Therapeutic peptides

Abstract

Therapeutic peptides having guanylyl cyclase C agonist activity are disclosed. The therapeutic peptides are analogues of the E. coli STa peptide with non-natural amino acid, isosteric or D-amino acid substituents. The therapeutic peptides are useful in the treatment of chronic ideopathic constipation, inflammatory bowel disease, and other diseases. Pharmaceutical compositions comprising the therapeutic peptides are also disclosed.

1 - 116 . (canceled) 
     
     
         117 . A therapeutic peptide comprising an amino acid sequence of SEQ ID NO: 41. 
     
     
         118 . The therapeutic peptide of  claim 117 , wherein the amino acid sequence is selected from:
 (a) SEQ ID NO: 42-53;   (b) SEQ ID NO: 60-69;   (c) SEQ ID NO: 100-125;   (d) SEQ ID NO: 150-175;   (e) SEQ ID NO: 200-529;   (f) SEQ ID NO: 600-2481; or   (g) SEQ ID NO: 2500-2543.   
     
     
         119 . A method for treating or preventing a disease or a disorder, wherein the method comprises administering to a patient a therapeutically effective amount the therapeutic peptide of  claim 117 , wherein the disease or disorder is selected from:
 (a) a gastrointestinal disorder;   (b) a respiratory disorder;   (c) a cardiovascular disorder;   (d) an inflammatory disorder;   (e) cancer;   (f) blood disorder;   (g) endocrine disorder;   (h) eye disorder;   (i) liver disorder;   (j) throat or oral disorder;   (k) prostate disorder;   (l) skin disorder;   (m) obesity; or   (n) kidney disorder.   
     
     
         120 . The method of  claim 119 , wherein:
 (a) the gastrointestinal disorder is constipation, chronic idiopathic constipation, irritable bowel syndrome, pain associated with irritable bowel syndrome, post infectious irritable bowel syndrome, inflammatory bowel disease, Crohn's Disease, ulcerative colitis, dyspepsia, non-ulcer dyspepsia, functional dyspepsia, chronic intestinal pseudo-obstruction, colonic pseudo-obstruction, duodenogastric reflux, gastroesophageal reflux disease, ileus inflammation, post-operative ileus, constipation associated with use of opiate pain killers, post-surgical constipation, gastroparesis, constipation associated with neuropathic disorders, heartburn and functional heartburn, celiac disease, poor gastrointestinal motility, gastric cancer, primary or metastatic colorectal, esophageal and stomach cancer or polyps;   (b) the respiratory disorder is cystic fibrosis, asthma or bronchitis, chronic obstructive pulmonary disease, emphysema, cibrosis and cronchitis;   (c) the cardiovascular disorder is congestive heart failure, high cholesterol, hypertension;   (d) the inflammatory disorder is nephritis, pancreatitis, bronchitis, tissue inflammation, organ inflammation, respiratory inflammation, necrotizing enterocolitis; inflammation of the lung, kidney, gastrointestinal system, and skin;   (e) the cancer is cancer of the colon and intestines, stomach, gastrointestinal tract, lung, liver, salivary gland, skin, esophagus, stomach, blood, eye, pancreas, anus, gallbladder, oral tissues, thyroid, prostate, urinary tract and bladder, and kidney, and melanoma; and   (f) the endocrine disorder is cystic fibrosis, diabetes, hyperthyroidism, and hypothyroidism;   (g) the eye disorder is dry eye and dry eye syndrome, retinal degeneration, tear gland disorders, eye inflammation, glaucoma, and age related macular degeneration;   (h) the oral disorder is dry mouth, Sjogren's Syndrome, xerostomia, salivary gland disorders, gum disease and periodontal disease; or   (i) other disorders such as benign prostatic hyperplasia, kidney failure and reflux neuropathy, liver cirrhosis and fibrosis, dry skin, xerosis, eczema, and psoriasis.   
     
