WO1991008747A1 - Molecules receptrices synthetiques reconnaissables a l'aide d'un rotavirus - Google Patents

Molecules receptrices synthetiques reconnaissables a l'aide d'un rotavirus Download PDF

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Publication number
WO1991008747A1
WO1991008747A1 PCT/US1990/007120 US9007120W WO9108747A1 WO 1991008747 A1 WO1991008747 A1 WO 1991008747A1 US 9007120 W US9007120 W US 9007120W WO 9108747 A1 WO9108747 A1 WO 9108747A1
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Prior art keywords
rotavirus
preventing
treating
composition
receptor
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PCT/US1990/007120
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English (en)
Inventor
Falguni Dasgupta
Cheryl A. Srnka
Roger A. Laine
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Glycomed Incorporated
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Publication of WO1991008747A1 publication Critical patent/WO1991008747A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
    • C07H15/06—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical being a hydroxyalkyl group esterified by a fatty acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/18—Acyclic radicals, substituted by carbocyclic rings

Definitions

  • viruses In order to infect cells and replicate, viruses bind specific receptors on the target cell surface. After attachment, the virus fuses with the cell membrane and is internalized where it uses the target cell's own metabolism to replicate. The initial attachment process is therefore essential to successful infection. For several viruses, a glycoprotein on the viral surface interacts with a specific target cell carbohydrate.
  • a rotavirus has a virion which attaches to the surface of a host cell. The attachment is brought about by the specific binding of the virion protein (the antireceptor) to a constituent of the cell surface (the receptor).
  • the antireceptor A classic example of an antireceptor is the hemagglutinin of influenza virus (orthomyxovirus).
  • the antireceptors are distributed throughout the surface of viruses which infect human cells.
  • Complex viruses such as vaccinia (a pox virus) and herpes symplex virus (a herpes virus), may have more than one species of antireceptor molecules.
  • antireceptor molecules may have several domains, each of which may react with a different receptor. Accordingly, complex structures and interactions are clearly involved with respect to receptors and
  • sialic acid appears to be an important component of the rotavirus receptor, Yolken et al., J. Clin. Invest. 79: 148-154 (1987), and asialo GM1 binds rotavirus and inhibits viral replication in plaque reduction assays, Willoughby et al., abstract from Proceedings of U.S.Japan International Rotavirus Meeting, Annapolis, MD, August
  • This invention relates generally to the field of rotavirus receptors. More particularly, this invention relates to synthetically produced compounds such as carbohydrate epitopes and analogs thereof, which compounds are of a minimum size recognized by the antireceptor of a rotavirus.
  • Rotaviruses are double stranded RNA viruses of the family Reoviridae. These viruses replicate in the intestinal epithelial cells of a wide range of animal species including most mammalian and avian species and are the major etiological agents of several gastrointestinal disorders in humans and other animals. For example, rotaviruses are responsible for infantile diarrhea and enteritis, causing infant morbidity and mortality. Rotaviruses also cause diarrheal illnesses in calves and piglets, as well as other mammals.
  • Viral binding molecules to which a rotavirus binds could be bound to antiviral drugs and rotaviral binding molecules by themselves could be used to hinder or prevent the subsequent infection of host cells.
  • a distinct advantage of such an approach over traditional methods of preventing viral infections, e.g. vaccines, is that the portion of the viral protein normally binding to the specific cell surface carbohydrate does not mutate.
  • antiviral agents which act by preventing viral binding to host cells are likely to remain effective in the face of mutations to other parts of the viral genome.
  • the present invention is based on the discovery of a variety of synthetic compounds of minimal size (such as carbohydrate epitopes or analogs thereof) which avidly bind rotavirus.
  • the compounds can be used to prevent interaction of the virus with a target cell and thus prevent viral infection.
  • These compounds can be bound to antiviral drugs and advantageously employed to treat rotaviral infections.
  • the discovery and chemical characterization of relatively small sugars able to bind rotavirus allows for the efficient production of compositions useful in the prevention and treatment of rotaviral infections.
  • a primary object of the present invention is to provide a rotavirus receptor compound.
  • Another object of the subject invention is directed to a composition for preventing or treating rotaviral infection comprising a therapeutically effective amount of
  • Yet another object of the subject invention is directed to methods of producing molecules able to bind rotavirus.
  • Still other objects of the subject invention include methods for preventing or treating rotaviral induced disorders by administering to a subject a therapeutically effective amount of a synthetic rotavirus receptors.
  • a feature of the present invention is that the molecules are of the smallest possible size which can still be recognized by the antireceptor of a rotavirus.
  • An advantage of the present invention is that the small sized receptor molecules can be linked to antiviral drugs to provide effective antiviral compositions.
  • Another advantage of the present invention is that the compounds can be liked to probes such as radioactive probes to form conjugates which can be used to test for the presence of rotavirus and/or the binding effectiveness of compound with respect to a rotavirus.
