US2020360476A1PendingUtilityA1
Tissue protective peptides and peptide analogs for preventing and treating diseases and disorders associated with tissue damage
Est. expiryJan 22, 2028(~1.5 yrs left)· nominal 20-yr term from priority
A61K 38/00A61K 38/1816A61P 1/16A61P 39/02A61P 9/10A61P 31/18A61K 38/10A61P 25/28A61P 13/00A61P 1/00A61P 43/00A61P 9/04A61P 35/00C07K 14/505C07K 14/435A61P 3/00A61P 39/00A61P 15/08A61P 15/00A61P 25/00A61P 9/00C07K 9/00A61P 7/06A61P 5/00A61P 1/14A61P 11/00A61P 31/04A61P 17/00A61P 19/08A61P 17/02A61P 19/00A61P 19/02A61K 38/18A61P 31/06C07K 7/06A61P 25/02A61P 3/10A61P 13/12A61P 21/00A61P 29/00A61P 13/02
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Claims
Abstract
The present invention provides peptides and peptide analogs that have tissue protective activities while having little or no potentially undesireable hematopoietic effects. The peptides and peptide analogs are useful in preventing and treating a variety of diseases and disorders associated with tissue damage.
Claims
exact text as granted — not AI-modified1 - 8 . (canceled)
9 . An isolated peptide comprising:
(i) a 9 to 29-residue peptide or peptide analog which has tissue protective activity in a responsive cell, tissue, or organ and which comprises the structural formula (VII):
(SEQ ID NO: 184)
X 1 -X 2 -X 3 -X 4
wherein:
X 1 is Leu (L), Ile (I), Gly (G), Val (V), Phe (F), Pro (P), or Ala (A);
X 2 is a positively charged amino acid;
X 3 is a negatively charged amino acid;
X 4 is Phe (F), Gly (G), Val (V), Leu (L), Ala (A), or Tyr (Y); or
(ii) a deleted form of structural formula (VI) in which at least one and up to two of residues X 1 , X 2 , X 3 , and X 4 are deleted; or
(iii) an altered form of structural formula (VI) in which at least one and up to two of residues X 1 , X 2 , X 3 , and X 4 is conservatively substituted with another residue.
10 . The isolated peptide of claim 9 , wherein the peptide has an amino acid sequence selected from the group consisting of:
Peptide EL
(SEQ ID NO: 185)
IITFESFKENLKDFLLVIPFDCWE;
Peptide EM
(SEQ ID NO: 186)
TAAPTRHPIHIKDGDWNEFRRKLT;
Peptide EN
(SEQ ID NO: 187)
VDVTYGPDTSGKDVFQKKKLGCQL;
Peptide EO
(SEQ ID NO: 188)
SGKDVFQKQGQSVQ;
Peptide EP
(SEQ ID NO: 189)
QELSQWTVRSIHDLRFISSHQTGI;
Peptide EQ
(SEQ ID NO: 190)
WSELTAEQELQRVAREVH;
Peptide ER
(SEQ ID NO: 191)
GASDSNVYDLLKDLEEGIQTLMGR;
Peptide ES
(SEQ ID NO: 192)
GICRNRVTNNVKDVTKLVANLPKD;
Peptide ET
(SEQ ID NO: 193)
FRIFNRSIDAFKDFVVASEETSDCV;
Peptide EU
(SEQ ID NO: 194)
VIQISNDLENLRDLLHVLAFSKSC;
Peptide EV
(SEQ ID NO: 195)
THFPGNLPNMLRDLRDAFSRVKTF;
Peptide EW
(SEQ ID NO: 196)
PGNLPNMLRDLRDAFSRVKTFFQM;
Peptide EX
(SEQ ID NO: 197)
LAQSKNFHLRPRDLISNINVIVLE;
Peptide EY
(SEQ ID NO: 198)
QDPYVKEAENLKKYFNAG;
Peptide EZ
(SEQ ID NO: 199)
VTDLNVQRKAIHELIQVMAELSPA;
Peptide FA
(SEQ ID NO: 200)
PGGAARCQVTLRDLFDRAVVLSHY;
Peptide FB
(SEQ ID NO: 201)
WGLAGLNSCPVKEANQSTLENFLE;
Peptide FC
(SEQ ID NO: 202)
DMTTHLILRSFKEFLQSSLRALRQ;
Peptide FD
(SEQ ID NO: 203)
GPVPPSTALRELIEELVNITQN;
Peptide FE
(SEQ ID NO: 204)
KDLLLHLKKLFREGRFN;
Peptide FF
(SEQ ID NO: 205)
RDTKIEVAQFVKDLLLHLKKLFRE;
Peptide FG
(SEQ ID NO: 206)
LDQIPGYLNRIHELLNGTRGLFPG;
Peptide FH
(SEQ ID NO: 207)
SPISSDFAVKIRELSDYLLQDYPV;
and
Peptide FI
(SEQ ID NO: 208)
YYGRILHYLKAKEYSHCAWTIVRV.
