Copolymers and preparation thereof

Details Copolymers and preparation thereof Copolymers and preparation thereof

2003-10-29

2004-11-30

Pezzuto, Helen L. (Department: 1713)

Synthetic resins or natural rubbers -- part of the class 520 ser

Synthetic resins

Polymers from only ethylenic monomers or processes of...

C526S217000, C526S219600, C526S234000, C526S264000, C526S288000, C526S291000, C526S303100, C526S304000, C526S307300, C526S317100, C526S328500, C526S347100

Reexamination Certificate

active

06825308

ABSTRACT:

FIELD OF INVENTION
This invention relates to copolymers containing N-Acetyl Glucosamine (NAG) of formula (1) having molecular weight ranging from 1,000 Daltons to 2,00,000 Daltons herein below
wherein,
R is H, CH
3
, C
2
H
5
, C
6
H
5
; R
1
is H, CH
3
, C
2
H
5
, C
6
H
5
; R
2
is H, CH
3
, C
2
H
5
, C
6
H
5
;
X varies between 4-10; m is from 3 to 500; n is from 2 to 50; p is from 2 to 50; L is OH, NH
2
,OCH
3
, NHCH(CH
3
)
2
; and
Y may be N-Acetyl Glucosamine (NAG), mannose, galactose, sialic acid, fructose, ribulose, erythrolose, xylulose, psicose, sorbose, tagatose, glucopyranose, fructofuranose, deoxyribose, galactosamine, sucrose, lactose, isomaltose, maltose, cellobiose, cellulose and amylose.
More particularly it relates to the said copolymers containing carbohydrate ligands and preparation thereof mentioned herein. Still more particularly it relates to copolymers which bind more strongly to lysozyme than NAG itself.
The copolymers of the present invention as mentioned above are prepared by reacting monomer of formula (2) herein below with polymerizable macromer of formula (3) claimed in another copending.
wherein,
R
1
is H, CH
3
, C
2
H
5
, C
6
H
5
, L is OH, NH
2
, OCH
3
and NHCH(CH
3
)
2
wherein,
R is H, CH
3
, C
2
H
5
, C
6
H
5
, R
2
is H, CH
3
, C
2
H
5
, C6H
5.
X may be between 4-10, p is from 2 to 50.
Y may be N-Acetyl Glucosamine (NAG), mannose, galactose, sialic acid, fructose, ribulose, erythrolose, xylulose, psicose, sorbose, tagatose, glucopyranose, fructofuranose, deoxyribose, galactosamine, sucrose, lactose, isomaltose, maltose, cellobiose, cellulose and amylose.
The copolymers may be used for inhibition of viral infections and the recoveries of biomolecules. The approach of synthesis of copolymers with ligand N-Acetyl Glucosamine (NAG) is a generic and can be used for other ligands such as sialic acid, galactose and mannose.
BACKGROUND OF THE INVENTION
Carbohydrates exhibit molecular diversity and wide structural variations, which makes carbohydrates alternative ligands for competitive binding to inhibit the infections. Sharon et al., (Science, 246:227-234,1989) reported carbohydrate portions of glyco-conjugate molecules to be an important entity in biology. One of the major advantage of carbohydrate modification may be that it can impart change in physical characteristics such as solubility, stability, activity, antibody recognition and susceptibility to enzyme.
Carbohydrates can be incorporated in polymer chain and can be utilized for binding to the receptors. Thereby, the polymers can be coupled with the other polymers containing ligands to impart multivalent effect.
Carbohydrates play a crucial role in biological phenomena and therefore such molecules have attracted the attention of chemists and biochemists. These biomolecules are ubiquitous, figuring prominently in various processes such as cell differentiation, cell growth, inflammation, viral and bacterial infection, tumorigenesis and metastasis (Rouhi A.,M., C & EN, September 23,62-66,1996).
Infections caused by bacteria and virus are a result of host receptor interactions. The foremost step for the infection is the adhesion of the ligands present on the infectious microbe to the receptors of the host cells. Adhesion and interactions have to be strong for a successful infection. If the adhesion is not adequate then normal defense mechanism can intercept this process. Viruses and bacteria for example interact with certain saccharides of the host cell. Bacteria express a large number of lectins and are used to adhere to glycocalyx of the host cell through a multivalent interactions. Agglutination of erythrocytes is a case in point.