  • isolated rotavirus receptor glycolipid is meant any sugar containing lipid that is capable of binding rotavirus.
  • the glycolipid can be isolated from intestinal cells as described in U.S. patent application Serial No.
  • rotavirus receptor compounds any of the synthetic compounds of the invention such as the carbohydrate epitopes or analogs therof which are capable of binding rotavirus as determined by standard viral binding assays including but not limited to overlay assays with thin layer chromatography plates and by probing receptor compounds adsorbed to PVC wells with labeled virus.
  • a receptor compound of the invention will bind a rotavirus more avidly than asialo G M1 , as determined by orcinol staining in comparison with known amounts of asialo G M1 .
  • glycolipid Ggose 4 Cer also known as G A1
  • TLC thin layer chromatography
  • the oligosaccharide moiety of the glycolipid G A1 is shown below as structural formula I and is Ggose 4 (also known as asialo GM1 OS). (Note that Ac is an acetyl moiety throughout.)
  • the oligosaccharide Ggose 3 is the oligosaccharide moiety of the glycolipid Ggose 3 Cer.
  • the compound of structural formula II below is Ggose 3 (also known as asialo GM2 OS).
  • oligosaccharide able to bind rotavirus is meant a sugar containing at least two, and preferably three or more saccharide units that has the ability to bind
  • oligosaccharides are equivalent to those produced by enzymatic cleavage of sugar moieties from isolated natural cell surface glycolipids able to bind rotavirus using arrays as defined above.
  • oligosaccharides can either be synthesized by direct cleavage of the isolated glycolipids or can be chemically synthesized using the present disclosure in combination with methods of chemical synthesis, cleavage and separation well known in the art.
  • terapéuticaally effective amount refers to the amount of a rotavirus receptor compound or conjugate of such a compound with an antiviral drug sufficient to prevent, (i.e., treat prophylactically), or treat, (i.e., reduce or eliminate the symptoms of rotavirus) induced disorders in a recipient subject when administered.
  • receptor sites for the antireceptor of a rotavirus are of particular interest to those involved in the research of the rotavirus and its infectious process. Since a rotavirus will readily attach to a receptor site, the production of receptor sites other than those present on cell surfaces would provide false hosts to the viruses and aid in preventing infection of the host cells to be protected. Further, by providing such receptors, it is possible to link other compounds to the receptors, such as antiviral drugs which can act to destroy the rotavirus after the rotavirus antireceptor has attached. A probe could be attached to or incorporated as part of the receptor so that the "tagged" receptor could be used to detect the presence of rotavirus.
  • This invention relates to (1) naturally cleaved and isolated and to (2) synthetically produced compounds such as carbohydrate epitopes or analogs thereof which are of a minimum size recognized by the antireceptor of a rotavirus.
  • the rotavirus receptor molecules of the invention are
  • Glycolipids can be isolated from cells receptive to rotavirus using any of several techniques for purifying glycolipids, well known in the art.
  • a particularly useful technique is a modified Folch extraction as developed by Svennerholm and Fredman, Biochim. Biophys. Acta 617: 97-109 (1980), the disclosure of which is incorporated by reference herein in its entirety to disclose such extraction
  • Isolated glycolipids known to act as receptors can be used for comparison purposes with the synthetic receptors of the present invention.
  • Carbohydrates and related compounds can also be conjugated or attached to support base surfaces using
  • the receptor compounds such as the carbohydrates or glycolipids can be tested for their ability to bind labeled rotavirus using thin layer chromatography plates, developed in a suitable solvent or by adsorbing the glycolipids to PVC wells and subsequently probing the immobilized receptor compounds with labeled virus.
  • the efficacy of the binding receptor compounds can be tested in vitro in standard plaque reduction assays. It is pointed out that saccharides per se cannot be directly tested in some of the assays. When such direct testing is not possible, the saccharide can be converted to its neoglycolipid form as explained further below.
  • the sugar moieties can be cleaved therefrom using enzymes, including but not limited to neuraminidase, beta- glucuronidase, alpha-galactosidase, beta-galactosidase, endogalactosidase, beta-hexosaminidase, ceramide glycanase, alpha-fucosidase, and the coenzymes sulfatase and
  • cleavage products can be tested for their ability to bind rotavirus as described above and compounds (such as the various carbohydrates of the invention) with binding capability can be further tested in standard rotavirus plaque reduction assays, such as described below.
  • receptor oligosaccharides can be synthesized by the sequential addition of appropriate single sugar units to a growing chain covalently linked to an insoluble solid support or by "block synthesis" where di- or trisaccharide blocks are synthesized which are then complexed to provide larger size oligosaccharides.
  • block synthesis where di- or trisaccharide blocks are synthesized which are then complexed to provide larger size oligosaccharides.
  • the minimum binding and inhibitory carbohydrate epitope can be determined and used. Further, these sugars can be structurally modified to create more avidly binding analogs. In order to determine the minimum size of a receptor molecule recognized by a rotavirus certain characteristics of such receptors were taken into consideration.
  • the compound is asialo GM2 OS also known as the asialo GM2 trisaccharide which is the saccharide portion of the entire glycolipid asialo GM2.
  • R is beta-D-galactopyranosyl
