Dpp-iv resistant gip hybrid polypeptides with selectable properties

Abstract

The present invention relates generally to novel GIP analogs and GIP hybrid polypeptides with selectable properties, useful as agents for the treatment and prevention of metabolic diseases and disorders, for example those which can be alleviated by control plasma glucose levels, insulin levels, and/or insulin secretion, positive inotropic effects, reduction of catabolic effects, slowing of gastric emptying. Such conditions and disorders include, but are not limited to, hypertension, dyslipidemia, cardiovascular disease, eating disorders, critical care, insulin-resistance, obesity, and diabetes mellitus of any kind, including type 1, type 2, and gestational diabetes.

What is claimed is: 
     
         1 . A method to treat or prevent cardiovascular disease or condition in a patient in need thereof comprising, administering to the patient a therapeutically effective amount of a gastric inhibitory polypeptide (GIP) compound,
 wherein
 said GIP compound is a GIP analog, derivative or hybrid polypeptide exhibiting at least one hormonal activity, said polypeptide comprising a first bio-active peptide hormone module covalently linked to at least one additional bio-active peptide hormone module; 
 the bio-active peptide hormone modules are independently selected from the group consisting of: component peptide hormones, fragments of component peptide hormones that exhibit at least one hormonal activity of the component peptide hormones, analogs and derivatives of component peptide hormones that exhibit at least one hormonal activity of the component peptide hormones, fragments of analogs and derivatives of component peptide hormones that exhibit at least one hormonal activity of the component peptide hormones, and peptidic enhancers; 
 the component peptide hormone of the first bio-active peptide hormone module is a GIP modified for resistance to DPP-IV; 
 the component peptide hormone of the at least one additional bio-active peptide hormone modules are independently selected from the group consisting of: amylin, adrenomedullin (ADM), calcitonin (CT), calcitonin gene related peptide (CGRP), intermedin, cholecystokinin (CCK), leptin, peptide YY (PYY), glucagon-like peptide-1 (GLP-I), glucagon-like peptide 2 (GLP-2), oxyntomodulin (OXM), a catestain, a natriuretic peptide, a urocortin family peptide, a neuromedin family peptide, exendin-3, and exendin-4; 
 the peptidic enhancers are independently selected from the group consisting of: structural motifs of component peptide hormones that impart a desired chemical stability, conformational stability, metabolic stability, bioavailability, organ/tissue targeting, receptor interaction, protease inhibition, plasma protein binding, or other pharmacokinetic characteristic to the GIP compound polypeptide, and structural motifs of analogs or derivatives of component peptide hormones that impart a desired chemical stability, conformational stability, metabolic stability, bioavailability, organ/tissue targeting, receptor interaction, protease inhibition, plasma protein binding, or other pharmacokinetic characteristic to the GIP compound polypeptide; and 
 at least one of the bio-active peptide hormone modules exhibits at least one hormonal activity of a component peptide hormone. 
   
     
     
         2 . The method of  claim 1 , wherein the patient is need of and benefits by an increase in cardiac contractility, a decrease blood pressure, acute vasodilatation, a decrease in systolic pressure, a decrease in diastolic pressure, plasma glucose lowering, insulin secretion, a slowing of gastric emptying, beta cell proliferation, weight loss, weight maintenance, a reduction in catabolic effects or any combination thereof. 
     
     
         3 . The method of  claim 2 , wherein the GIP compound provides to the patient an increase in cardiac contractility, a decrease blood pressure, acute vasodilatation, a decrease in systolic pressure, a decrease in diastolic pressure, plasma glucose lowering, insulin secretion, a slowing of gastric emptying, a reduction in catabolic effects or any combination thereof. 
     
     
         4 . The method of  claim 1 , wherein the GIP compound acts directly on cardiac cells. 
     
     
         5 . The method of  claim 1 , wherein the cardiovascular disease or condition is hypertension, pulmonary hypertension, congestive heart failure, cardiac insufficiency, reduced stroke volume, cardiomyopathy, decreased cardiac contractility, pulmonary congestion associated with cardiovascular conditions, pulmonary and systemic edema, decreased cardiac output, abnormal left ventricular function, diastolic blood pressure abnormalities, renal failure associated with decreased cardiac contractility, increased cardiovascular risk, myocardial infarction, and non-ischemic or ischemic heart tissue degeneration. 
     
     
         6 . The method of  claim 5 , wherein the increased cardiovascular risk is associated with elevated systolic pressure accompanied by normal diastolic pressure, associated with elevated diastolic pressure accompanied by normal systolic pressure, associated with elevated diastolic and systolic pressure, associated with elevated mean arterial blood pressure or any combination thereof. 
     
     
         7 . The method of  claim 1 , wherein the GIP compound provides a benefit of reducing elevated systolic pressure accompanied by normal diastolic pressure, of reducing the elevated diastolic pressure accompanied by normal systolic pressure, by reducing elevated diastolic and systolic pressure, by reducing elevated mean arterial blood pressure of any combination thereof. 
     
     
         8 . The method of  claim 1 , wherein the treating or preventing is selected from preventing the initiation of, delaying the initiation of, preventing the progression or advancement of, slowing the progression or advancement of, delaying the progression or advancement of, and reversing the progression of the disease or condition from an advanced to a less advanced stage. 
     
     
         9 . The method of  claim 1 , wherein the GIP compound comprises an amylin family hormone module. 
     
     
         10 . The method of  claim 1 , wherein the GIP compound comprises an amylin family hormone module that comprises an amylin/sCT/amylin chimera. 
     
     
         11 . The method of  claim 1 , wherein the GIP compound comprises a DPP-IV resistant GIP analog. 
     
     
         12 . The method of  claim 1 , wherein the GIP compound comprises a DPP-IV resistant GIP analog and an amylin family hormone module that comprises an amylin/sCT/amylin chimera, optionally joined with a linker.