US2015307572A1PendingUtilityA1
Bioactive peptides and methods of using same
Est. expiryJul 12, 2027(~1 yrs left)· nominal 20-yr term from priority
Inventors:Ronen ShemeshZurit LevineAmir ToporikChen HermeshYossef KligerEyal GoferAssaf WoolDvir DaharyYossi Cohen
A61P 7/02A61P 9/04A61P 9/10A61P 9/12A61P 9/00A61P 35/00A61P 37/02A61P 25/00A61P 29/00A61P 3/00A61P 25/28A61P 19/06A61K 38/00A61P 11/00A61P 11/06C07K 14/47C07K 14/472A61P 17/00C07K 16/18A61P 19/00A61P 1/04A61P 13/12A61P 13/00A61P 19/08C07K 14/78C07K 2317/34C07K 7/06A61P 17/02Y02A50/30
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Claims
Abstract
Disclosed are peptide ligands for G-protein coupled receptors that are useful for treating disorders associated with G-protein coupled receptor activation.
Claims
exact text as granted — not AI-modified1 - 21 . (canceled)
22 . A purified peptide less than 35 amino acids in length, said peptide comprising an amino acid sequence of Formula I: X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -X 17 -X 18 -X 19 -X 20 -X 21 -X 22 -X 23 -X 24 -X 25 -X 26 -X 27 -X 28 -X 29 -X 30 -X 31 -X 32 -X 33 wherein
X 1 is absent or G or a small naturally or non-naturally occurring amino acid; X 2 is absent or Q or a polar naturally or non-naturally occurring amino acid; X 3 is absent or K or a basic naturally or non-naturally occurring amino acid; X 4 is absent or G or a small naturally or non-naturally occurring amino acid; X 5 is absent or Q or S a polar naturally or non-naturally occurring amino acid; X 6 is absent or V or A or P or M or a hydrophobic naturally or non-naturally occurring amino acid; X 7 is absent or G or a small naturally or non-naturally occurring amino acid; X 8 is absent or P or L or A or naturally or non-naturally occurring amino acid; X 9 is absent or P or Q or a naturally or non-naturally occurring amino acid; X 10 is absent or G or a small naturally or non-naturally occurring amino acid; X 11 is absent or A or H or E or D or a hydrophobic or a small or an acidic naturally or non-naturally occurring amino acid; X 12 is absent or A or P or Q or S or R or H or a hydrophobic or a small naturally or non-naturally occurring amino acid; X 13 is absent or C or V or A or any amino acid other than C; X 14 is absent or R or K or Q or P or a basic or a polar naturally or non-naturally occurring amino acid; X 15 is absent or R or Q or S or a basic or a polar naturally or non-naturally occurring amino acid; X 16 is absent or A or L or H or Q or a hydrophobic or a small naturally or non-naturally occurring amino acid; X 17 is absent or Y or a hydrophobic or an aromatic naturally or non-naturally occurring amino acid; X 18 is absent or A or a hydrophobic or small naturally or non-naturally occurring amino acid; X 19 is absent or A or a hydrophobic small naturally or non-naturally occurring amino acid; X 20 is absent or F or a hydrophobic or an aromatic naturally or non-naturally occurring amino acid; X 21 is absent or S or T or a polar naturally or non-naturally occurring amino acid; X 22 is absent or V or a hydrophobic naturally or non-naturally occurring amino acid; X 23 is absent or G or hydrophobic or small naturally or non-naturally occurring amino acid or replaced by an Amide; X 24 is absent or R or a basic naturally or non-naturally occurring amino acid; X 25 is absent or R or a basic naturally or non-naturally occurring amino acid; X 26 is A or a hydrophobic or small naturally or non-naturally occurring amino acid; X 27 is Y or a hydrophobic or an aromatic naturally or non-naturally occurring amino acid; X 28 is A or a hydrophobic or small naturally or non-naturally occurring amino acid; X 29 is A or a hydrophobic or small naturally or non-naturally occurring amino acid; X 30 is F or a hydrophobic naturally or non-naturally occurring amino acid; X 31 is S or T or a polar naturally or non-naturally occurring amino acid; X 32 is V or a hydrophobic naturally or non-naturally occurring amino acid; X 33 is absent or G or hydrophobic or small naturally or non-naturally occurring amino acid or replaced by an amide; or a pharmaceutically acceptable salt thereof.
23 . The peptide of claim 22 , wherein said peptide binds to/and or activates a GPCR in the LGR family of receptors or the relaxin-related family of receptors.
24 . The peptide of claim 22 , wherein said peptide is isolated from a protein recombinantly produced in a prokaryotic or eukaryotic cell.
