Bioactive peptides and method of using same

• US 20120129776A1
• Filed: 09/18/2007
• Published: 05/24/2012
• Est. Priority Date: 09/18/2006
• Status: Active Grant

• Current Assignee: Compugen Ltd
• Original Assignee: Compugen Ltd
• Inventors: Cohen, Yossi, Shemesh, Ronen, Toporik, Amir, Levine, Zurit, Wool, Assaf, Dahary, Dvir, Hecht, Iris, Beiman, Merav, Rotman, Galit, Ayalon-Soffer, Michal
• Granted Patent: US 8,349,801 B2
• Time in Patent Office: Days
• US Class Current: 514/13.8
• CPC Class Codes: A61K 38/08 Peptides having 5 to 11 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 38/10 Peptides having 12 to 20 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 : for osteoporosis
• CPC Class Codes: A61P 21/00 : Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 : for peripheral neuropathies
• CPC Class Codes: A61P 25/04 : Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 : Antimigraine agents
• CPC Class Codes: A61P 25/16 : Anti-Parkinson drugs
• CPC Class Codes: A61P 25/24 : Antidepressants
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 25/30 : for treating abuse or dependence
• CPC Class Codes: A61P 25/36 : Opioid-abuse
• CPC Class Codes: A61P 27/06 : Antiglaucoma agents or miotics
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 : Antihyperlipidemics
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 39/06 : Free radical scavengers or antioxidants
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07K 14/47 : from mammals
• CPC Class Codes: C07K 5/101 : the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
• CPC Class Codes: C07K 7/06 : having 5 to 11 amino acids
• CPC Class Codes: C07K 7/08 : having 12 to 20 amino acids gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Disclosed are peptide ligands for G-protein coupled receptors that are useful for treating disorders associated with G-protein coupled receptor activation.

Claims

1. A peptide less than 30 amino acids in length, said peptide comprising the amino acid sequence of Formula I, wherein Formula I is

A¹-A²-A³-A⁴-A⁵-A⁶-A⁷-A⁸-A⁹-A¹⁰-A¹¹-A¹²-A¹³-A¹⁴-A¹⁵-A¹⁶-A¹⁷-A¹⁸-A¹⁹-A²⁰-A²¹-A²²-A²³-A²⁴-A²⁵-A²⁶, or a pharmaceutically acceptable salt thereof;

wherein

A¹ is absent or F or a hydrophobic non-naturally occurring amino acid;

A² is absent or A or a small non-naturally occurring amino acid;

A³ is absent or F or a hydrophobic non-naturally occurring amino acid;

A⁴ is absent or L or a hydrophobic non-naturally occurring amino acid;

A⁵ is absent or G or a small non-naturally occurring amino acid;

A⁶ is absent or Y or a hydrophobic non-naturally occurring amino acid;

A⁷ is absent or S or C;

A⁸ is absent or I or a hydrophobic non-naturally occurring amino acid;

A⁹ is absent or Y or a hydrophobic non-naturally occurring amino acid;

A¹⁰ is absent or L or a hydrophobic non-naturally occurring amino acid;

A¹¹ is absent or N or a polar non-naturally occurring amino acid;

A¹² is absent or R or a basic non-naturally occurring amino acid;

A¹³ is absent or K or a basic non-naturally occurring amino acid;

A¹⁴ is absent or R or a basic non-naturally occurring amino acid;

A¹⁵ is absent or R or a basic non-naturally occurring amino acid;

A¹⁶ is absent or G, or a small non-naturally occurring amino acid;

A¹⁷ is absent or D or a polar non-naturally occurring amino acid;

A¹⁸ is absent or P;

A¹⁹ is absent or A or a hydrophobic non-naturally occurring amino acid;

A²⁰ is absent or F or a hydrophobic non-naturally occurring amino acid;

A²¹ is absent or K or a basic non-naturally occurring amino acid;

A²² is absent or R or a basic non-naturally occurring amino acid;

A²³ is absent or R or a basic non-naturally occurring amino acid;

A²⁴ is absent or L or a hydrophobic non-naturally occurring amino acid;

A²⁵ is absent or R or a hydrophobic non-naturally occurring amino acid;

