AU5690599A - Cyclic prosaposin-derived peptides and uses thereof - Google Patents
Cyclic prosaposin-derived peptides and uses thereof Download PDFInfo
- Publication number
- AU5690599A AU5690599A AU56905/99A AU5690599A AU5690599A AU 5690599 A AU5690599 A AU 5690599A AU 56905/99 A AU56905/99 A AU 56905/99A AU 5690599 A AU5690599 A AU 5690599A AU 5690599 A AU5690599 A AU 5690599A
- Authority
- AU
- Australia
- Prior art keywords
- amino acid
- peptide
- acid
- hydrophobic amino
- seq
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 108090000765 processed proteins & peptides Proteins 0.000 title claims description 130
- 102000004196 processed proteins & peptides Human genes 0.000 title description 47
- 125000004122 cyclic group Chemical group 0.000 title description 20
- 102100036197 Prosaposin Human genes 0.000 title description 10
- 101710152403 Prosaposin Proteins 0.000 title description 10
- 150000001413 amino acids Chemical class 0.000 claims description 150
- 229940024606 amino acid Drugs 0.000 claims description 147
- 235000001014 amino acid Nutrition 0.000 claims description 147
- 230000002209 hydrophobic effect Effects 0.000 claims description 60
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 32
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 32
- 235000003704 aspartic acid Nutrition 0.000 claims description 32
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 32
- 235000013922 glutamic acid Nutrition 0.000 claims description 32
- 239000004220 glutamic acid Substances 0.000 claims description 32
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 30
- 238000000034 method Methods 0.000 claims description 30
- 102000001189 Cyclic Peptides Human genes 0.000 claims description 23
- 108010069514 Cyclic Peptides Proteins 0.000 claims description 23
- 208000016192 Demyelinating disease Diseases 0.000 claims description 23
- 206010012305 Demyelination Diseases 0.000 claims description 22
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 21
- 230000001537 neural effect Effects 0.000 claims description 21
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 20
- 239000004472 Lysine Substances 0.000 claims description 20
- 235000018977 lysine Nutrition 0.000 claims description 20
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 19
- 241000124008 Mammalia Species 0.000 claims description 19
- 239000004475 Arginine Substances 0.000 claims description 18
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 18
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims description 18
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims description 18
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 18
- 235000009697 arginine Nutrition 0.000 claims description 18
- 208000004296 neuralgia Diseases 0.000 claims description 18
- 208000021722 neuropathic pain Diseases 0.000 claims description 18
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims description 18
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 claims description 17
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims description 17
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims description 17
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 claims description 17
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 claims description 17
- 239000004473 Threonine Substances 0.000 claims description 17
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims description 17
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims description 17
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 claims description 17
- 229960000310 isoleucine Drugs 0.000 claims description 17
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 17
- 235000008521 threonine Nutrition 0.000 claims description 17
- 239000004474 valine Substances 0.000 claims description 17
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 claims description 16
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 claims description 16
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 16
- 235000009582 asparagine Nutrition 0.000 claims description 16
- 229960001230 asparagine Drugs 0.000 claims description 16
- 229930182817 methionine Natural products 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 15
- 230000023105 myelination Effects 0.000 claims description 15
- 230000014511 neuron projection development Effects 0.000 claims description 15
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 claims description 15
- 238000011282 treatment Methods 0.000 claims description 15
- 230000002401 inhibitory effect Effects 0.000 claims description 12
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 10
- 235000004279 alanine Nutrition 0.000 claims description 10
- 230000007850 degeneration Effects 0.000 claims description 10
- 238000007917 intracranial administration Methods 0.000 claims description 8
- 201000006417 multiple sclerosis Diseases 0.000 claims description 8