  • the compound is asialo GM1 OS also known as the asialo GM1 trisaccharide which is the saccharide portion of the entire glycolipid asialo GM1.
  • relevant hydroxyls for viral recognition are shown in boxes.
  • each "R” and “R” used with a super - or subscript is independently H, an alkyl which can be a simple straight or branched chain hydrocarbon or a hydrocarbyl, i.e., a hydrocarbon containing one or more heteroatoms most typically -OAc or a sugar.
  • the superscripts on the “R”s are generally used to show that each "R” is independently defined.
  • each "R” is independently H, -OAc, a hydrocarbon containing 1 to 6 carbons, or a sugar, e.g., beta-D-galactopyranosyl.
  • a wavy line in a structural formula indicates that the attached atom or moiety may be in either the alpha or beta position.
  • Reaction II below also begins with a starting compound selected from the group consisting of D-GalNAc, D- GlcHN 2 -HCl or D-GlcNHAc which compound by itself does not bind a rotavirus.
  • the starting compound is then modified by the addition of other saccharides to provide the needed sites and structures for attachment to the rotavirus.
  • receptor molecules include glycosylcholine epitopes or analogs thereof
  • receptor molecules can be further modified in an attempt to improve the binding affinity of the rotavirus to the receptor. This can be done by incorporating a second beta-D-GalNAC (in the case of asialo GM2) and a second beta- D-Gall-->3-beta-D-GalNAc (in the case of GM1) on the free secondary hydroxyl.
  • This type of addition is carried out by a mechanism in which suitable protected D-threitol or any other polyol with appropriately oriented hydroxyls is used as the acceptor in combination with a suitable glycosyl donor. The reaction scheme necessary in order to carry out such an addition is shown below in Reaction Scheme III.
  • the polyolic moiety could be D-iditol.
  • the D-iditol molecule provides different optical centers (D- and L-) at the C2 and C5. These optical centers can be O-glycosylated with GalNAC or beta-Gall-->3 GalNAc.
  • a reaction scheme for this procedure is shown below as Reaction Scheme IV.
  • the iditol can be obtained commercially or can be prepared from D-mannitol as shown above within Reaction Scheme IV.
  • the D- galactitol would offer the same optical centers at C2 and C5 as shown below within Reaction Scheme V.
  • Assays can be carried out on the compounds 5 and 13 shown above to determine their ability to act as receptors with respect to a rotavirus. Reactions can also be carried out on the newly formed C5-OH moieties 5 and 13 shown
  • FIGURE 4 Possible Micalte rstructure of a compound like
  • the compounds of the invention such as various carbohydrates or more specifically oligosaccharide epitopes and analogs thereof can be administered to a subject either prophylactically or after rotaviral infection.
  • inventive synthetic receptor molecules are administered with a
  • pharmaceutically acceptable carrier the nature of the carrier differing with the mode of administration, for example, oral administration, usually using a solid carrier and I.V. administration a liquid salt solution carrier.
  • the method of choice can be accomplished using a variety of excipients including, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium, stearate, sodium saccharin cellulose, magnesium carbonate, and the like.
  • These oral compositions may be taken in the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations, or powders.
  • Particularly useful is the administration of the subject carbohydrate receptor molecules directly in infant nutrient formulae or rehydration formulae, given to replenish electrolytes lost in severe bouts of diarrhea.
  • the receptor molecules of the invention can be administered orally, linked to supports such as beads, resins, or natural or synthetic polymers. Methods for binding substances to such supports are well known in the art.
  • the receptor compounds may also be administered in small lipid particles comprising these receptor molecules, such as in vesicles, micelles, or liposomes.
  • a sufficient amount of receptor molecules should be administered to bind to a substantial portion of the
  • rotavirus expected to cause or actually causing infection so that infection can either be prevented or ameliorated.
  • the oral compositions of the instant invention will contain from less than 1% to about 95% of the active ingredient, preferably about 10% to about 50%. Preferably, between about 12 ug and 1.2 mg will be administered to a child and between about 200 ug and 10 mg will be administered to an adult. The frequency of administration will be
  • rotavirus receptor molecules of the invention can be formulated in suppositories and, in some cases, aerosol and intranasal
  • the vehicle composition will include traditional binders and carriers such as, polyalkylene glycols, or triglycerides.
  • binders and carriers such as, polyalkylene glycols, or triglycerides.
  • Such suppositories may be formed from mixtures containing the active ingredient in the range of about 0.5% to about 10% (w/w), preferably about 1% to about 2%.
  • Intranasal formulations will usually include vehicles that neither cause irritation to the nasal mucosa nor significantly disturb ciliary function.
  • Diluents such as water, aqueous saline or other known substances can be employed with the subject invention.
  • the nasal formulations may also contain preservatives such as, but not limited to, chlorobutanol and benzalkonium chloride.
  • a surfactant may be present to enhance absorption of the subject proteins by the nasal mucosa.
  • the receptor molecules of the instant invention may also be administered as injectables.
  • injectable compositions are prepared as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection may also be prepared.
  • the preparation may also be emulsified or the active ingredient encapsulated in liposome vehicles.
  • the receptors in the form of glycolipids and carbohydrates or more specifically
