WO2006122127A1 - Compositions for administering rnaiii-inhibiting peptides - Google Patents
Compositions for administering rnaiii-inhibiting peptides Download PDFInfo
- Publication number
- WO2006122127A1 WO2006122127A1 PCT/US2006/017935 US2006017935W WO2006122127A1 WO 2006122127 A1 WO2006122127 A1 WO 2006122127A1 US 2006017935 W US2006017935 W US 2006017935W WO 2006122127 A1 WO2006122127 A1 WO 2006122127A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- rip
- pharmaceutical composition
- nanoparticle
- nanoparticles
- sequence
- Prior art date
Links
Classifications
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
- A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
- A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
-
- 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
Definitions
- the method further may be practiced on an individual at risk of having or suspected of having an infection caused by a bacteria, such as an individual who is suffering from burns, trauma, etc.
- the composition may be administered to treat an ongoing infection, delay the onset of symptoms of bacterial infection, or reduce the risk of developing an infection.
- the individual receiving the composition is infected or at risk of infection by bacteria in which RNAIII or TRAP plays a role in pathogenesis.
- the infection or risk thereof is due to Gram-positive bacteria, such as Streptococcus spp, including S. aureus and S. epidermidis, or an antibiotic resistant strain thereof.
- the pathogen may be Listeria spp, including L. innocua, and L. monoctogenes, Lactococcus spp, Enterococcus spp, Escherichia coli, Clostridium acetobtylicum, and Bacillus spp., including B. subtilus, B. anthracis, and B. cereus, or an antibiotic resistant strain thereof.
- FIGURE IA depicts the regulation of bacterial virulence via TRAP and agr.
- FIGURE 1 C depicts the antagonistic effect of RAP, which increases TRAP phosphorylation.
- FIGURE 2 depicts typical results of a representative in vitro ⁇ -lactamase assay for testing activity of RIP compositions of the invention.
- FIGURE 4 depicts a rat graft model system, which is representative of animal models useful for testing RIP compositions of the present invention.
- RIP sequences also include polypeptides comprising YSPXiTNF, where X 1 is C or W, and YKPITN.
- the RIP comprising the general formula YX 2 PXiTNF above is further modified by one or two amino acid substitutions, deletions, and other modifications, provided the RIP exhibits activity.
- Proteins, polypeptides and peptides of the invention can be purified or isolated.
- Sprays or foams provide convenient compositions for delivering RIP to the skin or otherwise poorly accessible mucosal surfaces.
- nasal sprays are useful for delivering RIP to nasal mucosal surfaces.
- Foams are particularly useful for delivering RIP to gums, e.g. in dental applications.
- Depositories or other implanted devices are particularly useful for sustained delivery of RIP to otherwise inaccessible mucosal surfaces, especially those such as the colon, which provide rapid absorption of delivered drugs into the blood.
- Mucosal surfaces useful for topical application of RIP compositions include mucous membranes of the conjunctiva, nasopharynx, oropharynx, vagina, colon, urethra, or urinary bladder, which are preferred when rapid adsorption is desired.
- peptide and protein drugs after oral administration generally is very low because of peptide instability in the gastrointestinal (GI) tract and low permeability of peptides through the intestinal mucosa; therefore, peptide drugs are usually injected to obtain therapeutic effects.
- Preferred nanoparticles comprise biodegradable and biocompatible polymers.
- Useful nanoparticles include biodegradable poly(alkylcyanoacrylate) nanoparticles made by the procedure set forth in Vauthier et at, Adv. Drug Del. Rev. 55: 519-48 (2003), herein incorporated by reference. Oral adsorption also may be enhanced using poly(-lactide-glycolide) nanoparticles coated with chitosan, which is a mucoadhesive cationic polymer. The manufacture of such nanoparticles is described, for example, in Takeuchi et al, Adv. Drug Del. Rev. 47: 39-54 (2001), also incorporated herein by reference.
- Nanoparticles are suitable for controlled release of RIP compositions administered through intratracheal (IT) and intravenous routes, as well. Nasal delivery of RIP compositions may be facilitated by use of the positively charged nanoparticles described in Somavarapu et al, J. Pharm. Pharmacol. 54 (Supp.): 131 (2002). Further, Poyner et al, J. Control. ReI. 35: 41-48 (1995) demonstrated the usefulness of nanoparticles for both IT and intravenous delivery in a comparison of liposomes and poly(lactic acid) (PLA) nanoparticles as delivery vehicles for tobramycin to treat a Pseudomonas aeruginosa infection in an animal model.