25 . The peptide of claim 22 , wherein said peptide is chemically synthesized in vitro.
26 . The peptide of claim 22 , wherein said peptide includes a C-terminal amidated amino acid.
27 . The peptide of claim 22 , wherein peptide is less than 30 amino acids.
28 . The peptide of claim 22 , wherein said peptide is less than 20 amino acids.
29 . The peptide of claim 22 , wherein said peptide is selected from the group consisting of:
(SEQ ID NO: 1)
AYAAFSV-Amide
(SEQ ID NO: 2)
AYAAFSV;
(SEQ ID NO: 3)
GQKGQVGPPGAACRRAYAAFSV-Amide;
(SEQ ID NO: 4)
GQKGQVGPPGAACRRAYAAFSV;
(SEQ ID NO: 5)
GQKGQVGPPGAAVRRAYAAFSV-Amide;
(SEQ ID NO: 6)
GQKGQVGPPGAAVRRAYAAFSV;
(SEQ ID NO: 7)
GQKGQVGPPGAACRRAYAAFSVGRRAYAAFSV-Amide;
(SEQ ID NO: 8)
GQKGQVGPPGAACRRAYAAFSVGRRAYAAFSV;
(SEQ ID NO: 9)
GQKGQVGPPGAAVRRAYAAFSVGRRAYAAFSV-Amide;
(SEQ ID NO: 10)
GQKGQVGPPGAAVRRAYAAFSVGRRAYAAFSV;
(SEQ ID NO: 11)
AYAAFSVG;
(SEQ ID NO: 12)
GQKGQVGPPGAACRRAYAAFSVG;
(SEQ ID NO: 13)
GQKGQVGPPGAAVRRAYAAFSVG;
(SEQ ID NO: 14)
GQKGQVGPPGAACRRAYAAFSVGRRAYAAFSVG;
(SEQ ID NO: 15)
GQKGQVGPPGAAVRRAYAAFSVGRRAYAAFSVG;
(SEQ ID NO: 20)
GQKGQVGPPGAACQRAYAAFSVG;
(SEQ ID NO: 21)
GQKGQVGPPGAPCQRAYAAFSVG;
(SEQ ID NO: 22)
GQKGQVGPPGAPCQRAYAAFSVG;
(SEQ ID NO: 23)
GQKGQAGLPGAQCPRAYAAFSVG;
(SEQ ID NO: 24)
GQKGQPGPQGHSCKQLYAAFSVG;
(SEQ ID NO: 25)
GQKGSMGAPGERCKSHYAAFSVG;
and
(SEQ ID NO: 26)
GQKGSMGAPGDHCKSQYAAFSVG.
30 . The peptide of claim 22 , wherein said peptide is conjugated or fused to a second peptide or polypeptide.
31 . A pharmaceutical composition comprising the peptide of claim 22 and a pharmaceutically acceptable carrier.
32 . A method of treating a disorder or a condition selected from the group consisting of hypertension associated disorder, cardiovascular disorder, fibrotic condition, endothelial dysfunction disease, respiratory disease, skin injury, condition associated with pregnancy, cancer, bone disease, ischemia-reperfusion injury, inflammatory disorder, autoimmune disorder, inflammatory condition associated with infection, kidney disease, and angiogenesis related condition, the method comprising administering to said subject a therapeutically effective amount of a peptide of claim 22 .
33 . The method of claim 32 , wherein said peptide is selected from a group consisting of SEQ ID NOs: 1-15, 20-26.
34 . The method of claim 32 , wherein the hypertension associated disorder is selected from a group consisting of hypertensive heart disease; antihypertension (blood pressure reduction); systemic and pulmonary high blood pressure; cerebrovascular disease and stroke; heart failure and stroke; left ventricular hypertrophy (LVH); congestive heart failure (CHF); hypertension, high blood pressure; vasodilation; renal hypertension; diuresis; nephritis; natriuresis; scleroderma renal crisis; angina pectoris (stable and unstable); myocardial infarction; heart attack; coronary artery disease; coronary heart disease; cardiac arrhythmias; atrial fibrillation; portal hypertension; raised intraocular pressure; vascular restenosis; chronic hypertension; valvular disease; myocardial ischemia; acute pulmonary edema; acute coronary syndrome; hypertensive retinopathy; hypertensive pregnancy sickness; preeclampsia; Raynaud's phenomenon; erectile dysfunction and glaucoma.
