Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-04-05
2001-02-13
Peselve, Elli (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S023000, C514S024000, C514S025000
Reexamination Certificate
active
06187762
ABSTRACT:
BACKGROUND OF THE INVENTION
Human rotavirus infection is a major cause of severe diarrhea in infants and young children, afflicting virtually every child at some point in the first several years of life (Glass et al.,
Science
265: 1389-1391 (1994)). The situation is particularly acute in developing countries, where rotavirus infection is responsible for 20-40% of hospitalizations for childhood diarrhea and an estimated 870,000 deaths. (Blacklow et al.,
New England J. Med
. 325: 252-264 (1991); LeBaron et al.,
J. Am. Med. Assoc
. 264: 983-988 (1990)).
Current methods for treating rotavirus infection are limited to rehydration and replacement of lost electrolytes. No methods for preventing or otherwise inhibiting the infection are currently in clinical use.
There is, thus, a need for an agent or agents capable of preventing infection by rotavirus or inhibiting a rotavirus infection.
SUMMARY OF THE INVENTION
The present invention relates to polymers comprising one or more fucoside moieties which can inhibit or prevent rotavirus infection in a mammal, monomers which can serve as starting materials in the synthesis of such polymers, and methods of use of such polymers in the treatment of rotavirus infection in a mammal.
The monomers of the present invention include polymerizable monomers comprising a fucoside moiety. In one embodiment, the monomer has a polymerizable functional group, such as an olefinic bond, to which the fucoside moiety is attached by a spacer group, for example, an alkylene group, or an alkylene group wherein one or more carbon atoms are substituted by heteroatoms, such as oxygen, nitrogen or sulfuir atoms.
The polymers of the present invention comprise fucoside moieties, such as pendant fucoside moieties. Such a polymer can be a homopolymer or a copolymer, and can have, for example, a polyacrylarnide, polyacrylate or polystyrene backbone. In one embodiment, the polymer is a copolymer comprising a fucoside-bearing monomer and acrylamide. In one embodiment, the polymers of the present invention include copolymers which comprise a glycoside-bearing monomer, a hydrophobic monomer and, optionally, one or more additional monomers, such as neutral hydrophilic monomers. Also included are copolymers which comprise two or more glycoside-bearing monomers, and, optionally, a neutral hydrophilic monomer.
In another embodiment, the present invention includes a method for treating a rotavirus infection in a mammal, for example, a human, by administering to the mammal a therapeutically effective amount of a polymer comprising one or more glycoside moieties, such as pendant glycoside moieties. The glycoside moieties can be, for example, fucoside moieties or sialic acid moieties. The polymer can be a homopolymer or a co-polymer. In one embodiment, the polymer is a copolymer comprising a glycoside-bearing monomer and acrylamide.
The present invention offers several advantages. It provides agents and a method for the treatment and prevention of rotavirus infection, of which there were previously none. In addition the fucoside-bearing polymers incorporate a relatively simple and inexpensive sugar.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is based on the discovery that polymers comprising pendant glycoside, particularly fucoside, moieties can interfere with the attachment of rotavirus to target cells, such as cells lining the intestinal lumen. It has been reported that glycoproteins containing sialic acid groups inhibit rotavirus infection in vitro and in vivo (Yolkin et al.,
J. Clin. Invest
. 79: 148-154 (1987)). These glycoproteins are isolated in small quantities, are poorly characterized, and are, therefore, not suitable as agents for the treatment of rotavirus infection. The invention relates to the incorporation of sialic acid, fucose and other related sugars into the side chains of synthetic polymers. This provides polymers with many potential sites of interaction with the virus, thereby binding tightly to the virus via a multiplicity of interactions, referred to herein as the “polyvalent effect” (Matrosovich,
FEBS Letters
252: 1-4 (1989)).
One aspect of the present invention includes a polymer comprising one or more fucoside moieties, preferably pendant fucoside moieties. The term “pendant”, as used herein, refers to a structural component of one or more polymer side chains which is not a part of the polymer backbone. Therefore, polymers of the present invention comprise side chains to which are attached fucoside moieties.