- PPA poly(lactic acid)
- Liposomal encapsulation was more efficient than nanosphere loading (85% vs. 30% respectively). Both carriers were of the same size and charge, with liposomes slightly more negatively charged. A faster release profile was observed for the lipid carrier, although the nanoparticles advantageously showed burst-release kinetics.
- liposomal tobramycin was more efficiently retained in the lung compared to free or nanoparticle encapsulated tobramycin. Both nanospheres and liposomes, however, maintained a major proportion of the drug in the lung following IT dosing. It is thus expected that both nanoparticle and liposomal carriers will be useful delivery systems for RIP compositions and that each may offer advantages for particular applications.
- Nanoparticles typically comprise either a polymeric matrix ("nanospheres") or a reservoir system comprising an oily core surrounded by a thin polymeric wall (“nanocapsules”), where the core comprises the RIP composition.
- Polymers suitable for the preparation of nanoparticles include poly(alkylcyanoacrylates), and polyesters such as poly(lactic acid) (PLA), poly(glycolic acid), poly(-caprolactone) and their copolymers.
- Nanoparticles may be fabricated using biodegradable polyesters, e.g., polymers of poly(lactic acid) (PLA) and copolymers that are manufactured with varying quantities of glycolic acid (PLGA).
- PLA poly(lactic acid)
- PLGA poly(lactic acid)
- PLGA copolymers that are manufactured with varying quantities of glycolic acid
- PLA is more hydrophobic in comparison to PLGA; therefore, PLA offers a relatively extended release profile.
- the ratio of glycolic acid to lactic acid in the copolymerization process effects the degradative properties of the resultant copolymer.
- low molecular weight (14 kDa) PLGA is copolymerized with a high (50%) glycolide content (PLGA 50:50).
- hydrophobic nanoparticles may be modified to minimize phagocytosis, allowing sustained systemic circulation of nanoparticles.
- hydrophobic nanoparticles are rapidly cleared from systemic circulation by the mononuclear phagocytic system (MPS), resulting in rapid deposition of nanoparticles in the liver or spleen.
- MPS mononuclear phagocytic system
- various modifications of the nanoparticle surface are possible to minimize phagocytosis, including modification with poly(ethylene glycol) (PEG).
- PEG poly(ethylene glycol)
- TRAP and TRAP phosphorylation in £ epidermidis, indicating that there is a similar quorum sensing mechanisms both in S. aureus and in S. epidermidis and the potential for RlP to interfere with biofilm formation and infections caused by both species.
- TRAP is conserved among all staphylococcal strains and species; therefore, RIP should be effective against any type of Staphylococcus.
- Lactococcus spp Enterococcus spp, Escherichia coli, Clostridium acetobtylicum, and Bacillus spp. This finding indicates that treatment aimed at disturbing the function of RAP in S. aureus also will be effective in treating L2-synthesizing bacteria as well.
- Candidate peptides also can be assayed for activity in vivo, for example by screening for an effect on Staphylococcus virulence factor production in a non-human animal model.
- the candidate peptide is administered to an animal that has been infected with Staphylococcus or that has received an infectious dose of Staphylococcus in conjunction with the candidate peptide.
- the candidate peptide can be administered in any manner appropriate for a desired result.
- the candidate peptide can be administered by injection intravenously, intramuscularly, subcutaneously, or directly into the tissue in which the desired affect is to be achieved, or the candidate can be delivered topically, orally, etc.
- the peptide can be used to coat a device that will then be implanted into the animal.
- the effect of the peptide can be monitored by any suitable method, such as assessing the number and size of Staphylococcus-associated lesions, microbiological evidence of infection, overall health, etc.
- Viable bacteria are quantified by culturing serial dilutions (0.1 mL) of the bacterial suspension on blood agar plates. All plates are incubated at 37 0 C for 48 hours and evaluated for number of CFUs per plate. The limit of detection for this method is approximately 10 CFU/mL.
- the quantities of active ingredients necessary for effective therapy will depend on many different factors, including means of administration, target site, physiological state of the patient, and other medicaments administered; therefore, treatment dosages should be titrated to optimize safety and efficacy.
- dosages used in vitro may provide useful guidance in the amounts useful for in vivo administration of the active ingredients.
- Animal testing of effective doses for treatment of particular disorders will provide further predictive indication of human dosage.
- concentration of the active ingredients in the pharmaceutical formulations typically vary from less than about 0.1%, usually at or at least about 2% to as much as 20% to 50% or more by weight, and will be selected primarily by fluid volumes, viscosities, etc., in accordance with the particular mode of administration selected.
