Compositions and methods for treating metabolic diseases

Abstract

The disclosure provides compositions and methods of treating a metabolic disease, such as, e.g., diabetes and hyperlipidemia, in a subject, by administering to the subject a therapeutically effective amount of a polypeptide derived from hepatitis B virus or a pharmaceutical composition comprising the polypeptide.

1 . A method of treating or preventing a metabolic disease, a cardiovascular disease, a heart diseases, or a kidney impairment in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a polypeptide or a pharmaceutical composition comprising the polypeptide to produce a serum concentration of the administered polypeptide at a concentration above a concentration threshold of 93 nmol/L, wherein the polypeptide comprises an amino acid sequence derived from Hepatitis B virus (HBV); wherein the metabolic disease chosen from diabetes; hyperglycemia; hypoglycemia; hyperinsulinemia; hyperlipidemia; hypertriglyceridemia; hypercholesterolemia; heart disease; metabolic syndrome; atherosclerotic disease; coronary heart disease; coronary artery disease; peripheral arterial disease; angina pectoris; cerebrovascular disease; acute coronary syndrome; myocardial infarction; stroke; cardiovascular disease; Alzheimer's disease; dyslipidemias; familial combined hyperlipidemia; familial hypertriglyceridemia; familial hypercholesterolemia; heterozygous hypercholesterolemia; homozygous hypercholesterolemia; familial defective apolipoprotein B-100; polygenic hypercholesterolemia; remnant removal disease; hepatic lipase deficiency; dyslipidemia caused by dietary indiscretion, hypothyroidism, drugs including estrogen and progestin therapy, beta-blockers, and thiazide diuretics; nephrotic syndrome; chronic renal failure; Cushing's syndrome; primary biliary cirrhosis; glycogen storage disease; hepatoma; cholestasis; acromegaly; insulinoma; isolated growth hormone deficiency; kidney impairment; obesity; and alcohol-induced hypertriglyceridemia; wherein the cardiovascular disease is an atherosclerotic disease. 
     
     
         2 . The method of  claim 1 , wherein the metabolic disease involves dysregulation of lipid metabolism and/or dysregulation of glucose metabolism. 
     
     
         3 . The method of  claim 1 , wherein the polypeptide is capable of reducing or stabilizing the level or activity of one or more chemical or biological molecules associated with metabolism in the subject, wherein the chemical or biological molecule is chosen from glucose, cholesterol, triglycerides, free fatty acids, amino acids, hormones, LDL-C, HDL-C, HbA1c, blood urea nitrogen, and minerals; or the polypeptide is capable of lowering the level of total cholesterol, triglycerides, and/or LDL-C in the subject. 
     
     
         4 . The method of  claim 1 , wherein the polypeptide is capable of lowering the level of glucose and/or HbA1c in the subject, or the polypeptide is capable of stabilizing the level of insulin in the subject. 
     
     
         5 . The method of  claim 1 , wherein the polypeptide is capable of reducing or stabilizing the level or value of one or more physiological parameters that measure metabolic changes chosen from glycemia, blood pressure, body weight, fat mass, body mass index (BMI), inflammation, atherosclerosis index, heart index, kidney index, total fat index, and homeostatic model assessment (HOMA) index. 
     
     
         6 . The method of  claim 1 , wherein the polypeptide comprises an amino acid sequence of the pre-S1 region of HBV genotype A, B, C, D, E, F, G, or H. 
     
     
         7 . The method of  claim 1 , wherein the polypeptide comprises the sequence of amino acids 13-59 of the pre-S1 region of HBV genotype C. 
     
     
         8 . The method of  claim 1 , wherein the polypeptide comprises an amino acid sequence selected from SEQ ID NOs: 21-40, or has at least about 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%% identity to an amino acid sequence selected from SEQ ID NOs: 21-40. 
     
     
         9 . The method of  claim 6 , wherein the polypeptide comprises at the N-terminus and/or the C-terminus a native flanking amino acid sequence from the pre-S1 region of HBV. 
     
     
         10 . The method of  claim 9 , wherein the native flanking amino acid sequence from the pre-S1 region of HBV has 1-10, 1-8, 1-5, or 1-3 amino acids in length. 
     
     
         11 . The method of  claim 1 , wherein the polypeptide comprises the glycine corresponding to amino acid 13 of the pre-S1 region of HBV genotype C, and or the asparagine corresponding to amino acid 20 of the pre-S1 region of HBV genotype C. 
     
     
         12 . The method of  claim 1 , wherein the polypeptide comprises an N-terminal modification with a hydrophobic group, and/or a C-terminal modification that is capable of stabilizing the polypeptide. 
     
     
         13 . The method of  claim 12 , wherein the hydrophobic group is chosen from myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, cholesterol, and arachidonic acid; and the C-terminal modification is amidation (amination) or isopentanediolization. 
     
     
         14 . The method of  claim 1 , wherein the polypeptide comprises SEQ ID NO: 23, and wherein the polypeptide further comprises an N-terminal modification with myristic acid and a C-terminal modification with amination; or wherein the polypeptide comprises SEQ ID NO: 3. 
     
     
         15 . The method of  claim 1 , wherein the polypeptide is capable of binding to sodium taurocholate cotransporting polypeptide (NTCP). 
     
     
         16 . The method of  claim 1 , wherein the serum concentration of the administered polypeptide in the subject is above 500 ng/ml. 
     
     
         17 . The method of  claim 1 , wherein the polypeptide or the pharmaceutical composition comprising the polypeptide is administered to the subject before, concurrently with, or after the administration of a therapeutically effective amount of at least one second agent. 
     
     
         18 . The method of  claim 17 , wherein the second agent is chosen from an antihyperlipidemic agent, an antihyperglycemic agent, an antidiabetic agent, an antiobesity agent, and a bile acid analogue. 
     
     
         19 . The method of  claim 18 , wherein the second agent is chosen from insulin, metformin, sitagliptin, colesevelam, glipizide, simvastatin, atorvastatin, ezetimibe, fenofibrate, nicotinic acid, orlistat, lorcaserin, phentermine, topiramate, obeticholic acid, and ursodeoxycholic acid. 
     
     
         20 . The method of  claim 1 , wherein the polypeptide or the pharmaceutical composition comprising the polypeptide is administered to the subject by at least one mode chosen from parenteral, intrapulmonary, intranasal, intralesional, intramuscular, intravenous, intraarterial, intraperitoneal, and subcutaneous administration.