  • oligosaccharides can be mixed with compatible, pharmaceutically acceptable excipients.
  • Suitable vehicles are, for example, water, saline, dextrose, glycerol, ethanol, or the like, and combinations thereof.
  • the vehicle may contain minor amounts of auxiliary substances such as wetting or emulsifying agents or pH buffering agents.
  • auxiliary substances such as wetting or emulsifying agents or pH buffering agents.
  • formulation to be administered will, in any event, contain a quantity of the receptor molecules adequate to achieve the desired state in the subject being treated.
  • the various receptor compounds of the present invention can be used by themselves or in combination with pharmaceutically acceptable excipient materials as described above. However, it is more preferable to use the receptor compounds of the invention as conjugates wherein the
  • the compounds of the invention are linked in some manner to an antiviral drug.
  • the receptor compounds of the invention act as biochemical delivery systems for the antiviral drugs .
  • many antiviral drugs are extremely toxic. Accordingly, it is desirable to provide such drugs to a patient in extremely small amounts. The smaller the amount of the drug delivered, the less toxic affects. However, the decrease in toxic affects must be balanced against the need to provide sufficient amounts of the drug in order to sufficiently destroy the virus.
  • the receptor compounds of the invention aid in solving the problem by providing the biochemical delivery system. By forming conjugates of the receptor molecules of the invention with antiviral drugs, the conjugates readily attach to the viruses and destroy them. Thereby, smaller amounts of the antiviral drug need be delivered to a patient to obtain efficatious results.
  • the receptor molecules of the invention could also be used as laboratory probes to test for the presence of a rotavirus in a sample. Such probes are preferably labeled such as with a radioactive label.
  • Rotavirus SA11 for use in the following experiment can be grown in and isolated from MA104 cells, available from Whittaker Bioproducts, Walkersville MD., using previously described methods. See, e.g. Yolken et al., J. Clin. Invest. 79: 148-154 (1987) and Kabcenell et al., J. Virol. 62: 2929 (1988), the disclosures of which are incorporated herein by reference in their entirety.
  • the virus can be iodinated using solid state iodobeads as reagent as described by
  • Autoradiography can be used to determine if the molecules bind rotavirus, and whether they bind to a higher degree than asialo GM1 which normally binds virus if present in 50 pmoles in a 2 mm streak.
  • the location of glycolipids on a plate can be detected by treatment with iodine before probing, or by spraying with orcinal after probing.
  • the above binding assay can be used for testing cleaved or synthesized sugar moieties and derivatives thereof after their attachment to lipids by means well known in the art of neoglycolipid synthesis.
  • the Ten Feizi method can be used whereby oligosaccharides are attached to phosphatidylethanolamine by reductive amination to make neoglycolipids.
  • rotavirus can be tested by synthesizing the neoglycolipid form of a saccharide and using the following technique.
  • neoglycolipid form to be tested are first adsorbed to PVC wells by evaporating the compound be tested out of
  • test lipid lipid-containing compound being tested should then be diluted with an equal volume of water to give stock solutions between 0 and 20 uM of test lipid.
  • the PVC 96 well microtiter plates Prior to use, the PVC 96 well microtiter plates should be washed by immersion and agitation in n-butanol for 30 minutes, rinsed in absolute ethanol and air dried. 50 ul of test solution should be added to the microtiter wells to yield between 0 and 1 nmole of test lipid with 130 pmoles each of phosphatidyl choline and cholesterol.
  • the PVC plates should be allowed to stand at room temperature for 80 minutes or just before the meniscus of the solution contacts the well bottom. Microtiter plates should then be washed three times with water and stored with water in each well until probed with labeled virus.
  • the putative receptor compounds can be probed as follows: 125 I-Rotavirus is to be diluted in complete PBS supplemented with 10 mg/ml BSA (Fraction V), pH 7.4, to give approximately 20,000 cpm/100ul. This volume should be added to each microtiter well and the plates incubated at 4°C. for 3 hours with gentle agitation. Following incubation, plates are to be washed three times with ice cold PBS to remove unbound virus. The bottom half of each well should then be clipped off and placed in vials for measurement of bound radioactivity. This procedure will indicate if the tested compound demonstrates the ability to bind rotavirus.
  • Soluble rotavirus binding substances can also be tested (for their ability to inhibit binding to an immobilized glycolipid) with this technique by first adding the putative rotavirus binders to microtiter wells in 50 ul volumes of PBS-BSA at twice the desired final concentration. Labeled rotavirus should then be added to the wells at approximately 20,000 cpm/50 ul and the radioactivity in the wells determined as above.
  • SA11 rotavirus (at 100 pfu) is to be incubated for 1 hr. with the compounds to be tested.
  • the monitor is to be added to 6 well plates containing confluent MA104 cells. The cells are to be incubated for one hour at 37°C, the inoculum removed and the cells washed once with EBSS medium. The cells are then to be overlaid with 3 mis of medium containing 0.7% agarose and the compounds to be tested.
  • inhibitors such as ovalbumin and bovine submaxillary mucin and substances known not to inhibit rotavirus, such as globoside and trihexosyl ceramide, can be added as positive and negative controls, respectively. After the overlay gels, the plates are to be incubated for 48 hours and the number of plaques counted.