- Nanoparticle compositions comprising REP
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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Physics & Mathematics (AREA)
- Biomedical Technology (AREA)
- Nanotechnology (AREA)
- Optics & Photonics (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2008511277A JP2008540544A (en) | 2005-05-10 | 2006-05-09 | Composition for administering an RNAIII inhibitory peptide |
AU2006244135A AU2006244135A1 (en) | 2005-05-10 | 2006-05-09 | Compositions for administering RNAIII-inhibiting peptides |
CA002605551A CA2605551A1 (en) | 2005-05-10 | 2006-05-09 | Compositions for administering rnaiii-inhibiting peptides |
EP06752455A EP1906985A4 (en) | 2005-05-10 | 2006-05-09 | Compositions for administering rnaiii-inhibiting peptides |
IL186911A IL186911A0 (en) | 2005-05-10 | 2007-10-25 | Compositions for administering rnaiii inhibiting peptides |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US67951605P | 2005-05-10 | 2005-05-10 | |
US60/679,516 | 2005-05-10 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2006122127A1 true WO2006122127A1 (en) | 2006-11-16 |
Family
ID=37396888
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2006/017935 WO2006122127A1 (en) | 2005-05-10 | 2006-05-09 | Compositions for administering rnaiii-inhibiting peptides |
Country Status (9)
Country | Link |
---|---|
US (1) | US20070092575A1 (en) |
EP (1) | EP1906985A4 (en) |
JP (1) | JP2008540544A (en) |
CN (1) | CN101189020A (en) |
AU (1) | AU2006244135A1 (en) |
CA (1) | CA2605551A1 (en) |
IL (1) | IL186911A0 (en) |
WO (1) | WO2006122127A1 (en) |
ZA (1) | ZA200709239B (en) |
Cited By (5)
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US7323179B2 (en) * | 1997-12-19 | 2008-01-29 | Naomi Balaban | Methods and compositions for the treatment and prevention of Staphylococcus and other bacterial infections |
EP2044934A1 (en) * | 2007-10-01 | 2009-04-08 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Dispersion of poloxamer-protein particles, methods of manufacturing and uses thereof |
US7534857B2 (en) * | 1997-12-19 | 2009-05-19 | Centegen, Inc. | Methods and compositions for the treatment and prevention of staphylococcal infections |
US7824691B2 (en) * | 2005-04-04 | 2010-11-02 | Centegen, Inc. | Use of RIP in treating staphylococcus aureus infections |
WO2017190619A1 (en) * | 2016-05-03 | 2017-11-09 | 重程投资管理(上海)有限公司 | Chemosynthetic cyclo-heptamodified peptide capable of inhibiting toxin of staphylococcus aureus and use thereof |
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US20080219976A1 (en) * | 1997-12-19 | 2008-09-11 | Naomi Balaban | Methods and compositions for treatment and prevention of staphylococcal infections |
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WO2012082765A2 (en) | 2010-12-16 | 2012-06-21 | The United State Of America. As Represented By The Secretary Department Of Health And Human Services | Methods for decreasing body weight and treating diabetes |
JP6204345B2 (en) | 2011-03-23 | 2017-09-27 | ザ・ユナイテッド・ステイツ・オブ・アメリカ・アズ・リプリゼンティド・バイ・ザ・セクレタリー・フォー・ザ・デパートメント・オブ・ヘルス・アンド・ヒューマン・サービシズ | Compositions and methods for enhancing stem cell pluripotency |
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JP6189829B2 (en) | 2011-05-13 | 2017-08-30 | ザ・ユナイテッド・ステイツ・オブ・アメリカ・アズ・リプリゼンティド・バイ・ザ・セクレタリー・フォー・ザ・デパートメント・オブ・ヘルス・アンド・ヒューマン・サービシズ | Direct reprogramming of somatic cells using ZSCAN4 and ZSCAN4-dependent genes |
CN102286072B (en) * | 2011-06-27 | 2013-12-18 | 中国人民解放军第四军医大学 | Staphylococcus aureus AgrC group induction system resistant auto-induced peptide (AIP) polypeptide derivatives and use thereof |
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AU2015226911B2 (en) | 2014-03-07 | 2018-03-01 | The Arizona Board Of Regents On Behalf Of The University Of Arizona | Non-narcotic CRMP2 peptides targeting sodium channels for chronic pain |
WO2016121829A1 (en) * | 2015-01-27 | 2016-08-04 | 昇一 城武 | Agent for treatment or prevention of dermatitis in which nanoparticles are used as active ingredient |
WO2018160772A1 (en) | 2017-02-28 | 2018-09-07 | The United State Of America, As Represented By The Secretary, Department Of Health & Human Services | Method of treating obesity, insulin resistance, non-alcoholic fatty liver disease including non-alcoholic steatohepatitis |
