酸对于S.aureus的IC50分别为8、32、>64μg/mL。
实施例3:ε-聚赖氨酸-双青霉素溶血毒性的测定
实验方法:
ε-聚赖氨酸-双青霉素来源:实施例1
采用微量稀释法测定,首先用PBS缓冲液(pH=7.4)配置ε-聚赖氨酸-双青霉素和对照药品(青霉素)的溶液(2000μg/mL),采用二倍稀释法对半稀释,然后加入样液等量的血细胞PBS悬浊液,得到各测试组的最终药物浓度分别为1000μg/mL、500μg/mL,250μg/mL,125μg/mL,62.5μg/mL、并利用等量PBS缓冲液以及0.1%Triton X-100加入血细胞悬浊液分别设置空白与阳性对照组。反复摇晃培养一小时。培养结束后离心,测试各样液上清液的OD405值,并依次计算溶血百分数,计算公式如下:
实验结果:
溶血毒性测试结果如图4所示。在测试的浓度范围内(62.5-1000μg/mL),ε-聚赖氨酸-双青霉素呈现出与其原料青霉素以及ε-聚赖氨酸相似的良好血液相容性,在远高于对于各类细菌IC50浓度下,溶血率始终低于20%。
实施例4:近似结构产品:
与本发明最为近似的已有产品为青霉噻唑酰多聚赖氨酸,见图5。青霉噻唑酰多聚赖氨酸最早在20世纪70年代被美国FDA批准通过并被作为测试青霉素过敏性的皮试试剂使用。该产品与本发明不同,其活性成分主要为青霉素环断开的青霉素噻唑酰与多聚赖氨酸的α-位氨基进行结合,且多聚赖氨酸的结构一般为羧基与α、ε-氨基无规连接的聚赖氨酸。
在制备方法上,通过实验可证明,采用Ceneva等人(参考文献1)制备青霉素多聚赖氨酸合成方法难以制备的ε-聚赖氨酸偶合单青霉素,收率较低(<10%),且相应产品在核磁共振氢谱化学位移在7-7.5ppm以及5.25-5.5ppm处(见图6)难以找到分别对应青霉素苯环和青霉素环的特征峰,而仅存在聚赖氨酸的特征峰型。进而本发明采用先制备活化酯再与聚赖氨酸偶合的方法制备。
为了支持和准确地确定本发明技术方案保护范围,进一步给出如下三个实施例:
实施例5
ε-聚赖氨酸-四青霉素的制备方法包括如下步骤:
(1)将3.72g(0.01mol)青霉素钾、2.06g N,N’-二环己基碳二亚胺及3.05g 1-羟基苯并三氮唑在pH=6水溶液与N,N-二甲基甲酰胺混合溶液内反应,反应的温度为10℃,反应的时间为1.5h,得到青霉素类抗生素活化酯,其结构式同实施例1。
(2)将步骤(1)所述青霉素类抗生素活化酯加入N,N-二甲基甲酰胺溶解,加入预先溶解的ε-聚赖氨酸水溶液反应,预先溶解的ε-聚赖氨酸与所述步骤(1)中制备的青霉素类抗生素活化酯投料摩尔比为4:1,反应的温度为10℃,反应的时间为10h。经冷藏透析得到所述青霉素修饰的ε-聚赖氨酸类抗菌肽。
通过1H-NMR对产品结构进行验证,可以得到ε-聚赖氨酸-四青霉素相应特征峰如图7所示。其中b-f与k-m的峰面积比(37:5)与投料比近似相符,进而,可以验证得出,该路径能合成ε-聚赖氨酸-四青霉素。
实施例6
ε-聚赖氨酸-单青霉素的制备方法包括如下步骤:
(1)3.72g(0.01mol)青霉素钾、2.88g 1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐及3.46g羟基琥珀酰亚胺在去离子水中反应,反应的温度为4℃,反应的时间为2h,得到青霉素类抗生素活化酯,其结构式同实施例1。
(2)将步骤(1)所述青霉素类抗生素活化酯加入四氢呋喃溶解,加入预先溶解的ε-聚赖氨酸水溶液反应,预先溶解的ε-聚赖氨酸与所述步骤(1)中制备的青霉素类抗生素活化酯投料摩尔比为4:1,反应的温度为4℃,反应的时间为10h。经透析得到所述青霉素修饰的ε-聚赖氨酸类抗菌肽。
通过1H-NMR对产品结构进行验证,可以得到ε-聚赖氨酸-单青霉素相应特征峰如图8所示。其中b-f与k-m的峰面积比(115:5)与投料比近似相符,进而,可以验证得出,该路径能合成ε-聚赖氨酸-单青霉素。
实施例7
ε-聚赖氨酸-双青霉素的制备方法包括如下步骤:
(1)将3.56g(0.01mol)青霉素钠、6.31g N,N’-二异丙基碳二亚胺及5.75g羟基琥珀酰亚胺在PBS缓冲溶液(pH=7.4)中反应,反应的温度为20℃,反应的时间为4h,得到青霉素类抗生素活化酯,其结构式同实施例1。
(2)将步骤(1)所述青霉素类抗生素活化酯加入四氢呋喃溶解,加入预先溶解的ε-聚赖氨酸水溶液反应,预先溶解的ε-聚赖氨酸与所述步骤(1)中制备的青霉素类抗生素活化酯投料摩尔比为2:1,反应的温度为20℃,反应的时间为8h。经透析得到所述青霉素修饰的ε-聚赖氨酸类抗菌肽。
通过1H-NMR对产品结构进行验证,可以得到ε-聚赖氨酸-双青霉素相应特征峰如图9所示。其中b-f与k-m的峰面积比(63:5)与投料比近似相符,进而,可以验证得出,该路径能合成ε-聚赖氨酸-双青霉素。
综合实施例1、5、6、7,本发明青霉素类抗生素盐:缩水剂:助剂摩尔投料比范围=1:(1~5):(1~5)。
上述对实施例的描述是为了便于该技术领域的普通技术人员能理解和使用本发明。熟悉本领域技术人员显然可以容易的对这些实施例做出各种修改,并把在此说明的一般原理应用到其他实施例中,而不必经过创造性的劳动。因此,本发明不限于上述实施例。本领域技术人员根据本发明的原理,不脱离本发明的范畴所做出的改进和修改都应该在本发明的保护范围之内。
Claims (6)
2.根据权利要求1所述的青霉素修饰的ε-聚赖氨酸类抗菌肽,其特征在于:所述青霉素类抗生素选自苄青霉素、苯氧甲基青霉素、羧苄青霉素、以及其他不含游离氨基的青霉素类抗生素的一种以上。
4.根据权利要求3所述的制备方法,其特征在于:步骤(1)中所述缩水剂选自N,N’-二异丙基碳二亚胺、N,N’-二环己基碳二亚胺、N,N'-二(2,6-二异丙基苯基)碳二亚胺、N,N'-二苯基碳二亚胺、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐中的一种以上。
5.根据权利要求3所述的制备方法,其特征在于:步骤(1)中所述助剂选自N-羟基邻苯二甲酰亚胺、N-羟基琥珀酰亚胺、1-羟基苯并三氮唑、N-羟基-7-氮杂苯并三氮唑、4-N,N-二甲基吡啶、4-吡咯烷基吡啶、N,N-二异丙基乙胺、N-甲基吗啉中的一种以上。
