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WO1986004064A1 - Compose et composition utilises pour la therapie et le diagnostic; utilisation de ce compose et de cette composition dans le traitement therapeutique et l'isolement de shigatoxine - Google Patents

Compose et composition utilises pour la therapie et le diagnostic; utilisation de ce compose et de cette composition dans le traitement therapeutique et l'isolement de shigatoxine Download PDF

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Publication number
WO1986004064A1
WO1986004064A1 PCT/SE1985/000539 SE8500539W WO8604064A1 WO 1986004064 A1 WO1986004064 A1 WO 1986004064A1 SE 8500539 W SE8500539 W SE 8500539W WO 8604064 A1 WO8604064 A1 WO 8604064A1
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WO
WIPO (PCT)
Prior art keywords
toxine
compound according
compound
hydrogen
residue
Prior art date
Application number
PCT/SE1985/000539
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English (en)
Inventor
Alf Lindberg
Sigfrid Svensson
Original Assignee
Biocarb Ab
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 Biocarb Ab filed Critical Biocarb Ab
Publication of WO1986004064A1 publication Critical patent/WO1986004064A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
    • C07H3/06—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • C07K14/24—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Enterobacteriaceae (F), e.g. Citrobacter, Serratia, Proteus, Providencia, Morganella, Yersinia
    • C07K14/25—Shigella (G)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/02—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms
    • C12Q1/04—Determining presence or kind of microorganism; Use of selective media for testing antibiotics or bacteriocides; Compositions containing a chemical indicator therefor
    • C12Q1/10—Enterobacteria
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56911—Bacteria
    • G01N33/56916—Enterobacteria, e.g. shigella, salmonella, klebsiella, serratia
    • 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