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Citations (1)
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US6291431B1 (en) * | 1997-12-19 | 2001-09-18 | Panorama Research | Methods and compositions for the treatment and prevention of Staphylococcal infections |
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FR2608942B1 (en) * | 1986-12-31 | 1991-01-11 | Centre Nat Rech Scient | PROCESS FOR THE PREPARATION OF COLLOIDAL DISPERSIBLE SYSTEMS OF A SUBSTANCE, IN THE FORM OF NANOCAPSULES |
US6447786B1 (en) * | 1994-10-04 | 2002-09-10 | New York University | Blocking expression of virulence factors in S. aureus |
US7323179B2 (en) * | 1997-12-19 | 2008-01-29 | Naomi Balaban | Methods and compositions for the treatment and prevention of Staphylococcus and other bacterial infections |
US6747129B1 (en) * | 1998-09-15 | 2004-06-08 | The Regents Of The University Of California | Target of RNAIII activating protein(TRAP) |
DE19852928C1 (en) * | 1998-11-17 | 2000-08-03 | Steffen Panzner | Structures in the form of hollow spheres |
EP2316490A3 (en) * | 2000-10-31 | 2012-02-01 | PR Pharmaceuticals, Inc. | Methods and compositions for enhanced delivery of bioactive molecules |
US20040052798A1 (en) * | 2002-09-12 | 2004-03-18 | Ceramoptec Industries, Inc. | Microbe reduction in the oral cavity with photosensitizers |
US20070015685A1 (en) * | 2005-04-04 | 2007-01-18 | Naomi Balaban | Bone cement compositions and the like comprising an RNAIII-inhibiting peptide |
-
2006
- 2006-05-09 AU AU2006244135A patent/AU2006244135A1/en not_active Abandoned
- 2006-05-09 JP JP2008511277A patent/JP2008540544A/en active Pending
- 2006-05-09 CA CA002605551A patent/CA2605551A1/en not_active Abandoned
- 2006-05-09 CN CNA2006800159859A patent/CN101189020A/en active Pending
- 2006-05-09 US US11/430,091 patent/US20070092575A1/en not_active Abandoned
- 2006-05-09 ZA ZA200709239A patent/ZA200709239B/en unknown
- 2006-05-09 EP EP06752455A patent/EP1906985A4/en not_active Withdrawn
- 2006-05-09 WO PCT/US2006/017935 patent/WO2006122127A1/en active Application Filing
-
2007
- 2007-10-25 IL IL186911A patent/IL186911A0/en unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6291431B1 (en) * | 1997-12-19 | 2001-09-18 | Panorama Research | Methods and compositions for the treatment and prevention of Staphylococcal infections |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7323179B2 (en) * | 1997-12-19 | 2008-01-29 | Naomi Balaban | Methods and compositions for the treatment and prevention of Staphylococcus and other bacterial infections |
US7534857B2 (en) * | 1997-12-19 | 2009-05-19 | Centegen, Inc. | Methods and compositions for the treatment and prevention of staphylococcal infections |
US7824691B2 (en) * | 2005-04-04 | 2010-11-02 | Centegen, Inc. | Use of RIP in treating staphylococcus aureus infections |
EP2044934A1 (en) * | 2007-10-01 | 2009-04-08 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Dispersion of poloxamer-protein particles, methods of manufacturing and uses thereof |
WO2009043874A1 (en) * | 2007-10-01 | 2009-04-09 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Dispersion of poloxamer- protein particles, methods of manufacturing and uses thereof |
US10123976B2 (en) | 2007-10-01 | 2018-11-13 | Institut National De La Sante Etde La Recherche Medicale (Inserm) | Dispersion of poloxamer-protein particles, methods of manufacturing and uses thereof |
WO2017190619A1 (en) * | 2016-05-03 | 2017-11-09 | 重程投资管理(上海)有限公司 | Chemosynthetic cyclo-heptamodified peptide capable of inhibiting toxin of staphylococcus aureus and use thereof |
US10905735B2 (en) | 2016-05-03 | 2021-02-02 | Zhongcheng Investment Management (Shanghai) Co., Ltd | Chemosynthetic cyclo-hepta modified peptide capable of inhibiting toxin of Staphylococcus aureus and use thereof |
Also Published As
Publication number | Publication date |
---|---|
AU2006244135A1 (en) | 2006-11-16 |
CA2605551A1 (en) | 2006-11-16 |
EP1906985A1 (en) | 2008-04-09 |
US20070092575A1 (en) | 2007-04-26 |
EP1906985A4 (en) | 2012-07-11 |
IL186911A0 (en) | 2008-02-09 |
ZA200709239B (en) | 2009-04-29 |
JP2008540544A (en) | 2008-11-20 |
CN101189020A (en) | 2008-05-28 |
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