     
         121 . A pharmaceutical composition in unit dose comprising the therapeutic peptide of  claim 117  and a pharmaceutically acceptable carrier, excipient or diluent. 
     
     
         122 . The pharmaceutical composition of  claim 121 , where the pharmaceutical composition further comprises an inhibitor of cGMP dependent phosphodiesterase, a chemotherapeutic agent, an anti-inflammatory agent, anti-viral agent, an anti-cancer agent, a phosphodiesterase inhibitor, an immunomodulating agent, cisdapride, Cimetropium, dolasetron, trimebutine maleate, diciclomine, cholestyramine, darifenacin, Calcium polycarbophil, ondansetron, tegaserod, hysvyamine sulfate, pinaverium bromide, mebeverine, granisetron, propanthiline bromide, alosetron hydrochloride, rifaximin, bumetanide analgesic agents, anti-obesity agents, agents used to treat gastrointestinal cancers, Crohn's Disease, Ulcerative Colitis, Constipation, Irritable Bowel Syndrome, and Postoperative Ileus. 
     
     
         123 . The pharmaceutical composition of  claim 121 , wherein the unit dose form is a powder tablet, a troche, a tablet matrix, a fluid carrier or gel capsule, a microencapsulated delivery system, small beads, a capsule, a gel capsule, a solution, a liposomal suspension, a transdermal formulation, a transmucosal formulation, a rectal retention formulation, a colonic release formulation, a suppository, an implant, a sustained release implant, a topical gel, ointment, cream or lotion, a gastric retention formulation, an inhalation formulation, a spray, an oral formulation, a controlled release formulation, a delayed release formulation, a sustained release formulation, an osmotic release device, or an osmotic burst release device. 
     
     
         124 . The pharmaceutical composition of  claim 123 , wherein the controlled release formulation:
 (a) is released over an interval between 1 and 24 hours;   (b) allows for a sudden release of the pharmaceutical composition into the location of the gastrointestinal tract, followed by a sustained or slow release into said location;   (c) allows for delayed release of the pharmaceutical composition to the gastrointestinal tract, followed by sustained release into said location;   (d) allows for delayed release of the pharmaceutical composition to the location of the gastrointestinal tract, followed by one or several sudden or burst releases into said location or several different locations;   (e) allows for the release of the pharmaceutical composition to the location of the gastrointestinal tract based on pH;   (f) is pH dependent;   (g) is time dependent;   (h) is temperature dependent;   (i) is ionic strength dependent;   (j) is viscosity dependent; or   (k) is a time delayed sudden release formulation.   
     
     
         125 . The pharmaceutical composition of  claim 121  wherein the pharmaceutical composition further comprises:
 (a) a targeting material; 
 (b) an inhibitor comprising a cGMP-specific phosphodiesterase; 
 (c) an anti-inflammatory agent 
 (d) a biologically active agent; 
 (e) a coating system; 
 (f) a pH sensitive coating; 
 (g) a pH triggered controlled release system; 
 (h) a slowly disintegrating core surrounded by a composition that targets the release; 
 (i) a compression coating; 
 (j) a pore forming agent; 
 (k) a suspending agent; 
 (l) a plasticizer; 
 (m) a stiffening agent; 
 (n) a wetting agent; 
 (o) a dispersing agents; 
 (p) an enteric coating; 
 (q) or combinations of above; or 
 (r) a disintegrant 
 
     
     
         126 . The pharmaceutical composition of  claim 125 , wherein the targeting material is selected from:
 (a) a water insoluble polymer;   (b) a swellable polymer;   (c) a swellable copolymer;   (d) an anionic or cationic hydrogel;   (e) a polyelectrolyte complex;   (f) a biodegradable polymer; and   (g) a water insoluble polymer and a pore forming agent.   
     