Definitions

  • a compound and a composition for therapeutic or diagnostic use and the use of such compound and composition for the-rapeutic treatment and isolation of Shigatoxine are provided.
  • the present invention relates to compounds and compositions which are useful for therapeutic treatment of disorders caused by the toxine of Shigella dysenteriae as well as profylaxis and diagnosis in connection herewith.
  • the invention also relates to a method of therapeutic treatment of mammals including man and a process for isolating the toxine in question.
  • necrosis of the epithelium of the colon is part of the pathogenesis of bacillary dyssnteria after infection with Shigella dysenteriae (see Davis, B.D., Dulbecco, R., Eisen, H.N., and Ginsberg, N.S. (eds) Microbiology Harper and Row, Publishers, Philadelphia, third edition, 1980).
  • the necrosis is due to an invasion of the bacterium into the epithelium to produce therein a toxine which appears to inhibit protein synthesis (see Brown, J .E.,. Rothman, S.W. and Doctor, B.P. (1980) Infect. Immun. 29, 98-107).
  • the purified toxine has a molecular weight of about 70 000 (see Brown, J.E., Griffin, D.E., Rothman, S.W. and Doctor, B.P. (1982) Infect. Immun. 36, 996-1005) and is composed of one heavy and four to five light subunits similar to the case for cholera toxine (see Olsnes, S. and Eiklid, K. (1980) J.Biol.Chem. 255, 284-289).
  • the toxine has recently been purified on a milligram scale (see Brown, J.E., Griffin, D.E., Rothman, S.W. and Doctor, B.P. (1982) Infect. Immun.
  • the present invention has for its main object to provide a compound or a composition which can be used therapeutically for the treatment of disorders due to infection with Shigella dvsenteriae and which can also be used for diagnosing the toxine generated by the just mentioned bacterium.
  • Another object of the invention is to provide a method for therapeutic treatment of mammals including man. Still another object of the invention is to provide a process for isolating the toxine of Shigella dysenteriae.
  • R 1 and R 2 independently are hydrogen, lower alkyl or acyl, with the proviso that R 1 is not hydrogen at the same time as R 2 is acetyl, or R 1 and R 2 together with the nitrogen atom to which they are connected form a cyclic imide, for example phthalimide, and wherein R 3 is hydrogen, an organic residue, such as a carbohydrate residue, or the residue of a natural or synthetic glycoconjugate.
  • R 1 and R 2 have the above meaning and wherein R 4 is hydrogen, an organic residue, such as a carbohydrate residue, or the residue of a natural or synthetic glycoconjugate.
  • R 1 is hydrogen or lower alkyl and R 2 is hydrogen, lower alkyl or acyl.
  • a preferred proviso is that R 1 and R 2 are not simultaneously hydrogen.
  • R 1 is hydrogen, whereas R 2 has the formula ( I I I ) :
  • R 5 , R 6 and R 7 idependently are hydrogen, lower alkyl or halogen. It is particularly preferred that R 5 , R 6 and R 7 all are fluoro or chloro, particularly fluoro. With regard to compound (II) it is preferred that -OR 3 is in ⁇ -configuration.
  • lower used in the present disclosure refers to a group containing 1-6 carbon atoms, particularly 1-4 carbon atoms and especially 1 or 2 carbon atoms.
  • the active substance constituted by the compound of formular (I) can be used as such or in combination with a pharmaceutically acceptable carrier.
  • the active substances according to the present invention can be formulated for use in human or veterinary medicine for therapeutic, profylactic or diagnostic uses.
  • the active constituents are normally administered orally or rectally or by injection in the form of a pharmaceutical preparation containing the active constituents in combination with a pharmaceutically acceptable carrier, which may be solid, semisolid or liquid, or as a capsule, and such compositions constitute a further aspect of the invention.
  • the compounds may also be used as such without carrier and in a form of an aqueous solution for injection.
  • pharmaceutical preparations there may be mentioned tablets, drops, solutions and suppositories.
  • the ac tive substance usually constitutes from 0.05 to 99% by weight of the preparation, for example from 0.1 to 50% for preparations intended for oral administration.
  • the active constituents can be admixed with a solid pulverulent or other carrier, for example lactose, saccharose, sorbitol, mannitol, starch, such as potatoe starch, corn starch, amylopectin, a cellulose derivative or gelatin and may also include lubricants, such as magnesium or calcium stearate, or polyethylene gl ⁇ col waxes compressed to form tablets or cause for dragees.
  • a solid pulverulent or other carrier for example lactose, saccharose, sorbitol, mannitol, starch, such as potatoe starch, corn starch, amylopectin, a cellulose derivative or gelatin and may also include lubricants, such as magnesium or calcium stearate, or polyethylene gl ⁇ col waxes compressed to form tablets or cause for dragees.
  • Liquid preparations for oral application can be in the form of elixires, syrups or suspensions, for example solutions containing from 0.1 to 20% by weight of active substance, sugar and a mixture of ethanol, water, glycerol, propylene, glycol and optionally other additives of a conventional character.
  • the dose by which the active constituents are administered may vary within wide limits and depend on different factors, such as the severity of the disorder, the age and the weight of the patient and can be individually adjusted. As a conceivable range for the quantity of active constituents that may be administered per day there may be mentioned from 0.1 to 2000 mg or from 1 mg to 2000 mg.
  • the present invention has also for an object to provide a method for therapeutic treatment of mammals including man, and in this treatment a therapeutically active amount of a substance or a composition in accordance with the invention is administered.
  • the present invention has furhtermore for an object to provide use of the composition or the substance according to the invention for therapeutic treatment or diagnosis.
  • composition or compound according to the present invention is thus useful in treatment of profylaxis or diagnosis of disorders caused by the toxine of Shigella dvsenteriae.
