+

WO2009006579A1 - Conjugués peptide-polymère - Google Patents

Conjugués peptide-polymère Download PDF

Info

Publication number
WO2009006579A1
WO2009006579A1 PCT/US2008/069169 US2008069169W WO2009006579A1 WO 2009006579 A1 WO2009006579 A1 WO 2009006579A1 US 2008069169 W US2008069169 W US 2008069169W WO 2009006579 A1 WO2009006579 A1 WO 2009006579A1
Authority
WO
WIPO (PCT)
Prior art keywords
conjugate
moiety
peptide
interferon
polymer
Prior art date
Application number
PCT/US2008/069169
Other languages
English (en)
Inventor
Ko-Chung Lin
Laurence I. Wu
Original Assignee
Pharmaessentia Corp.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Pharmaessentia Corp. filed Critical Pharmaessentia Corp.
Publication of WO2009006579A1 publication Critical patent/WO2009006579A1/fr

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
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A61K38/212—IFN-alpha
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61P31/12—Antivirals
    • 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
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • 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
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses

Definitions

  • PEG polyethylene glycol
  • This invention is based on the unexpected finding that a peptide moiety can be coupled to a polymer via an unsaturated linker to form a peptide-polymer conjugate for use as a protein drug.
  • the present invention features a polymer-peptide conjugate of the following formula: in which A is a polymer moiety; each of Gi and G 2 , independently, is a bond or a linking functional group; L is an alkenylene or alkynylene moiety; and B is a peptide moiety.
  • the polymer-peptide conjugate may have one or more of the following features: A is a polyalkylene oxide moiety having a molecular weight of 2-100 kD (preferably 12-30 kD), each of Gi and G 2 is a bond, B is an interferon moiety or a modified interferon moiety containing 1-4 additional amino acid residues, and L is C 6 alkenylene.
  • polyalkylene oxide moiety refers to a mono-valent radical derived from linear, branched, or star-shaped polyalkylene oxide.
  • the molecular weight of a polyalkylene oxide moiety may be 2-100 kD.
  • the polyalkylene oxide moiety is either saturated or unsaturated.
  • Examples of a polyalkylene oxide moiety include, but are not limited to, polyethylene oxide, polyethylene glycol, polyisopropylene oxide, polybutenylene oxide, and copolymers thereof.
  • Other polymers such as dextran, polyvinyl alcohols, polyacrylamides, or carbohydrate-based polymers can also be used to replace the polyalkylene oxide moiety, as long as they are not antigenic, toxic, or eliciting immune response.
  • the polyalkylene oxide moiety is either substituted or unsubstituted.
  • it can be methoxy-capped polyethylene glycol (mPEG).
  • peptide moiety refers to a mono-valent radical derived from either a naturally occurring peptide or a modified peptide.
  • the naturally occurring peptide can be interferon- ⁇ ,2b interferon- ⁇ , growth hormone, or antibody.
  • the modified peptide can be, e.g., a peptide containing interferon and 1-4 additional amino acid residues at the N-terminus of the interferon- ⁇ ,2b.
  • interferon is IFN representing an interferon- ⁇ ,2b moiety, the N-terminus of which is bonded to the carbonyl group.
  • linking functional group refers to a bi-valent functional group, one end being connected to the polymer moiety and the other end being connected to the peptide moiety. Examples include, but are not limited to, -O-, -S-, carboxylic ester, carbonyl, carbonate, amide, carbamate, urea, sulfonyl, sulf ⁇ nyl, amino, imino, hydroxyamino, phosphonate, or phosphate group.
  • alkenylene refers to a bi-valent straight or branched hydrocarbon containing 2-10 carbon atoms and one or more double bonds. Examples of alkenylene, but are not limited to, include ethenylenyl, propenylene, and 2-butylene.
  • alkynylene refers to a bivalent straight or branched hydrocarbon containing 2-10 carbon atoms and one or more triple bonds. Examples of alkynylene include, but are not limited to, ethynylene, 1-propynylene, and 2-butynylene.
  • Alkenylene and alkynylene mentioned herein include both substituted and unsubstituted moieties.
  • substituents include C 1 -C 10 alkyl, C 2 -C 1 0 alkenyl, C 2 -CiO alkynyl, C 3 -Cs cycloalkyl, C 5 -Cs cycloalkenyl, C 1 -C 10 alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C 1 -C 10 alkylamino, Ci-C 2O dialkylamino, arylamino, diarylamino, hydroxyamino, alkoxyamino, C 1 -C 10 alkylsulfonamide, arylsulfonamide, hydroxy, halogen, thio, C 1 -C 10 alkylthio, arylthio, cyano, nitro, acyl, acyloxy, carboxyl, and carboxylic ester.
  • the peptide -polymer conjugate described above can be in the free form or in the form of salt, if applicable.
  • a salt for example, can be formed between an anion and a positively charged group (e.g., amino) on a peptide-polymer conjugate of this invention. Suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, and acetate.