Many alterations and modifications of the naturally occurring O/N-glycosidic sugars are being reported and is an area of prime interest to the chemist and biochemist. Carbohydrates are usually linked to other moieties such as lipids or proteins. Belvilacqua et al., (Science, 243:1160,1989) have demonstrated the role of carbohydrates along with proteins and nucleic acids as a primary biological information carriers.
Recently few reports have been published to justify the use of carbohydrates in therapeutics for human, as they can play crucial role in prevention of viral and bacterial infections. Krepinsky et al. (U.S. Pat. No. 6,184,368, 2001) suggested the application of carbohydrates in preventing the infections. Mandeville, et al. (U.S Pat. No. 5,891,862,1999) reported the use of polyvalent polymers containing carbohydrates for the treatment of rotavirus infection.
Polyvalent molecules bind to the receptor molecules through multiple contacts, which results in strong binding. However, the synthesis of ligands is critical and involves multiple steps. The polyvalent interactions can be maximized by incorporation of ligands optimally tailored based on the understanding of the binding between the ligand and the host receptor. The enhanced interactions are important especially when the ligands are expensive e.g. sialic acid.
The inventors of the present invention have also observed that interactions can be enhanced by 1) appropriate incorporation of the ligand 2) incorporation of spacer chain and 3) steric stabilization/exclusion using polymers.
Spaltenstein et al., (J.Am.Chem. Soc.,113:686,1991) reported increased interaction between the receptor and ligand due to plurality of binding ligands and the receptors on the host surface. This was illustrated by the influenza virus hemagglutinin, which binds to neuraminic acid on the cell surface, which has a greater affinity for its receptor when a polyvalent structure is presented.
Protein carbohydrate interactions are of low affinity. If relative density and spatial arrangement of ligands incorporated is optimized, then the binding can be substantially enhanced. The enhanced interaction between molecular conjugate with a specific binding site of biomolecule also finds applications in affinity separations, drug delivery and biotechnology.
Design of high affinity protein carbohydrate binding systems can provide an alternative strategy for the treatment of infectious diseases e.g. influenza and rotavirus. This has the advantage as such agents will not have pathogen resistance to antibiotics and drugs. A new approach to treat influenza is based on the principle of inhibition of virus to the host cells. The inhibitors like sialic acid anchored to polymeric or liposomal carriers have been reported in the past.
Since monovalent interactions of natural oligosaccharides are weak, they need to be used in large quantities for an effective treatment. This problem can be overcome by synthesizing polyvalent carbohydrate molecules (Zopf, D., Roth, S. Lancet 347, 1017, 1996). The concept is attractive since it would provide a non-toxic therapeutic to a wide range of human diseases. But synthesis of such compounds is critical and requires knowledge of the host-cell binding mechanism.
Polymeric ligands that bind to the virus more powerfully than the Red Blood Cells will prevent the influenza infection. Similar binding is also involved in rotavirus infections. (Mandeville, et al. U.S. Pat. No. 6,187,762, 2001)
Advantage of carbohydrate modification lies in that it may impart change in physical characteristics such as solubility, stability, activity, antibody recognition and susceptibility to enzyme.
Sigal, et al., demonstrated (J. Am. Chem. Soc. 118:16, 3789-3800,1996) haemagglutination prevention by saccharides multivalent glycoconjugates, which bind to the bacterial lectins and thus inhibit bacterial adhesion. Damschroder et al. (U.S. Pat. No. 2,548,520,1951) demonstrated high molecular weight preformed polymers conjugated with unsaturated monomers or proteins. Synthesis of high molecular weight materials of this kind generally requires temperatures up to 100° C. Such high temperatures are not well tolerated by most of the proteins as they are thermolabile. Thus the methods described are unsuitable for producing polymers of biologically active molecules.
Carbohydrates can be used as functionalized ligands by incorporation into polymer b

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