The term “monomer”, as used herein, refers to both a molecule comprising one or more polymerizable functional groups prior to polymerization, and a repeating unit of a polymer. A copolymer is said to comprise two or more different monomers. A “fucoside-bearing monomer” is a monomer, either polymerized or unpolymerized, which comprises a fucoside moiety. Upon incorporation into a polymer, a facoside-bearing monomer comprises a pendant fucoside moiety.
The term “glycoside”, as used herein, is intended to refer to a carbohydrate residue, such as a residue obtained by removal of a hydrogen atom, for example, a hydroxyl hydrogen atom, from a pyranose or a furanose. Usually, a glycoside is formed by removal of a hydrogen atom from a hydroxyl group bonded to the anomeric carbon of a pyranose or a furanose. The term as used herein, however, also encompasses other types of sugar residues, such as the galactosamino moiety, which is derived from galactosamine by removal of a hydrogen atom of the amino group.
The present invention includes monomers which are starting materials in the synthesis of polymers comprising one or more fucoside moieties. Such a monomer comprises a fucoside moiety linked at the anomeric carbon to a spacer group via an atom, which can be, for example, a carbon atom, or a heteroatom, such as an oxygen, nitrogen or sulfur atom. In a preferred embodiment, the monomer is of Formula I,
wherein X is a spacer group and can be a straight chain or branched, substituted or unsubstituted alkylene group, wherein, optionally, one or more carbon atoms are substituted by a heteroatom, such as an oxygen, nitrogen or sulfur atom. Examples include a —(CH
2
)
n
— group, wherein n is an integer from about 2 to about 12, a substituted alkylene group, an oxaalkylene group, such as —(CH
2
)
2
O[(CH
2
)
2
O]
n
(CH
2
)
2
—, wherein n is an integer, or a thiaalkylene group, such as —(CH
2
)
n
S(CH
2
)
m
—, where n and m are each an integer. The fucoside moiety can be an &agr;- or &bgr;-L-fucoside or an &agr;- or &bgr;-D-fucoside moiety. This is indicated by the wavy line connecting Y to the sugar moiety in Formula I, which allows for either anomer. The spacer group is attached to the fucoside moiety via Y, which is, for example, a CH
2
or NH group, or an oxygen or sulfur atom, and is bonded to the anomeric carbon atom of the fucoside moiety. The spacer group is attached to the polymerizable unit via Z, which can be, for example, an oxygen atom, a phenylene group, an amidocarbonyl group, an oxycarbonyl group, an amino group or an aminomethylene group. The polymerizable unit can be, for example, an olefinic bond. R is a hydrogen atom or a methyl or ethyl group, and x, y, and z are each, individually, 0 or 1.
Additional examples of fucoside-bearing monomers of the present invention are of Formula II and Formula III, shown below. In Formula II, X is a spacer group, such as a straight chain or branched, substituted or unsubstituted alkylene group, wherein, optionally, one or more carbon atoms are substituted by a heteroatom, such as an oxygen, nitrogen or sulfur atom. Examples include a polymethylene group, such as —(CH
2
)
n
—, wherein n is an integer from about 2 to about 12, an oxaalkylene group, such as —(CH
2
)
2
O[(CH
2
)
2
O]
n
(CH
2
)
2
—, wherein n is an integer, or a thiaalkylene group, such as —(CH
2
)
n
S(CH
2
)
m
—, where n and m are each an integer. R in Formulas II and III can be a hydrogen atom or a methyl or ethyl group.
The invention also comprises fucoside-bearing monomers, wherein the fucoside moiety is at
Garigapati Venkata R.
Mandeville, III W. Harry
Neenan Thomas X.
Petersen John S.
GelTex Pharmaceuticals Inc.
Hamilton Brook Smith & Reynolds P.C.
Peselve Elli
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