  • a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on the polypeptide-polymer conjugate of this invention.
  • Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion.
  • the peptide-polymer conjugate may have one or more double bonds, or one or more asymmetric centers. Such a conjugate can occur as racemates, racemic mixtures, single enantiomers, individual diastereomers, diastereomeric mixtures, and cis- or trans- or E- or Z- double bond isomeric forms.
  • this invention features a method of preparing a peptide- polymer conjugate.
  • the method includes coupling A-Gi-L'-CHO with H 2 N-B', and reducing the coupling product to form a peptide-polymer conjugate of A-Gi-L'- CH 2 NHB'; in which A is a polymer moiety, Gi is a bond or a linking functional group, L' is an alkenylene or alkynylene, and H 2 N-B' is a N-terminus free peptide, e.g., interferon or a modified interferon.
  • Interferon is an immunomodulating medication for treating HCV or HBV infection. See, e.g., Journal of Vascular and Interventional Radiology 13 (2002): 191-196.
  • this invention features a method of treating hepatitis C virus (HCV) infection or hepatitis B virus (HBV) infection by an interferon-polymer conjugate of the following formula: wherein A is a polymer moiety; each of Gi and G 2 , independently, is a bond or a linking functional group; L is an alkenylene or alkynylene moiety; and B is a N- terminal free peptide interferon or modified interferon containing 1-4 additional amino acid residues at the N-terminus.
  • composition containing the just- described polypeptide-polymer conjugate for use in treating HCV infection or HBV infection is also within the scope of this invention.
  • This invention relates to peptide-polymer conjugates in which a peptide moiety is coupled to a polymer via an unsaturated linker.
  • Peptide-polymer conjugates of the present invention can be prepared by synthetic methods well known in the chemical art. For example, a linker molecule containing a leaving group (e.g., a bromide) can be first coupled to an mPEG containing a hydroxy end group through an ether linkage. Subsequently, a peptide molecule containing a functional group (e.g., an amine group) can be reacted with a functional group (e.g., an aldehyde functional group) of the linker to form a peptide- polymer conjugate of this invention.
  • a linker molecule containing a leaving group e.g., a bromide
  • an peptide molecule containing a functional group e.g., an amine group
  • a functional group e.g., an aldehyde functional group
  • the chemical reactions described above include using solvents, reagents, catalysts, protecting group and deprotecting group reagents, and certain reaction conditions. They may additionally include steps, either before or after the steps described specifically herein, to add or remove suitable protecting groups in order to ultimately allow for synthesis of a peptide-polymer conjugate. In addition, various synthetic steps may be performed in an alternate sequence or order to give the desired polypeptide-polymer conjugates.
  • Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing applicable peptide-polymer conjugates are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's
  • Scheme 1 shows an example of preparing peptide-polymer conjugates of this invention.
  • Chemical I has a polymer moiety and an aldehyde functional group. It can be reacted with peptide II, which has a free amino functional group.
  • the resulting product III is subsequently reduced, e.g., by hydrogenation or by NaBHsCN, to afford peptide-polymer conjugate IV.
  • a G 1 L' C H 2 - ' N H ⁇ rv A is a polymer moiety Gi is a bond or a linking functional group L' is alkenyl or alkynyl B is a peptide moiety
  • a peptide-polymer conjugate thus synthesized can be further purified by a method such as column chromatography or high-pressure liquid chromatography.
  • the peptide-polymer conjugate of the invention may be pharmaceutically active in the conjugate form. Alternatively, it can release a pharmaceutically active peptide in vivo (e.g., through hydrolysis) by enzymatically cleaving the linkage between the peptide moiety and the polymer moiety.
  • enzymes involved in in vivo cleaving linkages include oxidative enzymes (e.g., peroxidases, amine oxidases, or dehydrogenases), reductive enzymes (e.g., keto reductases), and hydrolytic enzymes (e.g., proteases, esterases, sulfatases, or phosphatases).
  • oxidative enzymes e.g., peroxidases, amine oxidases, or dehydrogenases
  • reductive enzymes e.g., keto reductases
  • hydrolytic enzymes e.g., proteases, esterases, sulfatases, or phosphatases.
  • one aspect of this invention relates to a method of administering an effective amount of one or more of the above-described peptide-polymer conjugates for treating a disease (e.g., HCV or HBV infection).
  • a disease can be treated by administering to a subject one or more of the peptide-polymer conjugates in an effective amount.
