WO1989009601A2 - Monosaccharides or polysaccharides used as antiviral agent - Google Patents

Monosaccharides or polysaccharides used as antiviral agent Download PDF

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Publication number
WO1989009601A2
WO1989009601A2 PCT/EP1989/000399 EP8900399W WO8909601A2 WO 1989009601 A2 WO1989009601 A2 WO 1989009601A2 EP 8900399 W EP8900399 W EP 8900399W WO 8909601 A2 WO8909601 A2 WO 8909601A2
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WO
WIPO (PCT)
Prior art keywords
gal
man
cells
polysaccharides
aids
Prior art date
Application number
PCT/EP1989/000399
Other languages
German (de)
English (en)
French (fr)
Other versions
WO1989009601A3 (en
Inventor
Werner E. G. MÜLLER
Original Assignee
Mueller Werner E G
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 Mueller Werner E G filed Critical Mueller Werner E G
Publication of WO1989009601A2 publication Critical patent/WO1989009601A2/de
Publication of WO1989009601A3 publication Critical patent/WO1989009601A3/de

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39583—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials not provided for elsewhere, e.g. haptens, coenzymes

Definitions

  • the invention relates to the use of natural and / or chemically modified mono- or polysaccharides as anti-viral agents with immunoprophylactic activity and immunotherapeutic activity, especially in combating AIDS and ARC, and is the subject of the claims
  • the invention is based on the finding that human immunodeficiency virus (HIV) proteins are glycosylated (S. Chakrabarti et al., Nature 320: 535, 1986). As will be shown below - and this is the object of the invention - antibodies directed against carbohydrate units can inactivate the virus and no longer make it infectious. It can be assumed that the virus is also inactivated in humans after the formation of antibodies (directed against sugar units) which are induced by injection of mono- and / or polysaccharides.
  • HCV human immunodeficiency virus
  • the natural products mono- and polysaccharides can be moo ⁇ f ⁇ z ⁇ ert by chemical methods.
  • the substances include the following groups of organic compounds
  • compositions (1) Naturally occurring mono- and polysaccharides:
  • the mono and ⁇ polysaccharides obtained are divided into the groups e.g. Glucomannane, Mannane and Galactane divided.
  • Modified MonO- and ⁇ polysaccharides (a) Chemically cross-linked mono- and polysaccharides.
  • HIV Human Immunodeficiency Virus
  • HTLV-III Human T-Cell Leukemia / Lymphotropic Virus Type III
  • LAV Lymphadenopathy-Associated Virus
  • HIV belongs to the type of RNA viruses. Virus infestation is the main cause of a spectrum of immunological disorders, of which AIDS in the form of Kaposi Sarcoms (KS) or ARC is the most clinically manifest. An effective therapeutic treatment for AIDS or ARC has not yet been possible.
  • the compounds used according to the invention are generally processed into pharmaceutical compositions which are available as dose units and can be administered parenterally (intramuscularly, intravenously and subcutaneously).
  • the agents contain at least one Veroinourg from the class of natural and / or modified mono- or for the treatment, elimination, relief or improvement of AIDS or ARC, or an immunodeficiency-bese ⁇ tigence effective Polysaccharides, optionally together with a pharmaceutically acceptable carrier and excipients.
  • a pharmaceutically acceptable carrier for example, such pharmaceutical compositions contain 0.5 to 98% by weight of at least one compound according to the invention together with a pharmaceutical carrier.
  • the agent is in the form of a dosage unit, it preferably contains 50 to 500 mg of the compound used according to the invention.
  • Agents for parenteral administration are generally in the form of a solution or suspension of the compound used according to the invention together with customary pharmaceutical carriers, for example in the form of an aqueous solution for intravenous injection or an oily suspension for intramuscular injection.
  • Agents suitable for parenteral administration are obtained by dissolving 0.1 to 10% by weight of the compound according to the invention in water or a carrier which consists of an aliphatic polyalcohol, such as glycerol, propylene glycol or polyethylene glycols or a mixture thereof.
  • the polyethylene glycols consist of a mixture of non-volatile, usually liquid polyethylene glycols, which are soluble in water as well as in organic liquids and their molecular weights. 200 to 1500 are enough.
  • the production of pharmaceutical agents is carried out using customary methods, for example by sterile filtration and filling into ampoules or dropper bottles of a solution of the compounds according to the invention in injection water together with customary additives, such as sodium chloride, sodium hydrogen phosphate, disodium EDTA (ethylenediaminotetraacetic acid disodium salt), or B ⁇ nz Sodium hyoxide to adjust the pH.
  • customary additives such as sodium chloride, sodium hydrogen phosphate, disodium EDTA (ethylenediaminotetraacetic acid disodium salt), or B ⁇ nz Sodium hyoxide to adjust the pH.
  • the method of treating AIDS or ARC involves administering a therapeutically (antiviral, immunotherapy and / or immunoprophylactically) effective amount of natural and / or modified mono- and / or polysaccharides thereof to a patient in need of this treatment.
  • the dosage depends primarily on the specific form of administration and the purpose of the therapy.
  • the size of the individual doses and the administration schedule can best be determined on the basis of an individual assessment of the respective case by the doctor, taking into account the age, weight and condition of the recipient, the route of administration and the type and severity of the disease.