A²⁶ is absent or D or a polar non-naturally occurring amino acid;

or a fragment of said peptide,

provided said peptide comprises SEQ ID NO;

29,

wherein said non-naturally occurring amino acid is selected from the group consisting of sarcosine (Sar), beta-alanine (beta-Ala), 3 aminopropionic (3-aP), 2,3 diaminopropionic (2,3-diaP) and alpha-aminisobutyric acid (Aib);

wherein said hydrophobic non-naturally occurring amino acid is t butylalanine (t BuA), t butylglycine (t BuG), N methylisoleucine (N MeIle), norleucine (Nle), methylvaline (Mvl), cyclohexylalanine (Cha), phenylglycine (Phg), NaI, beta2-thienylalanine (Thi), 2 naphthylalanine (2 Nal), or 1,2,3,4-tetrahydroisoquinoline-3 carboxylic acid (Tic);

wherein said basic non-naturally occurring amino acid is ornithine (Orn) or homoarginine (Har); and

/or wherein neutral/polar non-naturally occurring amino acid is citrulline (Cit), Acetyl Lys, or methionine sulfoxide (MSO);

or a non-naturally occurring amino acid of Table 6.

35. The peptide of claim 1, wherein the peptide is selected from the group consisting of:

FLGYCIYLNRKRRGDPAFKRRLRD (SEQ ID NO.

     9) monomer or dimer,

FLGYSIYLNRKRRGDPAFKRRLRD (SEQ ID NO.

     10),

IYLNRKRRGDPAFKRRLRD (SEQ ID NO.

     11),

FAFLGYSIYLNRKRRGDPAF (SEQ ID NO.

     12),

FAFLGYCIYLNRKRRGDPAF (SEQ ID NO.

     13) monomer or dimer,

FAFLGYCIYLNRKRRGDPAFKRRLRD (SEQ ID NO.

     20) monomer or dimer,

FLGYCIYLNRKRRGDPAF (SEQ ID NO.

     23) monomer or dimer,

RGDPAF (SEQ ID NO.

     24),

RRGDPAF (SEQ ID NO.

     25),

GDPAFKRRLRD (SEQ ID NO.

     28),

GDPAF (SEQ ID NO.

     29), and

IYLNRKRRGDPAF (SEQ ID NO.

     31).

36. The peptide of claim 1, wherein said peptide is conjugated or fused to a second peptide or polypeptide.

42. A pharmaceutical composition comprising the peptide of claim 1 and a pharmaceutically acceptable carrier.

51. A purified nucleic acid sequence encoding a peptide of claim 1.

52. A method of treating a disorder associated with hypertension, said method comprising administering to a subject in need thereof a therapeutically effective amount of the peptide of claim 1, or a nucleic acid molecule encoding the peptide of claim 1, wherein said peptide is Formula I, Formula II, Formula III, Formula IV or Formula V, and wherein said peptide is administered alone or in combination with another therapeutic agent.

55. A method of treating a cardiovascular disorder, said method comprising administering to a subject in need thereof a therapeutically effective amount of the peptide of claim 1, or a nucleic acid molecule encoding the peptide of claim 1, wherein said peptide is Formula I, Formula II, or Formula IV, and wherein said peptide is administered alone or in combination with another therapeutic agent.

58. A method of treating an ischemia-reperfusion injury related disorder, said method comprising administering to a subject in need thereof a therapeutically effective amount of the peptide of claim 1, or a nucleic acid molecule encoding the peptide of claim 1, wherein said peptide is Formula I, Formula II, or Formula IV, and wherein said peptide is administered alone or in combination with another therapeutic agent.

61. A method of treating a central nervous system (CNS) disorder or a peripheral nervous system (PNS) disorder in a subject, said method comprising administering to a subject in need thereof a therapeutically effective amount of the peptide of claim 1, or a nucleic acid molecule encoding the peptide of claim 1, and wherein said peptide is Formula I, Formula II, Formula III, Formula IV, or Formula V, and wherein said peptide is administered alone or in combination with another therapeutic agent.