- 238000007918 intramuscular administration Methods 0.000 claims description 7
- 238000001990 intravenous administration Methods 0.000 claims description 7
- 238000007920 subcutaneous administration Methods 0.000 claims description 7
- 230000000699 topical effect Effects 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 6
- 230000001737 promoting effect Effects 0.000 claims description 6
- 208000014674 injury Diseases 0.000 claims description 5
- 230000008736 traumatic injury Effects 0.000 claims description 5
- 230000001939 inductive effect Effects 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- 238000013270 controlled release Methods 0.000 claims description 3
- 230000004770 neurodegeneration Effects 0.000 claims description 3
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 3
- 208000037906 ischaemic injury Diseases 0.000 claims description 2
- 238000011200 topical administration Methods 0.000 claims description 2
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 claims 1
- 102000017852 Saposin Human genes 0.000 description 22
- 108050007079 Saposin Proteins 0.000 description 22
- 210000004027 cell Anatomy 0.000 description 20
- 241000700159 Rattus Species 0.000 description 15
- 230000000694 effects Effects 0.000 description 13
- 230000000508 neurotrophic effect Effects 0.000 description 13
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 12
- 206010012601 diabetes mellitus Diseases 0.000 description 12
- 238000000338 in vitro Methods 0.000 description 11
- 108010076038 prosaptide Proteins 0.000 description 11
- 108010025020 Nerve Growth Factor Proteins 0.000 description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
- 238000002347 injection Methods 0.000 description 9
- 239000007924 injection Substances 0.000 description 9
- 239000012071 phase Substances 0.000 description 9
- 210000001519 tissue Anatomy 0.000 description 9
- 102000007072 Nerve Growth Factors Human genes 0.000 description 8
- 230000030833 cell death Effects 0.000 description 8
- 230000008499 blood brain barrier function Effects 0.000 description 7
- 210000001218 blood-brain barrier Anatomy 0.000 description 7
- 238000001727 in vivo Methods 0.000 description 7
- 210000003061 neural cell Anatomy 0.000 description 7
- 239000003900 neurotrophic factor Substances 0.000 description 7
- 101800005149 Peptide B Proteins 0.000 description 6
- 210000003169 central nervous system Anatomy 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 108010091748 peptide A Proteins 0.000 description 6
- 239000002953 phosphate buffered saline Substances 0.000 description 6
- 210000004116 schwann cell Anatomy 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 208000002193 Pain Diseases 0.000 description 5
- 206010034620 Peripheral sensory neuropathy Diseases 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 230000000202 analgesic effect Effects 0.000 description 5
- 210000004556 brain Anatomy 0.000 description 5
- 230000002093 peripheral effect Effects 0.000 description 5
- 230000002265 prevention Effects 0.000 description 5
- 201000005572 sensory peripheral neuropathy Diseases 0.000 description 5
- KSDDQEGWVBODMD-OULINLAESA-N (2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-6-amino-2-[[(2S)-4-amino-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-amino-3-sulfanylpropanoyl]amino]-4-carboxybutanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]-3-methylbutanoyl]amino]hexanoyl]amino]-4-carboxybutanoyl]amino]-3-methylbutanoyl]amino]-3-hydroxybutanoyl]amino]hexanoyl]amino]-4-methylpentanoyl]amino]-3-methylpentanoyl]amino]-3-carboxypropanoyl]amino]-4-oxobutanoyl]amino]-4-oxobutanoyl]amino]hexanoyl]amino]-3-hydroxybutanoyl]amino]-4-carboxybutanoyl]amino]hexanoyl]amino]-4-carboxybutanoyl]amino]-3-methylpentanoyl]amino]-4-methylpentanoic acid Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CS)CC1=CC=CC=C1 KSDDQEGWVBODMD-OULINLAESA-N 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- 229930012538 Paclitaxel Natural products 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000003902 lesion Effects 0.000 description 4
- 239000002502 liposome Substances 0.000 description 4
- 108010009298 lysylglutamic acid Proteins 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 210000002161 motor neuron Anatomy 0.000 description 4
- 210000002241 neurite Anatomy 0.000 description 4
- 229960001592 paclitaxel Drugs 0.000 description 4
- 210000001428 peripheral nervous system Anatomy 0.000 description 4
- 230000017854 proteolysis Effects 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 230000001953 sensory effect Effects 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 4
- 230000000472 traumatic effect Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 102000006386 Myelin Proteins Human genes 0.000 description 3
- 108010083674 Myelin Proteins Proteins 0.000 description 3
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 3