  • the daily dose is 2-20, preferably 3-10, in particular 6-7 mg / kg body weight.
  • the duration of the treatment depends on the type and severity of the disease. It generally extends over several weeks, for example 4 to 8 weeks.
  • the compounds used according to the invention act in a variety of ways against the human immunodeficiency virus (HIV) and they stimulate the immune system, so that the body's defenses against AIDS, ARC and related diseases are never strengthened. These compounds are therefore useful for the immunotherapeutic and immunoprophylactic treatment of the diseases caused by the AIDS virus.
  • HIV human immunodeficiency virus
  • the antibodies were raised by the usual method (Ref .: A. Nowotny, Basic Exercises in Immunochemistry; Springer-Verlag, Berlin, 1979; pages 210-214).
  • White rabbits were treated once with 0.5 mg Gal or Man with complete Freund's adjuvant.
  • the animals were treated with the same dose of Man or Gal, but this time with Freund's incomplete adjuvant.
  • the serum was then obtained and the immunoglobulins were purified by the usual method by ion exchange chromatography on diethylaminoethyl cellulose (ref .: A. Nowotny; see above; pages 8-12).
  • the purified antibodies against Man were antibodies of the IgM class and those against Gal (now abbreviated anti-Gal) could be assigned to the IgG class.
  • the titer (the dilution of antiserum at which precipitation with the antigen was still discernible in the diffusion batch) was determined semiquantitatively using the Ouchterlony method (0. Ouchterlony, Acta Pathol. Microbiol. Scano. 26: 507, 1949).
  • the titer for anti-Man was 1064 and for anti-Gal 512.
  • the cell line H9 is a cloned OKT4 + T cell line in which the AIDS Virus of the isolate name HTLV-IIIB (belonging to HIV-1) increased (M. Popovic, MG Sarngadharan, E. Reed and RC Gallo; Science 224, 497-500 (1984)).
  • n hybrid polymers from the oligo- or polynucleotides oligodeoxyt hymidylsaure and poly adeny lsaure
  • 3H-dTTP 3 H - D esox yt hy mi di nt riphosphate
  • the samples were filtered through Millipore filters (0.45 ⁇ m), washed first with 5% TCA solution (5x) and then with 2 ml 70% ethanol. The filters were dried under a heating lamp, scintillation liquid was then added and the radioactivity was determined in a ⁇ -scintillation counter.
  • H9 cells (M: Popovic, MG Sarngadharan, E. Reed, RC Gallo, Science: 224, 497-500, 1984) were 30 with polybrene (commercially available hexadimetrin bromide; 2 ⁇ g / ml) Treated for min. At 37 ° C., washed free of polybrene and infected with 200,000,000 HTLV-III virus parts (isolated from H9 cell cultures according to M. Poppvic, see above) per 4 ⁇ 100,000 H9 cells.
  • polybrene commercially available hexadimetrin bromide
  • a not with Antibody (anti-Man or anti-Gal) treated part of these samples was used as a positive control sample, whereas different concentrations of the compound to be tested (anti-Man or ant-Gal) were added to the test samples.
  • the HTLV-III reverse transcriptase activity of these cultures was analyzed as described above.
  • the HTLV-III infected cells were fixed to toxoplasmosis slides with or without drug treatment. After fixation with methanol-acetone (1: 1) for 30 min at room temperature, the slides were stored in sealed plastic containers at -20 ° C until use.
  • the monoclonal antibodies were added to the cells, incubated at room temperature in a humidity chamber for 1 hour with PBS (phosphate buffer) containing 0.2550 Triton X-100, washed for 2 hours.
  • the cells were then treated with goat anti-mouse IgG (Capell Labs.) Labeled with fluorescein (FICT) for 1 h and washed with PBS buffer containing 0.25% Triton X-100 overnight. 50% glycerol was added to the slides and the cell fluorescence was determined with a Zeiss fluorescence microscope.
  • H9 cells as well as HTLV-IIIB infected H9 cells in a concentration of 0.2 ⁇ 1,000,000 cells / ml culture medium were used to inoculate a culture medium. After 4- After incubation for a day, the density of the H9 cells was 1.3 ⁇ 1,000,000 cells / ml, while the density of the H9 cells infected with HTLV-IIIB was only 0.5 ⁇ 1,000,000 cells / ml, these two values formed the Control values. Then samples of H9-HTLV-IIIB cells 0.2 x 1,000,000 cells / ml were treated with different concentrations of anti-Man and anti-Gal for 4 days. The following results were obtained:
  • anti-Man (and anti-Gal) at concentrations between 256 and 512 (128 and 256) titer units / ml increases the growth rate of H9-HTLV-IIIB cells to values which are in the range of the control ( 1,300,000 cells / ml), namely the H9 cells without HTLV-IIIB.
  • the mechanism of action of anti-Man and anti-Gal as an inhibitor of HIV multiplication has been identified as an inhibition of the association of HIV proteins with T4 cells (lymphocytes). This association is necessary for infection of the target cell (Ref .: RC Gallo et al., Progr. Allergy 37: 1, 1986).
  • the investigations were carried out as follows: 2,500,000 human blood lymphocytes were mixed in 1 ml batches with 125-iodine-radioactively labeled HIV protein (labeling according to: ACC Cuello et al., In: Immunohistochemistry. AC Cuello, editor. John Wiley & Sons, Inc. New York; pages 214-256; 1983) in physiological saline solution corresponding to earlier ones (M.
  • one of the compounds used according to the invention can be used individually or as a mixture with another compound according to the invention as active ingredient.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
PCT/EP1989/000399 1988-04-13 1989-04-13 Monosaccharides or polysaccharides used as antiviral agent WO1989009601A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19883812181 DE3812181A1 (de) 1988-04-13 1988-04-13 Arzneimittel, enthaltend natuerliche und/oder chemisch modifizierte mono- oder polysaccharide und deren verwendung
DEP3812181.6 1988-04-13