  • a subject can be identified by a health care professional based on results from any suitable diagnostic method.
  • treating is defined as the application or administration of a composition including a peptide-polymer conjugate to a subject (human or aminal), who has a disorder, a symptom of the disorder, a disease or disorder secondary to the disorder, or a predisposition toward the disorder, with the purpose to cure, alleviate, relieve, remedy, or ameliorate the disorder, the symptom of the disorder, the disease or disorder secondary to the disorder, or the predisposition toward the disorder.
  • “An effective amount” refers to an amount of a peptide-polymer conjugate which confers a therapeutic effect on the treated subject. The therapeutic effect may be objective (i.e., measurably by some tests or markers) or subjective (i.e., a subject gives an indication of or feels an effect).
  • a pharmaceutical composition contains an effective amount of at least one of the peptide-polymer conjugates described above and a pharmaceutical acceptable carrier. Further, this invention includes a method of administering an effective amount of one or more of the peptide - polymer conjugates to a patient with one or more diseases. Effective doses will vary, as recognized by those skilled in the art, depending on, e.g., the rate of hydrolysis of a peptide-polymer conjugate, the types of diseases to be treated, the route of administration, the excipient usage, and the possibility of co-usage with other therapeutic treatment.
  • a composition having one or more of the above-mentioned compounds can be administered parenterally, orally, nasally, rectally, topically, or buccally.
  • parenteral refers to subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, intraperitoneal, intratracheal or intracranial injection, as well as any suitable infusion technique.
  • a sterile injectable composition can be a solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol.
  • a non-toxic parenterally acceptable diluent or solvent such as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that can be employed are mannitol, water, Ringer's solution, and isotonic sodium chloride solution.
  • fixed oils are conventionally employed as a solvent or suspending medium (e.g., synthetic mono- or di-glycerides).
  • Fatty acid, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • oil solutions or suspensions can also contain a long chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents.
  • a long chain alcohol diluent or dispersant or carboxymethyl cellulose or similar dispersing agents.
  • Other commonly used surfactants such as Tweens or Spans or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for the purpose of formulation.
  • a composition for oral administration can be any orally acceptable dosage form including capsules, tablets, emulsions, and aqueous suspensions, dispersions, and solutions.
  • commonly used carriers include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried corn starch.
  • a nasal aerosol or inhalation composition can be prepared according to techniques well known in the art of pharmaceutical formulation.
  • such a composition can be prepared as a solution in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
  • a composition having one or more of the above-described compounds can also be administered in the form of suppositories for rectal administration.
  • a pharmaceutically acceptable carrier is routinely used with one or more active above-mentioned compounds.
  • the carrier in the pharmaceutical composition must be "acceptable” in the sense that it is compatible with the active ingredient of the composition (and preferably, capable of stabilizing the active ingredient) and not deleterious to the subject to be treated.
  • One or more solubilizing agents can be utilized as pharmaceutical excipients for delivery of an above-mentioned compound. Examples of other carriers include colloidal silicon oxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D&C Yellow # 10.
  • Compound 4 was prepared as a white powder by the same method as compound 3, except that 2-[5-bromo-(Z)-pent-3-enyl]-l,3-dioxolane was used in place of 2-[5-bromo-(£)-pent-3-enyl]-l,3-dioxolane.
  • a modified recombinant human interferon- ⁇ 2 b i.e., Pro-IFN
  • Pro-IFN was cloned by a PCR method using human genomic DNA as a template.
  • the oligonucleotides were synthesized based on the flanking sequences of human interferon- ⁇ 2 b (GenBank Accession # J00207).
  • the derived PCR products were subcloned into pGEM-T vector (Promega).
  • the IFN variant was PCR amplified again through the pGEM-T clones and subsequently subcloned into protein expression vector pET-24a (Novagen), a T7 RNA polymerase promoter driven vector, using Ndel/BamHI as the cloning sites.
  • Vector pET-24a was then transformed into E. coli BL21-CodonPlus (DE 3)-RIL (Stratagene) strain.