11 . An isolated peptide comprising:
(i) a 9 to 29-residue peptide or peptide analog which has tissue protective activity in a responsive cell, tissue, or organ and which comprises the structural formula (VIII):
(SEQ ID NO: 209)
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
wherein:
X 1 is Ala (A), Thr (T), Ser (S), Tyr (Y), Leu (L), Val (V), Ile (I), Phe (F), or Glu (E);
X 2 is any amino acid;
X 3 is Ser (S), Gln (Q), Asp (D), Leu (L), Glu (E), Cys (C), Asn (N), Arg (R), or Ala (A);
X 4 is Pro (P), Gly (G), Gln (Q), Leu (L), Thr (T), Asn (N), Ser (S), Phe (F), or Ile (I);
X 5 is any amino acid;
X 6 is Pro (P), Ser (S), Cys (C), Val (V), Lys (K), Thr (T), Leu (L), Ile (I), or Gln (Q);
X 7 is any amino acid;
X 8 is Thr (T), Pro (P), Leu (L), Arg (R), Gly (G), Tyr (Y), Gln (Q), Glu (E), Ile (I), or Ala (A);
X 9 is any amino acid;
X 10 is Pro (P), Asn (N), Glu (E), Asp (D), Thr (T), Leu (L), Ile (I), Gln (Q), Phe (F), or Trp (W);
X 11 is Trp (W), Leu (L), Ala (A), Met (M), Val (V), Ile (I), Phe (F), or Tyr (Y);
X 12 is a negatively charged amino acid;
X 13 is a positively charged amino acid;
X 14 is Val (V), Leu (L), Ala (A), or Phe (F);
X 15 is any amino acid;
X 16 is any amino acid;
X 17 is any amino acid;
X 18 is any amino acid;
X 19 is any amino acid;
X 20 is any amino acid;
X 21 Arg (R), Asp (D), Tyr (Y), Val (V), Ile (I), Leu (L), Lys (K), Ser (S), or Thr (T);
X 22 is any amino acid;
X 23 is any amino acid;
X 24 is Leu (L), Pro (P), Phe (F), Arg (R), Tyr (Y), Cys (C), Gly (G), Val (V), or Lys (K); or
(ii) a deleted form of structural formula (VIII) in which at least one and up to 15 residues 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 , and X 24 are deleted; or
(iii) an altered form of structural formula (VIII) in which at least one and up to eight of residues 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 , and X 24 is conservatively substituted with another residue.
12 . The isolated peptide of claim 11 , wherein the peptide has an amino acid sequence selected from the group consisting of:
Peptide FJ
(SEQ ID NO: 210)
ARSPSPSTQPWEHVNAIQEARRLL;
Peptide FK
(SEQ ID NO: 211)
ITFEKLVIP;
Peptide FL
(SEQ ID NO: 212)
TAQGEPFPNNLDKLCGPNVTDFPP;
Peptide FM
(SEQ ID NO: 213)
STDQWSELTEAERLQENLQAYRTF;
Peptide FN
(SEQ ID NO: 214)
YGLLYCFRKDMDKVETFLRIVQCR;
Peptide FO
(SEQ ID NO: 215)
LESQTVQGGTVERLFKNLSLIKKY;
Peptide FP
(SEQ ID NO: 216)
VQLSDSLTDLLDKFSNISEGLSNY;
Peptide FQ
(SEQ ID NO: 217)
ISEGLSNYSIIDKLVNIVDDLVEC;
Peptide FR
(SEQ ID NO: 218)
SSSTKKTQLQLEHLLLDLQMILNG;
Peptide FS
(SEQ ID NO: 219)
FNSNKKKRDDFEKLTNYSVTDLNV;
Peptide FT
(SEQ ID NO: 220)
ARCQVTLRDLFDRAVVLSHYIHNL;
Peptide FU
(SEQ ID NO: 221)
LDRVYNEEKRYTH;
Peptide FV
(SEQ ID NO: 222)
EANQSTLENFLERLKTIMREKYSK;
Peptide FW
(SEQ ID NO: 223)
LERSGLNIEDLEKLQMARPNILGL;
Peptide FX
(SEQ ID NO: 224)
LWRLVLAQRWMERLKTVAGSKMQG;
Peptide FY
(SEQ ID NO: 225)
TVAGSKMQGLLERVNTEIHFVTKC;
Peptide FZ
(SEQ ID NO: 226)
LHAFRIRAVTIDRVMSYLNAS;
and
Peptide GA
(SEQ ID NO: 227)
LQRIHQGLIFYEKLLGSDIFTGEP.