Publications (2)

Publication Number Publication Date
WO1989009601A2 true WO1989009601A2 (en) 1989-10-19
WO1989009601A3 WO1989009601A3 (en) 1989-12-14

Family

ID=6351831

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1989/000399 WO1989009601A2 (en) 1988-04-13 1989-04-13 Monosaccharides or polysaccharides used as antiviral agent

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DE (1) DE3812181A1 (enrdf_load_stackoverflow)
WO (1) WO1989009601A2 (enrdf_load_stackoverflow)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011047794A3 (en) * 2009-10-21 2011-10-13 Eth Zurich Medical utility of glycan-binding proteins and glycans

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3590126A (en) * 1968-04-02 1971-06-29 William R Porter Chitin antigens and method
IN141230B (enrdf_load_stackoverflow) * 1973-12-14 1977-02-05 Strategic Medical Res Corp
US4512972A (en) * 1980-06-30 1985-04-23 Kureha Chemical Industry Co., Ltd. Nasal preparation and processes for their production
JPS5823847B2 (ja) * 1981-02-06 1983-05-18 株式会社 林原生物化学研究所 抗ヒト蛋白質抗体の製造方法
US4522814A (en) * 1982-11-05 1985-06-11 Raphael Pappo Composition of matter from Cryptosiphonia woodii useful for the treatment of herpes simplex virus
DE3601136A1 (de) * 1986-01-16 1987-07-23 Max Planck Gesellschaft Hemmstoffe der reversen transkriptase fuer prophylaxe und therapie von retrovirus-infektionen in saeugetieren
EP0230574A3 (en) * 1986-01-31 1989-03-22 Yale University Pharmaceutical compositions against infections caused by lav/htlv iii virus and the use thereof
EP0240098A3 (en) * 1986-04-04 1989-05-10 Kabushiki Kaisha Ueno Seiyaku Oyo Kenkyujo Oligo and polysaccharides for the treatment of diseases caused by retroviruses
FR2598434B1 (fr) * 1986-05-12 1988-09-16 Pf Medicament Nouveaux immunomodulateurs obtenus par hemisynthese a partir d'un polysaccharide bacterien isole d'une souche mutante non capsulee de klebsiella pneumoniae

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011047794A3 (en) * 2009-10-21 2011-10-13 Eth Zurich Medical utility of glycan-binding proteins and glycans

Also Published As

Publication number Publication date
DE3812181A1 (de) 1989-10-26
WO1989009601A3 (en) 1989-12-14
DE3812181C2 (enrdf_load_stackoverflow) 1993-06-17

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