  • the high-expression clones were selected by maintaining the transformed E. coli BL21-CodonPlus (DE 3)-RIL in the presence of karamycin (50 ⁇ g/mL) and chloramphenical (50 ⁇ g/mL).
  • the batch fermentation used 150 mL of an overnight preculture inoculum and 3 L of the Terrific broth medium with karamycin (50 ⁇ g/mL), chloramphenical (50 ug/mL), 0.4% glycerol, and 0.5% (v/v) trace elements (10 g/L of FeSO 4 - 7H 2 O, 2.25 g/L of ZnSO 4 - 7H 2 O, 1 g/L of CuSO 4 - 5H 2 O, 0.5 g/L of MnSO 4 - H 2 O, 0.3 g/L OfH 3 BO 3 , 2 g/L of CaCl 2 - 2H 2 O, 0.1 g/L of (NH 4 ) 6 Mo 7 O 24 , 0.84 g/L EDTA, 50 ml/L HCl).
  • the dissolved oxygen concentration was controlled at 35% and the pH was kept at 7.2 by adding a 5 N NaOH aqueous solution.
  • a feeding solution containing 600 g/L of glucose and 20 g/L OfMgSO 4 • 7H 2 O was prepared. When the pH rose to a value greater than the set point, an appropriate volume of the feeding solution was added to increase the glucose concentration in the culture broth. Expression of the Pro-IFN gene was induced by adding IPTG to a final concentration of 1 mM and the culture broth was harvested after incubating for 3 hr.
  • the collected cell pellet was resuspended with TEN buffer (50 rnM Tris-HCl (pH 8.0), 1 mM EDTA, 100 rnM NaCl) in an approximate ratio of 1 : 10 (wet weight g/mL) and disrupted by a micro fluidizer, and then centrifuged at 10,000 rpm for 20 min.
  • the pellet containing inclusion body (IB) was washed twice with TEN buffer and centrifuged as described above.
  • the pellet containing IB was then suspended in 150 mL of a 4 M guanidium HCl (GuHCl) aqueous solution and centrifuged at 20,000 rpm for 15 min.
  • TEN buffer 50 rnM Tris-HCl (pH 8.0), 1 mM EDTA, 100 rnM NaCl
  • the IB was then solubilized in 50 mL of 6 M GuHCl solution.
  • the GuHCl solubilized material was centrifuged at 20,000 rpm for 20 min.
  • Refolding was initiated by dilution of denatured IB in 1.5 L of a freshly prepared refolding buffer (100 mM Tris-HCl (pH 8.0), 0.5 M L-Arginine, 2 rnM EDTA) that was stirred only during the addition.
  • the refolding reaction mixture was allowed to incubate for 48 hr without stirring.
  • the refolded recombinant human interferon- ⁇ ,2b (i.e., Pro-IFN) was dialyzed against 20 mM Tris buffer (with 2 mM EDTA and 0.1M urea, pH 7.0) for further purification by Q-Sepharose column chromatography.
  • the refolded recombinant human protein Pro-IFN was loaded onto a Q-
  • Sepharose column (GE Amersham Pharmacia, Pittsburgh, PA). The column was pre- equilibrated and washed with a 20 mM Tris-HCl buffer (pH 7.0). The product was eluted with a mixture of 20 mM Tris-HCl buffer (pH 7.0) and 200 mM NaCl. Fractions containing Pro-IFN was collected based on its absorbance at 280 nm. The concentration of Pro-IFN was determined by a protein assay kit using the Bradford method (Pierce, Rockford, IL).
  • the Q-Sepharose purified Pro-IFN (1 mg) prepared in Example 3 above was reacted with Compound 3.
  • the final reaction mixture contained 50 mM sodium phosphate (pH 6.0), 5 mM sodium cyanoborohydride (Aldrich, Milwaukee, WI) and 10 mg of Compound 3.
  • the mixture was then incubated at room temperature for 20 hr to form as a major product the mono-PEGylated Pro-IFN (Compound 5), which was then purified by SP XL Sepharose chromatography (GE Amersham Pharmacia, Pittsburgh, PA). Specf ⁇ cally, the SP column was pre-equilibrated and washed with a solution of 20 mM sodium acetate (pH 5.4).
  • Compound 5 was then eluted with a buffer containing 20 mM sodium acetate (pH 5.4) and 60 mM NaCl.
  • the unreacted IFN, i.e., Pro-IFN was eluted by a buffer containing 20 mM sodium acetate (pH 5.4) and 200 mM NaCl.
  • the eluted fractions were analyzed by gel electrophoresis with a 12% sodium dodecyl sulfate-polyacrylamide gel and the signals were detected by staining with Coomassie brilliant blue R-250 and silver stain. Fractions containing Compound 5 were collected based on their retention time and absorbance at 280 nm.
  • the concentration of Compound 5 was determined by a protein assay kit using the Bradford method (Pierce, Rockford, IL). The isolated yield of Compound 5 was 30%-40%.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Virology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biotechnology (AREA)
  • Zoology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne un conjugué peptide-polymère répondant à la formule suivante : A-G1-L-G2-B ; A est un fragment polymère ; chaque G1 et G2 est, indépendamment, une liaison ou un groupe de liaison fonctionnel ; L est un fragment alcénylène ou alcynylène ; et B est un fragment peptidique. Un procédé pour préparer un conjugué peptide-polymère et son utilisation pour traiter une infection par le virus de l'hépatite C ou une infection par le virus de l'hépatite B sont également décrits.
PCT/US2008/069169 2007-07-05 2008-07-03 Conjugués peptide-polymère WO2009006579A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US94809507P 2007-07-05 2007-07-05
US60/948,095 2007-07-05