     
         127 . The pharmaceutical composition of  claim 126 , wherein:
 (a) the swellable polymer comprises an acrylic copolymer, methacrylic acid polymer, polyvinylacetate, cellulose derivatives, carrageenan, polyvinyl pyrrolidone with molecular weight from 10 to 500 thousand, polyvinyl alcohol, hydroxypropylmethyl cellulose, n-vinyl lactames, starches, collagen, crosslinked polyacrilic acid, pectin, guar gum, xanthan gum, chitosan, ethyl cellulose, a EUDRAGIT polymer, or a cellulose derivative;   (b) the pore forming agent comprises saccharose, sodium chloride, potassium chloride, polyvinylpyrrolidone, polyethyleneglycol, a water soluble organic acid, a sugar or a sugar alcohol;   (c) the enteric coating comprises cellulose acetates phtalantate hydroxyl methyl cellulose acetate succinate, EUDRAGIT polymers, or a combination thereof;   (d) the biodegradable polymer comprises amethacrylic acid copolymers, polyvinyl acetate phthalate, hydroxypropylmethylcellulose, cellulose acetate trimelliate, or hydroxypropyl methyl cellulose acetate succinate, EUDRAGIT polymers, or combinations thereof; or   (e) the time delayed sudden release formulation comprises a combination of croscarmellose sodium, crospovidone, cross-linked sodium carboxymethyl cellulose, pregelatinized starch, calcium carboxymethyl cellulose, and magnesium aluminum silicate, at least one of an absorption enhancer, a binder, a hardness enhancing agent, a buffering agent, a filler, a flow regulating agent, a lubricant, a dispersant, a chelator, an antioxidant, a stabilizer, a preservative, and/or one or more other excipients.   
     
     
         128 . A method for treating or preventing a disease or a disorder, wherein the method comprises administering to a patient a therapeutically effective amount the pharmaceutical composition of  claim 121 , wherein the disease or disorder is selected from:
 (a) a gastrointestinal disorder;   (b) a respiratory disorder;   (c) a cardiovascular disorder;   (d) an inflammatory disorder;   (e) cancer;   (f) blood disorder;   (g) endocrine disorder;   (h) eye disorder;   (i) liver disorder;   (j) throat or oral disorder;   (k) prostate disorder;   (l) skin disorder;   (m) obesity; or   (n) kidney disorder.   
     
     
         129 . The method of  claim 128 , wherein:
 (a) the gastrointestinal disorder is constipation, chronic idiopathic constipation, irritable bowel syndrome, pain associated with irritable bowel syndrome, post infectious irritable bowel syndrome, inflammatory bowel disease, Crohn's Disease, ulcerative colitis, dyspepsia, non-ulcer dyspepsia, functional dyspepsia, chronic intestinal pseudo-obstruction, colonic pseudo-obstruction, duodenogastric reflux, gastroesophageal reflux disease, ileus inflammation, post-operative ileus, constipation associated with use of opiate pain killers, post-surgical constipation, gastroparesis, constipation associated with neuropathic disorders, heartburn and functional heartburn, celiac disease, poor gastrointestinal motility, gastric cancer, primary or metastatic colorectal, esophageal and stomach cancer or polyps;   (b) the respiratory disorder is cystic fibrosis, asthma or bronchitis, chronic obstructive pulmonary disease, emphysema, cibrosis and cronchitis;   (c) the cardiovascular disorder is congestive heart failure, high cholesterol, hypertension;   (d) the inflammatory disorder is nephritis, pancreatitis, bronchitis, tissue inflammation, organ inflammation, respiratory inflammation, necrotizing enterocolitis; inflammation of the lung, kidney, gastrointestinal system, and skin;   (e) the cancer is cancer of the colon and intestines, stomach, gastrointestinal tract, lung, liver, salivary gland, skin, esophagus, stomach, blood, eye, pancreas, anus, gallbladder, oral tissues, thyroid, prostate, urinary tract and bladder, and kidney, and melanoma;   (f) the endocrine disorder is cystic fibrosis, diabetes, hyperthyroidism, and hypothyroidism;   (g) the eye disorder is dry eye and dry eye syndrome, retinal degeneration, tear gland disorders, eye inflammation, glaucoma, and age related macular degeneration;   (h) the oral disorder is dry mouth, Sjogren's Syndrome, xerostomia, salivary gland disorders gum disease and periodontal disease; or   (i) other disorders such as benign prostatic hyperplasia, kidney failure and reflux neuropathy, liver cirrhosis and fibrosis, dry skin, xerosis, eczema, and psoriasis.   
     
