Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
2000-08-10
2002-10-22
Kunz, Gary L. (Department: 1647)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S007800, C435S174000, C514S002600
Reexamination Certificate
active
06468755
ABSTRACT:
The present invention is based, in part, on the discovery that aspirin reverses insulin resistance in liver and fat cells, e.g., by targeting IKK-&bgr;. Thus, IKK-&bgr; was discovered as a target for identifying compounds for the treatment of disorders associated with insulin resistance.
Accordingly, in one aspect, the invention features a method of identifying, evaluating or making a compound or agent, e.g., a candidate compound or agent, for treatment of a disorder characterized by insulin resistance. The method includes evaluating the ability of a compound or agent to interact with, e.g., bind, IKK-&bgr;, to thereby identify a compound or agent for the treatment of a disorder characterized by insulin resistance.
In a preferred embodiment, the disorder is diabetes, e.g., Type I or Type II diabetes, obesity, polycystic ovarian disease or syndrome X.
In a preferred embodiment, the compound is: a polypeptide, e.g., a randomly generated polypeptide which binds IKK-&bgr;; an antibody, e.g., an intrabody or a randomly generated antibody which binds IKK-&bgr;; a small molecule, e.g., a small molecule which binds IKK-&bgr;.
In a preferred embodiment, the method further includes contacting the identified compound with IKK-&bgr;, e.g., purified IKK-&bgr;, to thereby evaluate binding between the compound and IKK-&bgr;.
In a preferred embodiment, the method further includes contacting the identified compound with a cell, e.g., a fat cell or a liver cell, to thereby evaluate the effect of the compound on an IKK-&bgr; activity of the cell. For example, the ability of the compound to modulate, e.g., reduce or reverse, insulin resistance in a cell.
In a preferred embodiment, the method further includes administering the identified compound to a subject to, evaluate the effect of the compound on insulin resistance. In a preferred embodiment, the subject is a mouse (e.g., a NOD mouse, an ob/ob mouse, a db/db mouse) or a rat (e.g., a Zucker fatty rat, a streptozotocin rat).
In another aspect, the invention features a method of identifying a compound or agent for treatment of a disorder characterized by insulin resistance. The method includes contacting IKK-&bgr;, or a cell expressing IKK-&bgr; with a test compound; and determining whether the test compound binds to IKK-&bgr;, to thereby identify a compound.
Methods for identifying a compound or an agent can be performed, for example, using a cell free assay. For example, the IKK-&bgr; can be immobilized to a suitable substrate, e.g., glutathoine sepharose beads or glutathoine derivatized microtiter plates, using a fusion protein which allows for IKK-&bgr; to bind to the substrate, e.g., a glutathoine-S-transferase/IKK-&bgr; fusion protein.
In a preferred embodiment, the ability of a test compound to bind IKK-&bgr; can be determined by detecting the formation of a complex between IKK-&bgr; and the compound. The presence of the compound in complex indicates the ability to bind IKK-&bgr;.
In a preferred embodiment, IKK-&bgr; is further contacted with aspirin.
In another preferred embodiment, a compound is identified using a cell based assay. These methods include identifying a compound based on its ability to modulate, e.g., inhibit, an IKK-&bgr; activity of the cell. For example, the ability of a compound to modulate, e.g., reduce or reverse, insulin resistance in a cell, e.g., a fat cell or a liver cell, can be determined.
In a preferred embodiment, the method further includes contacting the identified compound with IKK-&bgr;, e.g., purified IKK-&bgr;, to thereby evaluate binding between the compound and IKK-&bgr;.
In a preferred embodiment, the method further includes contacting the identified compound with a cell, e.g., a fat cell or a liver cell, to thereby evaluate the effect of the compound on an IKK-&bgr; activity of the cell. For example, the ability of the compound to modulate, e.g., reduce or reverse, insulin resistance in a cell can be evaluated.