64. A method of treating an inflammatory disorder in a subject, said method comprising administering to a subject in need thereof a therapeutically effective amount of the peptide of claim 1, or a nucleic acid molecule encoding the peptide of claim 1, wherein said peptide is Formula I, Formula II, Formula III, Formula IV, or Formula V, and wherein said peptide is administered alone or in combination with another therapeutic agent.

67. A method of treating inflammatory conditions associated with an infection, said infection being a bacterial infection or viral infection or an infection caused by another type of pathogen, in a subject, said method comprising administering to a subject in need thereof a therapeutically effective amount of the peptide of claim 1, or a nucleic acid molecule encoding the peptide of claim 1, wherein said peptide is Formula I, Formula II, or Formula IV, and wherein said peptide is administered alone or in combination with another therapeutic agent.

70. A method of treating a metabolic disorder in a subject, said method comprising administering to a subject in need thereof a therapeutically effective amount of the peptide of claim 1, or a nucleic acid molecule encoding the peptide of claim 1, wherein said peptide is Formula I, Formula II, or Formula IV, and wherein said peptide is administered alone or in combination with another therapeutic agent.

73. A method of treating a fibrotic condition in a subject, involving tissue remodeling following inflammation or ischemia-reperfusion injury, said method comprising administering to a subject in need thereof a therapeutically effective amount of the peptide of claim 1, or a nucleic acid molecule encoding the peptide of claim 1, wherein said peptide is Formula I, Formula II, Formula III, Formula IV, or Formula V, and wherein said peptide is administered alone or in combination with another therapeutic agent.

76. A method of prevention and treatment of a disease in a subject, involving reduction of oxygen reactive species with consequent endothelial dysfunction, said method comprising administering to a subject in need thereof a therapeutically effective amount of the peptide of claim 1, or a nucleic acid molecule encoding the peptide of claim 1, wherein said peptide is Formula I, or Formula II, and wherein said peptide is administered alone or in combination with another therapeutic agent.

79. A method of treating a respiratory disease in a subject, said method comprising administering to a subject in need thereof a therapeutically effective amount of the peptide of claim 1, or a nucleic acid molecule encoding the peptide of claim 1, wherein said peptide is Formula I, Formula II, or Formula IV, and wherein said peptide is administered alone or in combination with another therapeutic agent.

82. A method of preventing or treating a skin injury or tissue repair, said method comprising administering to a subject in need thereof a therapeutically effective amount of the peptide of claim 1, or a nucleic acid molecule encoding the peptide of claim 1, wherein said peptide is Formula I, Formula II, or Formula IV, and wherein said peptide is administered alone or in combination with another therapeutic agent.

85. A method of treating a bone disease in a subject, said method comprising administering to a subject in need thereof a therapeutically effective amount of the peptide of claim 1, or a nucleic acid molecule encoding the peptide of claim 1, wherein said peptide is Formula II, or Formula IV, and wherein said peptide is administered alone or in combination with another therapeutic agent.

88. A method of treating a urogenital disorder or a genitor-urological disorder in a subject, said method comprising administering to a subject in need thereof a therapeutically effective amount of the peptide of claim 1, wherein said peptide is Formula I, Formula II, and wherein said peptide is administered alone or in combination with another therapeutic agent.

91. A method of activating or inducing chemoattraction of blood cells to a site of injury in a subject, said method comprising administering to a subject in need thereof a therapeutically effective amount of the peptide of claim 1, or a nucleic acid molecule encoding the peptide of claim 1, wherein said peptide is Formula II, or Formula IV, and wherein said peptide is administered alone or in combination with another therapeutic agent.

94. A method of treating a cytopenia in a subject, said method comprising administering to a subject in need thereof a therapeutically effective amount of the peptide of claim 1, or a nucleic acid molecule encoding the peptide of claim 1, wherein said peptide is Formula I, Formula II, or Formula IV, and wherein said peptide is administered alone or in combination with another therapeutic agent.

97. A method of treating an immune related disorder in a subject, said method comprising administering to a subject in need thereof a therapeutically effective amount of the peptide of claim 1, or a nucleic acid molecule encoding the peptide of claim 1, wherein said peptide is Formula I, Formula II, or Formula IV, and wherein said peptide is administered alone or in combination with another therapeutic agent.