  • R 3 of formula (I) can designate the residue of a natural or synthetic glycoconjugate.
  • Substituent R 3 may also be constituted by a macromolscular carrier to which the active part of the compound according to the invention is coupled.
  • the coupling can suitably be provided by a covalent coupling obtained via a coupling arm.
  • a macromolscular carrier there may be used a synthetically or naturally occurring polypeptide, polysaccharide, other polymer or particle.
  • the coupling arm between the structural element and macromolecular carrier suitably consists of :
  • the compound or composition according to the invention can be used to determine the presence of the toxine of Shigella dvsenteriae in a sample taken from a mammal including man.
  • the compound which constitutes active receptor vis-a-vis the Shigatoxine can be identified or quantified in native biological material, the procedure using antibodies, the generation of which has been induced by the use of a compound or a composition according to the invention.
  • the invention can be used for isolation of the toxine of Shigella dvsenteriae from a culture containing such toxine, a compound according to the invention being associated with a macromolecular or particular carrier and the culture being brought into contact with the carrier to bind the toxine thereto, the toxine being then released from the carrier and recovered.
  • the toxine can suitably be released by providing in a column containing such carrier a change in pH.
  • the toxine may also be relsased by displacement while utilizing a compound according to the invention in free form.
  • the toxine may be released by treatment with a borate buffer or by treatment with so called chaiotropic ions.
  • substituent R 3 and R 4 in the compound of formula (I) or formula (II) as given above it can be of any type as long as it does not negatively effect the conditions in connection with the practical application of the invention.
  • the said substituent may be hydrogen, lower alkyl or lower acyl, but R 1 can also be constituted by the residue of a natural or synthetic glycoconjugate, whereby the compound according to the invention thus is a glycoconjugate, for example a glycolipid.
  • Globotetraosy lceramide (from human red cell membranes) was treated with trifluoroacetic acid/trifluoroacetic acidanhydride (TFA/TFAA) (1:100; v/v; 20 ml) at 100°C for 48 hours. After cooling the reaction mixture was evaporated to dryness. The residue was dissolved in 10 ml glacial acetic acid, 10 ml distilled water being then added. The mixture was heated at 100°C for 4 hours and then evaporated into dryness. 10 ml water and 10 ml chloroform/methanol (2:1; v/v) were added and the mixture was shaken. The organic phase was separated and another 10 ml chloroform/methanol were added. After shaking the organic phase was separated and the aqueous phase was evaporated into dryness.
  • TFA/TFAA trifluoroacetic acid/trifluoroacetic acidanhydride
  • the crude product was gelcromatographed on Sephadex G15 (2x100 cm) using water as an eluent.
  • the fractions containing tetrasaccharide were combined and freezedried, 43 mg of product being obtained.
  • the cells were cultivated in Eagle's minimal essential medium having added thereto a fetal calf serum (Sibco), final concentration 5%; 10mM NaHCO 3 ; 1mM glutamin; and 100 lU/ml streptomycine and penicillin (Gibco).
  • the cellcultures were incubated in 3% CO 2 at 37°C for 3 days (HeLa-celIs) or for 7 days (Vero-oells). Trypsinized cells for experimental use were suspended in medium, centrifuged and resuspended either in phosphate-buffered physiological saline (PBS) (0.05 M, pH7.2 ) for the binding studies or in a medium for toxicity studies. The cells were counted under microscope and immediately used.
  • PBS phosphate-buffered physiological saline
  • Toxine (18 ⁇ g protein in 10 ⁇ l PBS) were labelled with 250 uCi 125 I using Bolton Hunter reagent (2200 Ci mmol; New England Nuclear). Separation of the toxine from unbound isotope was obtained using gel cromatography with Sephadex G25 column (10x0.6 cm) (Pharmacia Fine Chemicals) and PBS as an eluting liquid. Labelled toxine was stored at +4°C until used.
  • Isotope-labelled toxine was dialuted to a concentratrion of 1.25 ⁇ g protein/ml with PBS having added thereto bovine serum albumin (BSA, Sigma Chemical) 1 mg/ml. Dialuted toxine was preincubated with antigen, compound (I) according to Example 1 above dialuted in PBS or only with PBS for 1 hour at +25°C. Then cells were added suspended in PBS and the mixture was stirred for 1 hour at +25°C. Controls containing toxine but no cells were incubated in parallel. The total volume of each experiment was 0.3 ml. Each reaction mixture was then stored on top of a discontinuous Percoll gradient (Pharmacia Fine Chemicals).
  • BSA bovine serum albumin
  • the gradient was prepared by adding 1 ml of 100% Percoll (9 ml concentrate + 1 ml 15% NaCl) to a polycarbonate tube, 4 ml of 20% Percoll in PBS and at last 1 ml PBS being added on top. The gradient was centrifuged for 15 minutes at 800xg +4°C. The cells form bands between 20% and 100% Percoll. The top layers containing toxine not bound to the cells were transferred with a Pasteur pipette to another polycarbonate tube. Both fractions are counted in a gammacounter (Packard Instruments).
  • FIG. 1 the binding of the toxine to cells as a function of the quantity of labelled toxine is shown. The binding is shown in relation to Vero-cells ( ⁇ ) , to HeLa-cells (+), to resistent HeLa-cells (o) and no cells ( ⁇ ).
  • FIG. 2 there is a corresponding diagram concerning 125 J-labelled toxine binding to Vero-cells after competition of labelled toxine (100 ng) with unlabelled toxine.
  • Fig. 3 there is shown a diagram over the inhibition of the binding of 125 J-label led Shigatoxine to Vero-cells.
  • Toxine 100 ng was in the experiments preincubated with galabiose (+), globotetraose ( ⁇ ) , 1 , 1' , 1''-triacetylcitotriose ( ⁇ ) and the compound according to Example 1 above (o), respectively, before the addition of 2 x 10 5 Vero-cells.
  • Each testpoint in the diagram represents the average of two experiments.
  • 50% inhibition at a concentration of the active compound of about 1.2 mg/ml.