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Abstract

On décrit des molécules qui sont actives comme sites de récepteurs de rotavirus. On obtient synthétiquement ces molécules à partir de dérivés de sucre qui possèdent une grandeur minimum reconnue par l'antirécepteur d'un rotavirus. Les molécules sont utiles pour l'étude de l'interaction entre l'antirécepteur et la plupart des sites de récepteur afin de développer des médicamments utiles pour le blocage de la connexion entre de tels virus et les cellules hôtes. De plus, on peut modifier les molécules de façon à augmenter le degré auquel elles attirent les sites antirécepteurs du virus et/ou les modifier en faisant fixer à celles-ci de composés antiviraux qui sont efficaces quant à la destruction du virus une fois que la molécule réceptrice se lie au virus. On peut obtenir des molécules réceptrices synthétiques reconnaissables à l'aide d'un rotavirus par la modification des sites hydroxyles de N-acétyle-D-galactosamine (GaLNAc) dans la proximité immédiate de la liaison glycosidique du GalNac. On enseigne des modifications semblables à d'autres résidus de sucre afin d'obtenir des molécules réceptrices synthétiques similaires qui sont reconnaissables à l'aide d'un rotavirus comme récepteur.
PCT/US1990/007120 1989-12-13 1990-12-05 Molecules receptrices synthetiques reconnaissables a l'aide d'un rotavirus WO1991008747A1 (fr)

