Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-08-06
2001-08-14
Gitomer, Ralph (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S008100, C514S002600, C536S053000, C536S055200, C435S007100
Reexamination Certificate
active
06274568
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to compounds for altering cell surface sialic acids and methods of using such compunds for modulating cellular lectin interactions with a glycoconjugate. The invention further relates to the use of such compounds for modulating cell growth.
BACKGROUND OF THE INVENTION
Lectins are proteins or glycoproteins that bind to sugar residues present in a glycoconjugate. The biological functions of lectins are based primarily on their capacity to recognize and target particular glycoconjugates. Lectins are candidates for attachment and recognition at cellular membranes as the sugar portions of glycoproteins and glycolipids are exposed at the outer surface of the protein-lipid bilayers that constitute these membranes. Various phenomena of cell—cell recognition are attributed to lectin-sugar interactions including mitogenic stimulation, pathogen attachment to a cell surface and immunologic stimulation.
Myelin associated glycoprotein (MAG) (Mukhopadhyay, et al.
Neuron
13:757, 1994; McKerracher, et al.
Neuron
13:805, 1994) is a sialic acid binding lectin and a member of the “siglec” family of immunoglobulin-like lectins (Crocker et al,
Glycobiology,
8, 1998; Kelm et al.,
Eur.J.Biochem.
255:663, 1998). In the nervous system, MAG functions in the stabilization of the myelin sheath surrounding axons (Lassmann et al.,
Glia
19:104, 1997; Sheikh et al.,
Proc. Natl. Acad. Sci. U.S.A.
96:7532, 1999), and in the control of axon cytoarchitecture (Yin et al.,
J. Neurosci.
18:1953, 1998).
A feature of axons in the peripheral nerves of adult mammals is that after interruption, they are able to regenerate through the distal nerve stump to reconnect with their targets and re-establish function. The same is not true however in the central nervous system (CNS). Axons injured in the brain, optic nerve or spinal cord of adult mammals do not successfully regrow. This leads to an irreversible disruption of neuronal circuits and permanent neurologic disability.
An increasing number of molecules regulating the growth of neuronal processes are being identified. Of considerable interest is the finding that the nervous system contains molecules which function to inhibit or restrict axonal growth. MAG recognition of sialoglycoconjugate targets on the surface of neuronal cells has been implicated in MAG inhibition of nerve regeneration (e.g. spinal cord) following injury (McKerracher et al.,
Neuron
13, 805, 1994; Mukhopadhyay et al.,
Neuron,
12:757, 1994; Schnaar et al.,
Ann. N.Y. Acad. Sci.
845:92, 1998). Sialic acids, a substituent of sialoglycoconjugates, are prominent termini of mammalian glycoconjugates and are binding determinants for cell—cell recognition lectins. Binding of the sialic acid-dependent lectin, myelin-associated glycoprotein (MAG), to nerve cells is implicated in the inhibition of nerve regeneration after injury. Sialic acids differ from other mammalian monosaccharides in their complexity, bearing a carboxylic acid group, an N-acyl substituent, and an exocyclic glycerol side chain (Varki,
Glycobiology
2:25, 1992; Schauer,
Adv. Carbohydr. Chem. Biochem.
40:131, 1982). Variety in sialic acid linkages as well as N- and O-acyl substituents results in a large number of unique structural determinants. Cell—cell recognition proteins, as well as pathogens and toxins, take advantage of the structural diversity and cell surface disposition of sialic acids for highly specific recognition and binding (McEver,
Glycoconj. J.
14:585, 1997; Varki,
FASEB J.
11:248, 1997; Kelm et al.,
Glycoconj.J.,
13:913, 1996; Miller-Podraza et al.,
Glycoconj.J.
14:467, 1997).