101. A method of treating a cancer or inflammation associated with cancer in a patient, said method comprising administering to a subject in need thereof a therapeutically effective amount of the peptide of claim 1, or a nucleic acid molecule encoding the peptide of claim 1, wherein said peptide is Formula I, Formula II, or Formula IV and wherein said peptide is administered alone or in combination with another therapeutic agent.

104. A method of treating or controlling pain in a patient, said method comprising administering to a subject in need thereof a therapeutically effective amount of the peptide of claim 1, or a nucleic acid molecule encoding the peptide of claim 1, wherein said peptide is Formula I, Formula III, Formula IV, or Formula V, and wherein said peptide is administered alone or in combination with another therapeutic agent.

107. A method of treating a kidney disease in a patient, said method comprising administering to a subject in need thereof a therapeutically effective amount of the peptide of claim 1, or a nucleic acid molecule encoding the peptide of claim 1, wherein said peptide is Formula I, Formula II, Formula III, Formula IV or Formula V, and wherein said peptide is administered alone or in combination with another therapeutic agent.

110. A method of treating a blood disease in a patient, said method comprising administering to a subject in need thereof a therapeutically effective amount of the peptide of claim 1, or a nucleic acid molecule encoding the peptide of claim 1, wherein said peptide is Formula I, or Formula II, and wherein said peptide is administered alone or in combination with another therapeutic agent.

113. A method of treating an angiogenesis related disease in a patient, said method comprising administering to a subject in need thereof a therapeutically effective amount of the peptide of claim 1, or a nucleic acid molecule encoding the peptide of claim 1, wherein said peptide is Formula I, Formula II, or Formula IV, and wherein said peptide is administered alone or in combination with another therapeutic agent.

117. A method of treating a genetic polymorphism consequent diseases in a patient, said method comprising administering to a subject in need thereof a therapeutically effective amount of the peptide of claim 1, or a nucleic acid molecule encoding the peptide of claim 1, wherein said peptide is Formula I, or Formula II, and wherein said peptide is administered alone or in combination with another therapeutic agent.

120. A method of preventing or treating a organic alterations produced by aging in a patient, said method comprising administering to a subject in need thereof a therapeutically effective amount of the peptide of claim 1, or a nucleic acid molecule encoding the peptide of claim 1, wherein said peptide is Formula I, or Formula II, and wherein said peptide is administered alone or in combination with another therapeutic agent.

122. A method of preventing or treating alopecia in a patient, including chemotherapy-induced alopecia, said method comprising administering to a subject in need thereof a therapeutically effective amount of the peptide of claim 1, or a nucleic acid molecule encoding the peptide of claim 1, wherein said peptide is Formula I, Formula II, or Formula IV, and wherein said peptide is administered alone or in combination with another therapeutic agent.

124. A method of preventing or treating diseases that involve alterations in the muscular differentiation, maturation and regeneration in muscular atrophies in a patient, said method comprising administering to a subject in need thereof a therapeutically effective amount of the peptide of claim 1, or a nucleic acid molecule encoding the peptide of claim 1, wherein said peptide is Formula I, or Formula II, and wherein said peptide is administered alone or in combination with another therapeutic agent.

127. An antibody that selectively binds to an epitope in the peptide of claim 1.

131. The method of claim 55, wherein said cardiovascular disorder is selected from a group consisting of peripheral vascular diseases and coronary artery diseases, coronary heart disease;

myocardial infarction;

heart injury;

congestive heart failure (CHF);

myocardial failure;

myocardial hypertrophy;

ischemic cardiomyopathy;

systolic heart failure;

diastolic heart failure;

stroke;

thrombotic stroke;

concentric LV hypertrophy, myocarditis;

cardiomyopathy;

hypertrophic cardiomyopathy;

myocarditis;

decompensated heart failure;

ischemic myocardial disease;

congenital heart disease;

angina pectoris;

prevention of heart remodeling or ventricular remodeling after myocardial infarction;

ischemia-reperfusion injury in ischemic and post-ischemic events, myocardial infarct;

cerebrovascular accident;

mitral valve regurgitation;

hypertension;

hypotension;

restenosis;

fibrosis;

thrombosis; and

platelet aggregation.

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