     
         130 . A secretagogue comprising a guanylate cyclase C receptor agonist. 
     
     
         131 . The secretagogue of  claim 130 , wherein the guanylate cyclase C receptor agonist is a therapeutic peptide comprising an amino acid sequence of SEQ ID NO: 41. 
     
     
         132 . A method for treating or preventing a disease or a disorder, wherein the method comprises administering to a patient a therapeutically effective amount of the secretagogue of  claim 130 , and wherein the disease or disorder is selected from:
 (a) a gastrointestinal disorder;   (b) pain;   (c) a respiratory disorder;   (d) a cardiovascular disorder;   (e) an inflammatory disorder; or   (f) cancer   (g) blood disorder;   (h) endocrine disorder;   (i) eye disorder;   (j) liver disorder;   (k) throat or oral disorder;   (l) prostate disorder;   (m) skin disorder;   (n) obesity; or   (o) kidney disorder.   
     
     
         133 . The method of  claim 132 , wherein:
 (a) the gastrointestinal disorder is constipation, chronic idiopathic constipation, irritable bowel syndrome, pain associated with irritable bowel syndrome, post infectious irritable bowel syndrome, inflammatory bowel disease, Crohn's Disease, ulcerative colitis, dyspepsia, non-ulcer dyspepsia, functional dyspepsia, chronic intestinal pseudo-obstruction, colonic pseudo-obstruction, duodenogastric reflux, gastroesophageal reflux disease, ileus inflammation, post-operative ileus, constipation associated with use of opiate pain killers, post-surgical constipation, gastroparesis, constipation associated with neuropathic disorders, heartburn and functional heartburn, celiac disease, poor gastrointestinal motility, gastric cancer, primary or metastatic colorectal, esophageal and stomach cancer or polyps;   (b) the respiratory disorder is cystic fibrosis, asthma or bronchitis, chronic obstructive pulmonary disease, emphysema, cibrosis and cronchitis;   (c) the cardiovascular disorder is congestive heart failure, high cholesterol, hypertension;   (d) the inflammatory disorder is nephritis, pancreatitis, bronchitis, tissue inflammation, organ inflammation, respiratory inflammation, necrotizing enterocolitis; inflammation of the lung, kidney, gastrointestinal system, and skin;   (e) the cancer is cancer of the colon and intestines, stomach, gastrointestinal tract, lung, liver, salivary gland, skin, esophagus, stomach, blood, eye, pancreas, anus, gallbladder, oral tissues, thyroid, prostate, urinary tract and bladder, and kidney, and melanoma;   (f) the endocrine disorder is cystic fibrosis, diabetes, hyperthyroidism, and hypothyroidism;   (g) the eye disorder is dry eye and dry eye syndrome, retinal degeneration, tear gland disorders, eye inflammation, glaucoma, and age related macular degeneration;   (h) the oral disorder is dry mouth, Sjogren's Syndrome, xerostomia, salivary gland disorders gum disease and periodontal disease; or   (i) other disorders such as benign prostatic hyperplasia, kidney failure and reflux neuropathy, liver cirrhosis and fibrosis, dry skin, xerosis, eczema, and psoriasis.   
     
     
         134 . The method of  claim 132 , wherein the secretagogue is administered into a location in a gastrointestinal tract selected from distal jejunum, ileum, cecum, or ascending colon; and the gastrointestinal disorder is selected from constipation, chronic idiopathic constipation, or constipation dominant irritable bowel syndrome or mixed irritable bowel syndrome. 
     
     
         135 . The method of  claim 134 , wherein the secretagogue is released slowly over a period from 1 to 8 hours.