N-acetylneuraminic acid (NeuAc), the predominant sialic acid in nature, is synthesized in vivo by a multi step pathway (Roseman,
Chem. Phys. Lipids,
5:270, 1970) beginning with the conversion of N-acetylglucosamine to N-acetylmannosamine-6-phosphate by a bifunctional epimerase/kinase (Hinderlich et al.,
J. Biol. Chem.,
272:24313, 1997; Kundig et al.,
J. Biol. Chem.
241:5619, 1966). ManNAc-6-P is converted to NeuAc-9-P by condensation with phosphoenol pyruvate, and then to CMP-NeuAc which is the activated NeuAc donor for glycolipid and glycoprotein oligosaccharide biosynthesis (Watson et al.,
J. Biol. Chem.
241:5627, 1966; Kean and Roseman,
J. Biol. Chem.,
241:5643, 1966). Hydroxylation of NeuAc (in the CMP-NeuAc form) by a specific hyroxylase converts NeuAc to N-glycolylneuraminic acid (NeuGc), a member of the sialic acid family which is rare (or absent) in humans, but is common in non-neural tissues of many other species (Kawano et al.,
J. Biol. Chem.,
270:16458, 1995; Chou et al.,
Proc. Natl. Acad. Sci. U.S.A.
95:11751, 1998). However, this pathway can be short-circuited by addition of unnatural N-acylmannosamines, including N-propanoyl-, N-butanoyl-, N-pentanoyl-, and N-levulinoylmannosamine, among others (Angelino et al.,
Carbohydr. Res.,
276:99, 1995; Yarema et al.,
J. Biol. Chem.
273:31168, 1998). These precursors are taken up, converted to the corresponding sialic acids, and expressed on cell surface glycoconjugates.
Recently, it was reported that certain sialoglycoconjugates bearing N-acetylneuraminic acid (NeuAc) but not N-glycolylneuraminic acid (NeuGc) support MAG binding (Collins et al.,
J. Biol. Chem.
272:1248, 1997). Given the sensitivity of MAG binding to changes in sialic acid substructure, it would be desirable to develop biosynthetic precursors which would result in modification of a large proportion of the nerve cell sialic acid, rendering the cells resistant to the growth inhibitory effects of MAG binding. Knowledge of such precursors would form a basis for developing drug therapies which interfere with MAG's inhibitory effects, thus enhancing regeneration of nerves. The present invention provides compounds to address these needs, and provides improved methods for treating nerve injury.
SUMMARY OF THE INVENTION
The present invention is based on the discovery of a novel compound associated with cell—cell and cell-molecule interactions. The invention provides novel compounds, and methods of using such compounds, for modulating a cell surface sialoglycoconjugate. The compounds of the invention can be used as biosynthetic precursors for altering the response of a cell to a lectin, a pathogenic microbe or an immune system cell. Thus, the present invention provides a means for modulating a cell surface sialoglycoconjugate such that its recognition by a molecule or cell is altered.
It is an object of the present invention to provide a compound effective in modulating a cell surface sialoglycoconjugate. In accordance with one aspect of the present invention, an acylated mannosamine compound is provided.
In accordance with another aspect of the invention a method for modulating lectin binding to a cell surface by contacting a cell with a acylated mannosamine is provided.
In another aspect, the invention provides a method for modulating neuronal cell growth by contacting the cell with a therapeutically effective amount of a composition containing a acylated mannosamine.
In yet another aspect, the invention provides a method for the treatment of a lectin-mediated cell disorder by administering to a subject a therapeutically effective amount of a compound containing an acylated N-mannosamine, or a pharmaceutical composition thereof.
In another aspect, the invention provides a method for ameliorating a neuronal-associated disorder in a subject by administering to the subject having such a disorder, a therapeutically effective amount of a composition containing a acylated mannosamine.
In accordance with another aspect of the invention, a method is provided for ameliorating a lectin-mediated cell disorder, in a subject having the disorder, by administering to the subject a therapeutically effective amount of a composition which modulates the activity of the lectin associated with the disorder.
In yet another aspect, the invention provides a method of identifying a compound which modulates lectin-mediated inhibition of neuronal cell growth by contacti
Collins Brian E.
Fralich Thomas J.
Ichikawa Yoshitak
Schnaar Ronald L.
Fish & Richardson P.C.
Gitomer Ralph
Khare Devesh
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