Publications (1)

Publication Number Publication Date
WO2009006579A1 true WO2009006579A1 (fr) 2009-01-08

Family

ID=40226541

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2008/069169 WO2009006579A1 (fr) 2007-07-05 2008-07-03 Conjugués peptide-polymère

Country Status (4)

Country Link
CN (1) CN101343318A (fr)
AR (1) AR067453A1 (fr)
TW (1) TW200911288A (fr)
WO (1) WO2009006579A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004033425A1 (fr) * 2002-10-09 2004-04-22 Genoscience Derives de pyrrolidine utilises pour traiter l'infection par le virus de l'hepatite c
US20070025966A1 (en) * 2004-05-19 2007-02-01 Maxygen, Inc. Interferon-alpha polypeptides and conjugates

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004033425A1 (fr) * 2002-10-09 2004-04-22 Genoscience Derives de pyrrolidine utilises pour traiter l'infection par le virus de l'hepatite c
US20070025966A1 (en) * 2004-05-19 2007-02-01 Maxygen, Inc. Interferon-alpha polypeptides and conjugates

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HARRIS ET AL.: "Effect of pegylation on pharmaceuticals", NATURE, vol. 2, 2003, pages 214 - 221 *

Also Published As

Publication number Publication date
AR067453A1 (es) 2009-10-14
CN101343318A (zh) 2009-01-14
TW200911288A (en) 2009-03-16

Similar Documents

Publication Publication Date Title
US20070185135A1 (en) Drug-Polymer Conjugates
US8143214B2 (en) Protein-polymer conjugates
WO2009006579A1 (fr) Conjugués peptide-polymère
EP2509593B1 (fr) Conjugués protéines-polymères
EP2313457B1 (fr) Conjugués peptide-polymère

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08781348

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08781348

Country of ref document: EP

Kind code of ref document: A1

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载