35 . The method of claim 32 , wherein the cancer is selected from a group consisting of colon cancer, lung cancer, breast cancer, prostate cancer, brain cancer, pancreatic cancer, ovarian cancer, kidney cancer, testicular cancer, bone cancer, osteosarcoma, liver cancer, melanoma, glioma, sarcoma, leukemia, or lymphoma, and wherein the cancer is invasive or metastatic.
36 . The method of claim 32 , wherein the bone disease is selected from a group consisting of osteoporosis; osteoarthritis; osteopetrosis; bone inconsistency; osteosarcoma; and cancer metastasis to the bone.
37 . The method of claim 32 , wherein the ischemia-reperfusion injury is associated with ischemic and post-ischemic events in organs and tissues and is selected from a group consisting of thrombotic stroke; myocardial infarction; angina pectoris; embolic vascular occlusions; peripheral vascular insufficiency; splanchnic artery occlusion; arterial occlusion by thrombi or embolisms, arterial occlusion by non-occlusive processes such as following low mesenteric flow or sepsis; mesenteric arterial occlusion; mesenteric vein occlusion; ischemia-reperfusion injury to the mesenteric microcirculation; ischemic acute renal failure; ischemia-reperfusion injury to the cerebral tissue; intestinal intussusception; hemodynamic shock; tissue dysfunction; organ failure; restenosis; atherosclerosis; thrombosis; platelet aggregation, ischemia-reperfusion injury following cardiac surgery; organ surgery; organ transplantation; angiography; cardiopulmonary and cerebral resuscitation.
38 . The method of claim 32 , wherein the inflammatory condition is associated with an infection, and is selected from the group consisting of a viral infection caused by human immunodeficiency virus I (HIV-1) or HIV-2, acquired immune deficiency (AIDS), West Nile encephalitis virus, coronavirus, rhinovirus, influenza virus, dengue virus, HCV, HBV, HAV, hemorrhagic fever; an otological infection; severe acute respiratory syndrome (SARS), sepsis and sinusitis.
39 . The method of claim 32 , wherein the inflammatory disorder is selected from the group consisting of gastritis, gout, gouty arthritis, arthritis, rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, ulcers, chronic bronchitis, asthma, allergy, acute lung injury, pulmonary inflammation, airway hyper-responsiveness, vasculitis, septic shock and inflammatory skin disorders, including but not limited to psoriasis, atopic dermatitis, eczema.
40 . An antibody that selectively binds to an epitope in the peptide of claim 22 .
41 . The antibody of claim 39 , wherein said peptide is selected from the group consisting of
(SEQ ID NO: 1)
AYAAFSV-Amide
(SEQ ID NO: 2)
AYAAFSV;
(SEQ ID NO: 3)
GQKGQVGPPGAACRRAYAAFSV-Amide;
(SEQ ID NO: 4)
GQKGQVGPPGAACRRAYAAFSV;
(SEQ ID NO: 5)
GQKGQVGPPGAAVRRAYAAFSV-Amide;
(SEQ ID NO: 6)
GQKGQVGPPGAAVRRAYAAFSV;
(SEQ ID NO: 7)
GQKGQVGPPGAACRRAYAAFSVGRRAYAAFSV-Amide;
(SEQ ID NO: 8)
GQKGQVGPPGAACRRAYAAFSVGRRAYAAFSV;
(SEQ ID NO: 9)
GQKGQVGPPGAAVRRAYAAFSVGRRAYAAFSV-Amide;
(SEQ ID NO: 10)
GQKGQVGPPGAAVRRAYAAFSVGRRAYAAFSV;
(SEQ ID NO: 11)
AYAAFSVG;
(SEQ ID NO: 12)
GQKGQVGPPGAACRRAYAAFSVG;
(SEQ ID NO: 13)
GQKGQVGPPGAAVRRAYAAFSVG;
(SEQ ID NO: 14)
GQKGQVGPPGAACRRAYAAFSVGRRAYAAFSVG;
(SEQ ID NO: 15)
GQKGQVGPPGAAVRRAYAAFSVGRRAYAAFSVG;
(SEQ ID NO: 20)
GQKGQVGPPGAACQRAYAAFSVG;
(SEQ ID NO: 21)
GQKGQVGPPGAPCQRAYAAFSVG;
(SEQ ID NO: 22)
GQKGQVGPPGAPCQRAYAAFSVG;
(SEQ ID NO: 23)
GQKGQAGLPGAQCPRAYAAFSVG;
(SEQ ID NO: 24)
GQKGQPGPQGHSCKQLYAAFSVG;
(SEQ ID NO: 25)
GQKGSMGAPGERCKSHYAAFSVG;
and
(SEQ ID NO: 26)
GQKGSMGAPGDHCKSQYAAFSVG.Join the waitlist — get patent alerts
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