13 - 23 . (canceled)
24 . A pharmaceutical composition comprising the isolated peptide of claim 11 and a pharmaceutically acceptable carrier.
25 . The pharmaceutical composition of claim 24 , wherein the composition is formulated for oral, intranasal, ocular, inhalational, transdermal, rectal, sublingual, or parenteral administration.
26 . (canceled)
27 . A method of treating a subject suffering from a disease associated with tissue damage, the method comprising the step of administering to the subject an effective amount of the isolated peptide of claim 11 .
28 . The method of claim 27 , wherein the disease associated with tissue damage is caused by cancer, ischemic, traumatic, toxic, or inflammatory injuries.
29 . The method of claim 27 , wherein the disease associated with tissue damage is a cardiovascular disease, cardiopulmonary disease, respiratory disease, kidney disease, disease of the urinary system, disease of the reproductive system, bone disease, skin disease, gastrointestinal disease, endocrine abnormality, metabolic abnormality, cognitive dysfunction, or a disease or disorder of the central or peripheral nervous system.
30 . (canceled)
31 . A method for preventing, treating, ameliorating, or managing cancer, a neoplastic disorder, inflammation, or toxic agent exposure in a subject in need thereof comprising administration to said subject an effective amount of an isolated peptide consisting of a sequence of no more than 30 amino acids and comprising the amino acid motif:
(a) H 1 -N 1 -(L) n -P 1 -H 2 , wherein n is 0-1; (SEQ ID NO: 23) or (b) H 1 -P 1 -(L) n -N 1 -H 2 , wherein n is 0-1; (SEQ ID NO: 24) and wherein H 1 and H 2 are hydrophobic amino acids, N 1 is a negatively charged amino acid, L 1 is a polar amino acid, and P 1 is a positively charged amino acid; and wherein said peptide has cellular protective activity.
32 . The method of claim 31 , wherein the isolated peptide is:
Peptide D
(APPRLICDSRVLERYLLEAKEAE, SEQ ID NO.: 14),
Peptide A
(NITVPDTKVNFYAWKRMEVG, SEQ ID NO.: 2),
Peptide B
(QQAVEVWQGLALLSEAVLRGQALLV, SEQ ID NO.: 3),
Peptide C
(GCAEHCSLNENITVPDTKVN, SEQ ID NO.: 4),
Peptide E
(RYLLUNITTGC, SEQ ID NO.: 15),
Peptide IC
(QEQLERALNSS, SEQ ID NO.: 281),
Peptide IS
(CSLNENIQEQLERALNSS, SEQ ID NO.: 296),
Peptide IQ
(QEQLERALNSSLRRYINMLTRTR, SEQ ID NO.: 294),
Peptide BV
(WEHVNAIQEARRLL, SEQ ID NO.: 114),
or
Peptide BX
(KIRSDLTALTESYVKH, SEQ ID NO.: 116).
33 - 46 . (canceled)
47 . The methods of claim 28 , wherein the disease associated with tissue damage is cancer.
48 . The method of claim 47 , wherein the cancer is infiltrating breast cancer, pre-invasive breast cancer, inflammatory breast cancer, Paget's disease, metastatic breast cancer, recurrent breast cancer, appendix cancer, bile duct cancer, extrahepatic bile duct cancer, colon cancer, esophageal cancer, gallbladder cancer, gastric cancer, intestinal cancer, liver cancer, pancreatic cancer, rectal cancer, stomach cancer, adrenal cancer, bladder cancer, kidney cancer, penile cancer, prostate cancer, testicular cancer, urinary cancer, cervical cancer, endrometrial cancer, fallopian tube cancer, ovarian cancer, uterine cancer, vaginal cancer, vulvar cancer, eye cancer, head and neck cancer, jaw cancer, laryngeal cancer, pharyngeal cancer, oral cancer, nasal cavity cancer, salivary gland cancer, sinus cancer, throat cancer, thyroid cancer, tongue cancer, tonsil cancer, Hodgkin's disease, leukemia, acute lymphocytic leukemia, acute granulocytic leukemia, acute myelogenous leukemia, chronic lymphatic leukemia, chronic myelogenous leukemia, multiple myeloma, lymphoma, b-cell lymphoma, lymph node cancer, bone cancer, osteosarcoma, melanoma, skin cancer, basal cell cancer, squamous cell cancer, sarcoma, Ewing's sarcoma, Kaposi's sarcoma, brain cancer, astrocytoma, glioblastoma, glioma, pituitary gland cancer, spinal cord cancer, lung cancer, adenocarcinoma, oat cell cancer, non-small cell lung cancer, small cell lung cancer, squamous cell cancer, or mesothelioma.