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  • Chemical & Material Sciences (AREA)
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  • Saccharide Compounds (AREA)

Abstract

Un composé utilisé dans le traitement, la prophylaxie ou le diagnostic de troubles provoqués par la toxine de Shigella dysenteriae a la formule (I), dans laquelle R1 et R2 sont indépendamment hydrogène, alcoyle ou acyle inférieur, à condition que R1 ne soit pas de l'hydrogène lorsque R2 est de l'acétyle, ou R1 et R2 forment avec l'atome d'azote auquel ils sont liés une imide cyclique, la phtalamide par exemple, et R3 est de l'hydrogène, un résidu organique, tel qu'un résidu d'hydrate de carbone, ou le résidu d'un glycoconjugué naturel ou synthétique. Une composition comprend ce composé associé à un excipient ou diluant pharmaceutiquement acceptable. Un procédé de traitement permet de déterminer la présence de la toxine, un procédé permet d'identifier ou de quantifier ce composé, et un procédé permet d'isoler la toxine.
PCT/SE1985/000539 1984-12-27 1985-12-20 Compose et composition utilises pour la therapie et le diagnostic; utilisation de ce compose et de cette composition dans le traitement therapeutique et l'isolement de shigatoxine WO1986004064A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE8406626-5 1984-12-27
SE8406626A SE8406626D0 (sv) 1984-12-27 1984-12-27 Forening och komposition for terapeutisk eller diagnostisk anvendning jemte anvendning av sadan forening och komposition for terapeutisk behandling och isolering av shigatoxin

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WO1986004064A1 true WO1986004064A1 (fr) 1986-07-17

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EP (1) EP0205547A1 (fr)
AU (1) AU5300486A (fr)
SE (1) SE8406626D0 (fr)
WO (1) WO1986004064A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990001488A1 (fr) * 1988-08-12 1990-02-22 Symbicom Aktiebolag Analogues de recepteurs synthetiques
GB2223579A (en) * 1988-06-24 1990-04-11 Hsc Res Dev Corp Verocytotoxin Receptor Array
WO1990006109A1 (fr) * 1988-11-28 1990-06-14 The United States Of America, Represented By The Secretary, United States Department Of Commerce Adherences de mycoplasma pneumoniae et de mycoplasma hominus a du sulfature
US5217715A (en) * 1988-08-01 1993-06-08 The United States Of America As Represented By The Department Of Health And Human Services Carbohydrate receptor for bacteria and method for use thereof
WO1997049431A3 (fr) * 1996-06-21 1998-03-12 Synsorb Biotech Inc UTILISATION D'OLIGOSACCHARIDES POUR NEUTRALISER DES TOXINES DE $i(E. COLI)
US5849714A (en) * 1996-06-21 1998-12-15 Synsorb Biotech Inc. Treatment of bacterial dysentery
EP0610356B1 (fr) * 1991-10-18 2001-01-31 SYNSORB Biotech Inc. Traitement de la dysenterie bacterienne