6.根据权利要求3所述的制备方法,其特征在于:步骤(2)中,所述预先溶解的ε-聚赖氨酸与所述步骤(1)中制备的青霉素类抗生素活化酯投料摩尔比为1-20。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111393635.9A CN114159461A (zh) | 2021-11-23 | 2021-11-23 | 青霉素修饰的ε-聚赖氨酸类抗菌肽及其制备方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111393635.9A CN114159461A (zh) | 2021-11-23 | 2021-11-23 | 青霉素修饰的ε-聚赖氨酸类抗菌肽及其制备方法 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN114159461A true CN114159461A (zh) | 2022-03-11 |
Family
ID=80480412
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202111393635.9A Pending CN114159461A (zh) | 2021-11-23 | 2021-11-23 | 青霉素修饰的ε-聚赖氨酸类抗菌肽及其制备方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN114159461A (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115894942A (zh) * | 2022-11-07 | 2023-04-04 | 同济大学 | 聚己内酯修饰的超支化梳型聚赖氨酸及应用 |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4183910A (en) * | 1978-04-20 | 1980-01-15 | Levine Bernard B | Method for testing to predict and/or diagnose allergy to penicillins, and compounds and compositions for use in such tests |
CN102370994A (zh) * | 2010-08-09 | 2012-03-14 | 朱大勋 | 青霉素类药物皮试试剂及其制备方法 |
US20120122788A1 (en) * | 2009-07-20 | 2012-05-17 | Merck Patent Gesellschaft Mit Beschrankter Haftung | E-polylysine conjugates and the use thereof |
CN110041523A (zh) * | 2019-04-15 | 2019-07-23 | 同济大学 | 低代树枝状聚赖氨酸类抗菌肽及其制备方法 |
CN110054713A (zh) * | 2019-04-19 | 2019-07-26 | 同济大学 | 含抗菌肽的两亲性接枝共聚物及其制备方法和应用 |
CN110330656A (zh) * | 2019-07-08 | 2019-10-15 | 同济大学 | 含抗菌肽的两亲性接枝共聚物及其制备方法和应用 |
CN111518172A (zh) * | 2020-04-21 | 2020-08-11 | 同济大学 | 高代树枝状聚赖氨酸类抗菌肽及其制备方法 |
-
2021
- 2021-11-23 CN CN202111393635.9A patent/CN114159461A/zh active Pending
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4183910A (en) * | 1978-04-20 | 1980-01-15 | Levine Bernard B | Method for testing to predict and/or diagnose allergy to penicillins, and compounds and compositions for use in such tests |
US20120122788A1 (en) * | 2009-07-20 | 2012-05-17 | Merck Patent Gesellschaft Mit Beschrankter Haftung | E-polylysine conjugates and the use thereof |
CN102470181A (zh) * | 2009-07-20 | 2012-05-23 | 默克专利有限公司 | ε-聚赖氨酸缀合物及其用途 |
CN102370994A (zh) * | 2010-08-09 | 2012-03-14 | 朱大勋 | 青霉素类药物皮试试剂及其制备方法 |
CN110041523A (zh) * | 2019-04-15 | 2019-07-23 | 同济大学 | 低代树枝状聚赖氨酸类抗菌肽及其制备方法 |
CN110054713A (zh) * | 2019-04-19 | 2019-07-26 | 同济大学 | 含抗菌肽的两亲性接枝共聚物及其制备方法和应用 |
CN110330656A (zh) * | 2019-07-08 | 2019-10-15 | 同济大学 | 含抗菌肽的两亲性接枝共聚物及其制备方法和应用 |
CN111518172A (zh) * | 2020-04-21 | 2020-08-11 | 同济大学 | 高代树枝状聚赖氨酸类抗菌肽及其制备方法 |
Non-Patent Citations (3)
Title |
---|