49 . The methods of claim 28 , wherein the disease associated with tissue damage is inflammation.
50 . The method of claim 49 , wherein the inflammation is appendicitis, blepharitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chorioamnionitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, endocarditis, endometritis, epicondylitis, epididymitis, fibrositis, gastritis, gingivitis, glossitis, hidradenitis suppurativa, iritis, laryngitis, mastitis, myocarditis, myositis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis (pneumonia), prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tonsillitis, uveitis, urethritis, vaginitis, vulvitis, asthma, systemic lupus erythematosus, myasthenia gravis, tendonitis, angiitis, chronic bronchitis, pancreatitis, osteomyelitis, rheumatoid arthritis, psoriatic arthritis, glumeronephritis, optic neuritis, temporal arteritis, encephalitis, meningitis, traverse myelitis, dermatomyositis, polymyositis, necrotizing fasciitis, hepatitis, necrotizing entercolitis, pelvic inflammatory disease, inflammatory bowel disease, ulcerative colitis, Chron's disease, ileitis, enteritis, proctitis, vasculitis, vascular stenosis, restenosis, hypotension, Type-1 diabetes, Kawasaki disease, Decum's disease, chronic obstructive pulmonary disease, psoriasis, artherosclerosis, scleroderma, Sjogren's syndrome, mixed connective tissue disease, rosacea, gastric ulcers, duodenal ulcers, Alzheimer's disease, adult onset Still's disease, acute retinal pigment epitheliitis, Tietze's syndrome, Bechçet's disease, white dot syndrome, acute posterior multifocal placoid pigment epitheliopathy, serpiginous choroiditis, birdshot chorioretinopathy, multifocal choroiditis with panuveitis, diffuse subretinal fibrosis syndrome, punctuate inner choroidopathy, multiple evanescent white dot syndrome, diffuse unilateral subacute neuroretinitis, granuloma annulare, irritable bowel syndrome, gastroenteritis, Grave's disease, multiple sclerosis, Dupuytren's contracture, graft rejection diseases, allograft rejection, graft-v-host disease, skin graft rejection, solid organ transplant rejection, bone marrow transplant rejection, inflammatory dermatoses, viral cutaneous pathologies such as those derived from human papilloma virus, HIV, or RLV infection, bacterial, fungal and or other parasital cutaneous pathologies, cutaneous lupus erythematosus, Hyper IgG4 disease, allergies, allergic diseases, inflammation resulting from blunt trauma, inflammation resulting from contusions, inflammation resulting allergies, rheumatic disease, childhood arthritis, rheumatoid arthritis, Churg-Strauss syndrome, fibromyalgia, giant cell (temporal) arteritis, gout, Henoch-Schoenlin purpura, hypersensitivity vasculitis, ankylosing spondylitis, capsulitis, rheumatic fever, rheumatic heart disease, systemic lupus erythematosus, polymyalgia rheumatica, osteoarthritis, polyarteritis nodosa, Reiter's syndrome, sports related injuries, runner's knee, tennis elbow, frozen shoulder, Achilles tendonitis, plantar fasciitis, bursitis, Osgood-Schlatter disease, repetitive stress injuries, cumulative trauma diseases, focal dystonia, carpal tunnel syndrome, intersection syndrome, reflex sympathetic dystrophy syndrome, stenosing tenosynovitis, De Quervain's syndrome, trigger finger/trigger thumb, thoracic outlet syndrome, tendonitis, tenosynovitis, radial tunnel syndrome, Raynaud's disease, ganglion, gamer's thumb, Wii-itis, inflammation resulting from infections.
51 . The methods of claim 28 , wherein the disease associated with tissue damage results from exposure to a toxic agent.
52 - 55 . (canceled)
56 . An isolated nucleic acid comprising a nucleotide sequence encoding the isolated peptide of claim 11 .
57 . An expression vector comprising the nucleic acid of claim 56 .
58 . A host cell comprising the expression vector of claim 57 .
59 . A method of recombinantly producing an isolated peptide comprising the step of isolating the peptide from the host cell of claim 58 .
60 . (canceled)Cited by (0)
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