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US45002689A 1989-12-13 1989-12-13
US450,026 1989-12-13
US55400590A 1990-07-17 1990-07-17
US554,005 1990-07-17
US56668890A 1990-08-13 1990-08-13
US566,688 1990-08-13

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997033896A1 (fr) * 1996-03-15 1997-09-18 Geltex Pharmaceuticals, Inc. Polymeres polyvalents pour le traitement d'infections dues au rotavirus
WO1998012203A1 (fr) * 1996-09-20 1998-03-26 Geltex Pharmaceuticals, Inc. Saccharides fonctionnalises par un acide utilises en tant qu'agents anti-infectieux polyvalents

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4341763A (en) * 1981-03-10 1982-07-27 Smithkline-Rit Methods of vaccinating humans against rotavirus infection
JPS58154513A (ja) * 1982-03-09 1983-09-14 Sendai Biseibutsu Kenkyusho 予防及び治療薬
US4464360A (en) * 1980-05-09 1984-08-07 Hakon Leffler Glycosphingalipids for inhibiting bacterial adherence
US4657849A (en) * 1980-03-05 1987-04-14 Svenska Sockerfabriks Ab Compositions and methods useful for uropathogenic bacterial identification or diagnosis and inhibition of adherence of uropathogenic bacteria to cells having a structural element similar to that of the active principle of the invention
US4665060A (en) * 1982-03-22 1987-05-12 Biocarb Ab Therapeutic treatment employing oligosaccharides
US4831021A (en) * 1983-07-21 1989-05-16 Burroughs Wellcome Co. Ganglioside derivatives
US4859769A (en) * 1985-01-14 1989-08-22 Symbicom Ab Antiviral agents
US4918009A (en) * 1985-12-11 1990-04-17 Svenska Sockerfabriks Ab Method of controlling the regioselectivity of glycosidic bonds

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4657849A (en) * 1980-03-05 1987-04-14 Svenska Sockerfabriks Ab Compositions and methods useful for uropathogenic bacterial identification or diagnosis and inhibition of adherence of uropathogenic bacteria to cells having a structural element similar to that of the active principle of the invention
US4464360A (en) * 1980-05-09 1984-08-07 Hakon Leffler Glycosphingalipids for inhibiting bacterial adherence
US4341763A (en) * 1981-03-10 1982-07-27 Smithkline-Rit Methods of vaccinating humans against rotavirus infection
JPS58154513A (ja) * 1982-03-09 1983-09-14 Sendai Biseibutsu Kenkyusho 予防及び治療薬
US4665060A (en) * 1982-03-22 1987-05-12 Biocarb Ab Therapeutic treatment employing oligosaccharides
US4831021A (en) * 1983-07-21 1989-05-16 Burroughs Wellcome Co. Ganglioside derivatives
US4859769A (en) * 1985-01-14 1989-08-22 Symbicom Ab Antiviral agents
US4918009A (en) * 1985-12-11 1990-04-17 Svenska Sockerfabriks Ab Method of controlling the regioselectivity of glycosidic bonds

Non-Patent Citations (15)