ERIC MACY ET AL.: "Penicilloyl-Polylysine Stability and Clinical Use Over Time", vol. 11, no. 4, pages 10 - 11 * |
曾戎: "《多糖基高分子-药物轭合物的设计、合成、表征和评价》", 华南理工大学出版社, pages: 69 - 75 * |
黄国昌等: "ε-聚赖氨酸研究进展", vol. 24, no. 6, pages 538 - 544 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115894942A (zh) * | 2022-11-07 | 2023-04-04 | 同济大学 | 聚己内酯修饰的超支化梳型聚赖氨酸及应用 |
CN115894942B (zh) * | 2022-11-07 | 2024-01-12 | 同济大学 | 聚己内酯修饰的超支化梳型聚赖氨酸及应用 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Chakraborty et al. | Nanoconjugated vancomycin: new opportunities for the development of anti-VRSA agents | |
Sahariah et al. | Antimicrobial peptide shows enhanced activity and reduced toxicity upon grafting to chitosan polymers | |
Tajdini et al. | Production, physiochemical and antimicrobial properties of fungal chitosan from Rhizomucor miehei and Mucor racemosus | |
DE69532760T2 (de) | Mittel zur verabreichung von antigenen | |
WO2013112548A1 (en) | Gamma-aapeptides with potent and broad-spectrum antimicrobial activity | |
CN104520309A (zh) | 抗真菌抗生素两性霉素b的n-取代第二代衍生物及其制备方法和应用 | |
CN114159461A (zh) | 青霉素修饰的ε-聚赖氨酸类抗菌肽及其制备方法 | |
CN110041523B (zh) | 低代树枝状聚赖氨酸类抗菌肽及其制备方法 | |
CN114478834B (zh) | 一种胍基透明质酸抗菌聚合物及其制备方法和应用 | |
CN111518172B (zh) | 高代树枝状聚赖氨酸类抗菌肽及其制备方法 | |
Agresti et al. | Specific interactions between diphenhydramine and α-helical poly (glutamic acid)–A new ion-pairing complex for taste masking and pH-controlled diphenhydramine release | |
US20230022581A1 (en) | Sulfhydryl modified hyaluronic acid, preparation method therefor and use thereof | |
US8470958B1 (en) | Antibiotic-bound poly(caprolactone) polymer | |
CN109517162B (zh) | 可注射水凝胶及制备方法 | |
KR102358980B1 (ko) | 폴리에틸렌피페라진 유도체와의 히알루로니다제 컨쥬게이트를 생성시키기 위한 방법 및 생성된 컨쥬게이트의 용도 | |
Ma et al. | Preparation of imidazole acids grafted chitosan with enhanced antioxidant, antibacterial and antitumor activities | |
CN105924456A (zh) | 一种减少不良反应的头孢米诺钠化合物及其制剂 | |
CN110776560A (zh) | 一种黑鲷抗菌肽AS-hepc3(48-56)及其应用 | |
US8410046B2 (en) | Antibiotic peptide derived from ribosomal protein L1 of Helicobacter pylori and use thereof | |
Jang et al. | The preparation and characterization of low molecular and water soluble free-amine chitosan | |
CN105601550B (zh) | 具有活性基团的刺激敏感多功能多异氰酸酯 | |
Janiszewska et al. | Amphiphilic dendrimeric peptides as model non-sequential pharmacophores with antimicrobial properties | |
KR101512759B1 (ko) | 이온성 작용기가 곁사슬 또는 말단에 도입된 온도감응성 폴리에틸렌글리콜/폴리에스터 블록 공중합체 및 이의 제조방법 | |
CN107189054B (zh) | 一种含有缩醛键的聚乙二醇、衍生物及其合成方法 | |
CN102718779B (zh) | 注射用头孢唑肟钠及其制备方法、原料药头孢唑肟钠的合成方法 |
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 | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20220311 |