In a preferred embodiment, the method further includes administering the identified compound to a subject to evaluate the effect of the compound on insulin resistance. In a preferred embodiment, the subject is a mouse (e.g., a NOD mouse, an ob/ob mouse, a db/db mouse) or a rat (e.g., a Zucker fatty rat, a streptozotocin rat).
In a preferred embodiment, the compound is: a polypeptide, e.g., a randomly generated polypeptide which interacts with, e.g., binds, IKK-&bgr;; an antibody, e.g., an intrabody or a randomly generated antibody which interacts with IKK-&bgr;; a small molecule, e.g., a small molecule which interacts with IKK-&bgr;.
In a preferred embodiment, the compound is a compound other than aspirin.
In a preferred embodiment, the disorder is diabetes, e.g., Type I or Type II diabetes, obesity, polycystic ovarian disease or syndrome X.
In another aspect, the invention features a method of identifying a compound or agent for treatment of diabetes, e.g., Type I or Type II diabetes. The method includes contacting IKK-&bgr;, or a cell expressing IKK-&bgr; with a test compound; and determining whether the test compound binds to IKK-&bgr;, to thereby identify a compound for treatment of diabetes.
Methods for identifying a compound or an agent can be performed, for example, using a cell free assay. For example, the IKK-&bgr; can be immobilized to a suitable substrate, e.g., glutathoine sepharose beads or glutathoine derivatized microtiter plates, using a fusion protein which allows for IKK-&bgr; to bind to the substrate, e.g., a glutathoine-S-transferase/IKK-&bgr; fusion protein.
In a preferred embodiment, the ability of a test compound to bind IKK-&bgr; can be determined by detecting the formation of a complex between IKK-&bgr; and the compound. The presence of the compound in complex indicates the ability to bind IKK-&bgr;.
In a preferred embodiment, IKK-&bgr; is further contacted with aspirin.
In another preferred embodiment, a compound is identified using a cell based assay. These methods include identifying a compound based on its ability to modulate, e.g., inhibit, an IKK-&bgr; activity of the cell. For example, the ability of a compound to modulate, e.g., reduce or reverse, insulin resistance in a cell, e.g., a fat cell or a liver cell, can be determined.
In a preferred embodiment, the method further includes contacting the identified compound with IKK-&bgr;, e.g., purified IKK-&bgr;, to thereby evaluate binding between the compound and IKK-&bgr;.
In a preferred embodiment, the method further includes contacting the identified compound with a cell, e.g., a fat cell or a liver cell, to thereby evaluate the effect of the compound on an IKK-&bgr; activity of the cell. For example, the ability of the compound to modulate, e.g., reduce or reverse, insulin resistance in a cell.
In a preferred embodiment, the method further includes administering the identified compound to a subject to evaluate the effect of the compound on insulin resistance. In a preferred embodiment, the subject is a mouse (e.g., a NOD mouse, an ob/ob mouse, a db/db mouse) or a rat (e.g., a Zucker fatty rat, a streptozotocin rat).
In a preferred embodiment, the compound is: a polypeptide, e.g., a randomly generated polypeptide which interacts with, e.g., binds, IKK-&bgr;; an antibody, e.g., an intrabody or a randomly generated antibody which interacts with IKK-&bgr;; a small molecule, e.g., a small molecule which interacts with IKK-&bgr;.
In a preferred embodiment, the compound is a compound other than aspirin.
In another aspect, the invention features a method of treating a subject having a disorder characterized by insulin resistance. The method includes: administering a compound or agent which interacts with, e.g., binds, IKK-&bgr;, to thereby treat the disorder.
In a preferred embodiment, the disorder is diabetes, e.g., Type I or Type II diabetes, obesity, polycystic ovarian disease or syndrome X.
In a preferred embodiment, the compound is: a compound other than aspirin; a polypeptide, e.g., a randomly generated polypeptide which interacts with IKK-&bgr;; an antibody, e.g., an intrabody or a randomly generated antibody
DeBerry Regina M.
Fish & Richardson PC
Joslin Diabetes Center, Inc.
Kunz Gary L.
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