* Cited by examiner, † Cited by third party
Title
CARBOHYDRATE RESEARCH, Volume 138, issued 1985, DAHMEN et al., "Synthesis of Di-Tri-, and Tetra-Saccharides Corresponding to Receptor Structure Pnenmoniae", pages 17-28. *
CARBOHYDRATE RESEARCH, Volume 167, issued 1987, S. SATO et al., "Total Synthesis of X Hapten, III3 Fuc-Alpha-nLc4Cer", pages 197-210. *
CHEMICAL ABSTRACTS, Volume 104, 223817p, issued 1986, OTNAESS et al., "Studies on Nonimmunoglobulin Inhibitory Activity in Human Milk Against E.Coli Heat-Labile Enterotoxin, Rotavirus, and Respiratory Syncytial Virus", pages 520-521; & NESTLE NUTR. WORKSHOP SER., 5, (Hum. Milk Banking), 85-92, see pages 520-521. *
INFECTION AND IMMUNITY, Volume 14, Number 2, issued August 1976, C.A. MEBUS et al., "Diarrhea in Gnotobiotic Calves caused by the Reovirus-Like Agent of Human Infantile Gastroenteritis", pages 471-474. *
INFECTION AND IMMUNITY, Volume 14, Number 3, issued September 1976, J.G. LECCE et al., "Reovirus-Like Agent Association with Fetal Diarrhea in Neonatal Pigs", pages 816-825. *
INFECTION AND IMMUNITY, Volume 29, Number 3, issued September 1980, J.W. BASTARDO et al., "Attachment of SA-11 Rotavirus to Erythrocyte Receptors", pages 1134-1140. *
JOURNAL OF CLINICAL INVESTIGATION, Volume 79, issued January 1987, R.H. YOLKEN et al., "Sialic Acid Glycoproteins Inhibit in Vitro and in Vivo Replication of Rotaviruses", pages 148-154. *
JOURNAL OF GENERAL VIROLOGY, Volume 68, issued 1987, M. SABARA et al., "Biochemical Evidence for the Oligomeric Arrangement of Bovine Rotavirus Nucleocapsid Protein and its Possible Significance in the Immunogenicity of this Protein", pages 123-133. *
JOURNAL OF VIROLOGY, Volume 53, Number 1, issued January 1985, M. SABARA et al., "Preliminary Characterization of an Epitope Involved in Neutralization and Cell Attachment that is Located on the Major Bovine Rotavirus Glycoprotein", pages 58-66. *
JOURNAL OF VIROLOGY, Volume 63, Number 11, issued November 1989, K.S. AU et al., "Receptor Activity of Rotavirus Nonstructural Glycoprotein NS28", pages 4553-4562. *
JOURNAL OF VIROLOGY, Volume 64, Number 10, issued October 1990, R.E. WILLOUGHBY et al., "Rotaviruses Specifically Bind to the Neutral Glycosphinogolipid Asialo-GM1", pages 4830-4835. *
PROCEEDINGS OF U.S.-JAPAN INTERNATIONAL ROTAVIRUS MEETING; issued August 1989, (ANNAPOLIS, MD), WILLOUGHBY et al., "Rotaviruses Bind Specifically to the Neutral Glycolipid Asialo-GM1". *
SCIENCE, Volume 207, issued 11 January 1980, R.G. WYATT et al., "Human Rotavirus Type 2: Cultivation in Vitro", pages 189-191. *
THE EMBO JOURNAL, Volume 8, Number 6, issued 1989, C.C. BERGMANN et al., "Topology of the Non-Structural Rotavirus Receptor Glycoprotein NS28 in the Rough Endoplasmic Reticulum", pages 1695-1703. *
VIROLOGY, Volume 171, issued 1989, K. NISHIKAWA et al., "Rotavirus VP7 Neutralization Epitopes of Serotype 3 Strains", pages 503-515. *

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* Cited by examiner, † Cited by third party
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WO1997033896A1 (fr) * 1996-03-15 1997-09-18 Geltex Pharmaceuticals, Inc. Polymeres polyvalents pour le traitement d'infections dues au rotavirus
US5891862A (en) * 1996-03-15 1999-04-06 Geltex Pharmaceuticals, Inc. Polyvalent polymers for the treatment of rotavirus infection
US6187762B1 (en) 1996-03-15 2001-02-13 Geltex Pharmaceuticals, Inc. Polyvalent polymers for the treatment of rotavirus infection
WO1998012203A1 (fr) * 1996-09-20 1998-03-26 Geltex Pharmaceuticals, Inc. Saccharides fonctionnalises par un acide utilises en tant qu'agents anti-infectieux polyvalents
US5821312A (en) * 1996-09-20 1998-10-13 Geltex Pharmaceuticals, Inc. Acid-functionalized saccharides as polyvalent anti-infectives
US5939537A (en) * 1996-09-20 1999-08-17 Geltex Pharmaceuticals Inc. Acid-functionalized saccharide monomers
US6235720B1 (en) 1996-09-20 2001-05-22 Geltex Pharmaceuticals, Inc. Acid-functionalized saccharide polymers

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