Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2001-03-21
2003-07-08
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S645000, C514S335000
Reexamination Certificate
active
06589995
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the field of medical therapy for diabetes. More specifically, the present invention relates to a new method for preventing and/or treating diabetes.
2. Description of the Related Art
Early in the course of type 2 diabetes, pancreatic &bgr;-cell function is sufficient such that in many patients, oral hypoglycemic agents are adequate for the treatment of the disease. As type 2 diabetes progresses, however, high blood glucose (sugar) concentrations appear to lead to the loss of capacity of the &bgr;-cells in the pancreatic islets to produce sufficient amounts of insulin to control the blood glucose. Thus, a vicious cycle arises wherein high blood glucose destroys &bgr;-cell function leading to even higher blood glucose and worsening of the condition. The mechanism by which glucose may be toxic to &bgr;-cells, however, has remained unknown.
Recent data suggests that glucose shares an important property with streptozotocin (STZ), a diabetogenic toxin that has been used for the past several decades to create animal models of diabetes (1). It has been shown that both high levels of glucose and streptozotocin stimulate O-linked glycosylation of a 135 kD protein present in pancreatic islets called p135 (2). Increased O-glycosylation of p135 causes beta-cell death. This suggests a mechanism for how the high levels of glucose present in the pre-diabetic (or early diabetic) state may cause full-blown diabetes to develop.
The prior art is deficient in the lack of effective means of blocking p135 O-glycosylation specifically, or the O-glycosylation of any other proteins generally. The prior art is also deficient in the lack of an effective means for preventing and/or treating diabetes. The present invention fulfills these long-standing needs and desires in the art.
SUMMARY OF THE INVENTION
The present invention is based on the fact that both glucose and the diabetogenic compound streptozotocin stimulate p135 O-glycosylation in pancreatic islets (2). The present invention shows that it is possible to pharmacologically block this process of O-glycosylation from occurring. The present invention in addition demonstrates the basic molecular structure on an inhibitor of such O-linked protein glycosylation.
In one embodiment of the present invention, there is provided a new method for inhibiting the process of O-linked protein glycosylation wherein the compound (Z)-1-[N-(3-Ammoniopropyl)-N-(n-propyl)amino] diazen-ium-1,2-diolate (Also known as PAPA NONOate or NOC-15) is used to inhibit O-glycosylation.
In another embodiment of the present invention, there is provided a new method for inhibiting p135 O-linked protein glycosylation wherein the compound (Z)-1-[N-(3-Ammoniopropyl)-N-(n-propyl)amino] diazen-ium-1,2-diolate (Also known as PAPA NONOate or NOC-15) is used to inhibit pancreatic beta-cell O-glycosylation.
In another embodiment of the present invention, there is provided a new method for inhibiting streptozotocin-induced pancreatic beta-cell p135 O-linked protein glycosylation wherein the compound (Z)-1-[N-(3-Ammoniopropyl)-N-(n-propyl)amino] diazen-ium-1,2-diolate (Also known as PAPA NONOate or NOC-15) is used.
In another embodiment of the present invention, the molecular structure of the compound (Z)-1-[N-(3-Ammoniopropyl)-N-(n-propyl)amino] diazen-ium-1,2-diolate (Also known as PAPA NONOate or NOC-15) is provided and is shown to be an analog of N-acetylglucosamine, when the latter is drawn in its linear form.
In another embodiment of the present invention, the molecular structure of the compound (Z)-1-[N-(3-Ammoniopropyl)-N-(n-propyl)amino] diazen-ium-1,2-diolate (Also known as PAPA NONOate or NOC-15) is provided and compared to the structures of similar compounds that do not inhibit O-glycosylation, indicating what structural aspects are necessary for inhibition of protein O-glycosylation.
In another embodiment of the present invention, the concept of using NOC-15, NOC-15-related molecules, other structural analogs of N-acetylglucosamine, or other related molecules to inhibit O-linked protein glycosylation is proposed, with the idea that such inhibition will be useful in the prevention and/or treatment of diabetes.
In another embodiment of the present invention, the concept of using NOC-15, NOC-15-related molecules, other structural analogs of N-acetylglucosamine, or other related molecules to inhibit the pancreatic beta-cell enzyme O-linked N-acetylglucosamine transferase (OGT) is proposed, with the idea that such inhibition will be useful in the prevention and/or treatment of diabetes.
In another embodiment of the present invention, the concept of using NOC-15, NOC-15-related molecules, other structural analogs of N-acetylglucosamine, or other related molecules to inhibit O-linked protein glycosylation in tissues other than pancreatic beta-cells is proposed, with the idea that O-glycosylation may be an important pathway in other disease processes and that inhibition of this pathway may be of great clinical utility.
In another embodiment of the present invention, the concept of using NOC-15, NOC-15-related molecules, other structural analogs of N-acetylglucosamine, or other related molecules to inhibit O-linked N-acetylglucosamine transferase (OGT) in tissues other than pancreatic beta-cells is proposed, with the idea that O-glycosylation may be an important pathway in other disease processes and that inhibition of this pathway may be of great clinical utility.
REFERENCES:
patent: 6361995 (2002-03-01), Konrad et al.
patent: 6391895 (2002-05-01), Towart et al.
Haendeler et al., “Effects of redox-related congeners of NO on apoptosis and caspase-3 activity”, Nitric Oxide, 1997, (4) 282-93, Medline Abstract, AN: 1998368273.
Konrad Robert
Kudlow Jeffrey
Adler Benjamin Aaron
Fay Zohreh
Kwon Brian-Yong
UAB Research Foundation
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