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0035484A2 (fr) * 1980-03-05 1981-09-09 Gunilla Petterson Källenius Composition à usage thérapeutique ou diagnostique
EP0080442A2 (fr) * 1981-10-23 1983-06-01 Carbohydrates International AB Procédé pour la préparation de dérivés de di-galactose
EP0089939A1 (fr) * 1982-03-22 1983-09-28 BioCarp AB Compositions à emploi thérapeutique ou diagnostique contenant des oligosaccharides
EP0098252A2 (fr) * 1982-06-23 1984-01-11 Biocarb Ab Glycosides, glycoconjugates et leur procédé de préparation
EP0132242A2 (fr) * 1983-07-15 1985-01-23 Symbicom Ab Un composé et une composition pour application thérapeutique ou diagnostique
EP0133170A2 (fr) * 1983-07-15 1985-02-13 Ab Symbicom Un composé et une composition pour application thérapeutique ou diagnostique et une méthode de traitement thérapeutique

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0035484A2 (fr) * 1980-03-05 1981-09-09 Gunilla Petterson Källenius Composition à usage thérapeutique ou diagnostique
EP0080442A2 (fr) * 1981-10-23 1983-06-01 Carbohydrates International AB Procédé pour la préparation de dérivés de di-galactose
EP0089939A1 (fr) * 1982-03-22 1983-09-28 BioCarp AB Compositions à emploi thérapeutique ou diagnostique contenant des oligosaccharides
EP0098252A2 (fr) * 1982-06-23 1984-01-11 Biocarb Ab Glycosides, glycoconjugates et leur procédé de préparation
EP0132242A2 (fr) * 1983-07-15 1985-01-23 Symbicom Ab Un composé et une composition pour application thérapeutique ou diagnostique
EP0133170A2 (fr) * 1983-07-15 1985-02-13 Ab Symbicom Un composé et une composition pour application thérapeutique ou diagnostique et une méthode de traitement thérapeutique

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Acta Chemica Scandinavica, B 36, 1982, No. 8, K-E. Falk et al., " Proton NMR studies of a tetrasaccharide which is a receptor for uropathogenic E. coli bacteria", pages 558-560 *
Microbiology Reviews, Vol 47, No. 4, Dec. 1983, L. Eidels et al, "Membrane receptors for bacterial toxins", pages 596-620, especially pages 608-610 *
Proceedings of the 7th International Symposium on Glycoconjugates, Lund-Ronneby, July 17-23, 1983, Ed. by M.A. Chester et al, Lund, J.E. Brown et al, "Identification of the receptor glycolipid for the toxin of Shigella dysenteriae", pages 678-679 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2223579A (en) * 1988-06-24 1990-04-11 Hsc Res Dev Corp Verocytotoxin Receptor Array
GB2223579B (en) * 1988-06-24 1993-10-20 Hsc Res Dev Corp Verocytotoxin receptor assay
US5217715A (en) * 1988-08-01 1993-06-08 The United States Of America As Represented By The Department Of Health And Human Services Carbohydrate receptor for bacteria and method for use thereof
US5386027A (en) * 1988-08-01 1995-01-31 The United States Of America As Represented By The Department Of Health & Human Services Carbohydrate receptor for bacteria and method for use thereof
WO1990001488A1 (fr) * 1988-08-12 1990-02-22 Symbicom Aktiebolag Analogues de recepteurs synthetiques
US5474986A (en) * 1988-08-12 1995-12-12 Symbicom Aktiebolag Method for treating galabiose-binding bacteria infections
WO1990006109A1 (fr) * 1988-11-28 1990-06-14 The United States Of America, Represented By The Secretary, United States Department Of Commerce Adherences de mycoplasma pneumoniae et de mycoplasma hominus a du sulfature
US5089479A (en) * 1988-11-28 1992-02-18 Krivan Howard C Adhesion of mycoplasma pneumoniae and mycoplasma hominus to sulfatide
EP0610356B1 (fr) * 1991-10-18 2001-01-31 SYNSORB Biotech Inc. Traitement de la dysenterie bacterienne
WO1997049431A3 (fr) * 1996-06-21 1998-03-12 Synsorb Biotech Inc UTILISATION D'OLIGOSACCHARIDES POUR NEUTRALISER DES TOXINES DE $i(E. COLI)
US5849714A (en) * 1996-06-21 1998-12-15 Synsorb Biotech Inc. Treatment of bacterial dysentery
US6121242A (en) * 1996-06-21 2000-09-19 Synsorb Biotech, Inc. Treatment of bacterial dysentery

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EP0205547A1 (fr) 1986-12-30
AU5300486A (en) 1986-07-29
SE8406626D0 (sv) 1984-12-27

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