- HJOSVGCWOTYJFG-WDCWCFNPSA-N Thr-Glu-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N)O HJOSVGCWOTYJFG-WDCWCFNPSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- -1 aromatic amino acids Chemical class 0.000 description 3
- 125000000613 asparagine group Chemical group N[C@@H](CC(N)=O)C(=O)* 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 3
- 238000012217 deletion Methods 0.000 description 3
- 230000037430 deletion Effects 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 210000005064 dopaminergic neuron Anatomy 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 239000012894 fetal calf serum Substances 0.000 description 3
- 239000012634 fragment Substances 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 238000010253 intravenous injection Methods 0.000 description 3
- 208000036546 leukodystrophy Diseases 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 210000005012 myelin Anatomy 0.000 description 3
- 210000005036 nerve Anatomy 0.000 description 3
- 210000002569 neuron Anatomy 0.000 description 3
- 201000001119 neuropathy Diseases 0.000 description 3
- 230000007823 neuropathy Effects 0.000 description 3
- 239000000816 peptidomimetic Substances 0.000 description 3
- 208000027232 peripheral nervous system disease Diseases 0.000 description 3
- 208000033808 peripheral neuropathy Diseases 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 230000008929 regeneration Effects 0.000 description 3
- 238000011069 regeneration method Methods 0.000 description 3
- 210000000278 spinal cord Anatomy 0.000 description 3
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 3
- 229960001052 streptozocin Drugs 0.000 description 3
- 210000003523 substantia nigra Anatomy 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- APHUDFFMXFYRKP-CIUDSAMLSA-N Asn-Asn-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC(=O)N)N APHUDFFMXFYRKP-CIUDSAMLSA-N 0.000 description 2
- UQBGYPFHWFZMCD-ZLUOBGJFSA-N Asp-Asn-Asn Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O UQBGYPFHWFZMCD-ZLUOBGJFSA-N 0.000 description 2
- 108010005939 Ciliary Neurotrophic Factor Proteins 0.000 description 2
- 102100031614 Ciliary neurotrophic factor Human genes 0.000 description 2
- 108091035707 Consensus sequence Proteins 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 208000004454 Hyperalgesia Diseases 0.000 description 2
- KOSWSHVQIVTVQF-ZPFDUUQYSA-N Leu-Ile-Asp Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(O)=O)C(O)=O KOSWSHVQIVTVQF-ZPFDUUQYSA-N 0.000 description 2
- 201000011442 Metachromatic leukodystrophy Diseases 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 102000015336 Nerve Growth Factor Human genes 0.000 description 2
- 208000028389 Nerve injury Diseases 0.000 description 2
- 101100342977 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) leu-1 gene Proteins 0.000 description 2
- 208000018737 Parkinson disease Diseases 0.000 description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 2
- 108090000631 Trypsin Proteins 0.000 description 2
- 102000004142 Trypsin Human genes 0.000 description 2
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 230000001919 adrenal effect Effects 0.000 description 2
- 238000003782 apoptosis assay Methods 0.000 description 2
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 210000003050 axon Anatomy 0.000 description 2
- 230000006399 behavior Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 208000015114 central nervous system disease Diseases 0.000 description 2
- 210000001638 cerebellum Anatomy 0.000 description 2
- 210000002932 cholinergic neuron Anatomy 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 230000000875 corresponding effect Effects 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 210000000609 ganglia Anatomy 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 238000002513 implantation Methods 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 230000000302 ischemic effect Effects 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 230000005923 long-lasting effect Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 210000003007 myelin sheath Anatomy 0.000 description 2
- 230000008764 nerve damage Effects 0.000 description 2
- 229940053128 nerve growth factor Drugs 0.000 description 2
- 210000000578 peripheral nerve Anatomy 0.000 description 2
- 230000005522 programmed cell death Effects 0.000 description 2
- 206010036807 progressive multifocal leukoencephalopathy Diseases 0.000 description 2
- 238000011552 rat model Methods 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000002207 retinal effect Effects 0.000 description 2
- 230000035807 sensation Effects 0.000 description 2
- 235000004400 serine Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 239000012588 trypsin Substances 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
- LSMDIAAALJJLRO-XQXXSGGOSA-N Ala-Thr-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O LSMDIAAALJJLRO-XQXXSGGOSA-N 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- 102000004400 Aminopeptidases Human genes 0.000 description 1
- 108090000915 Aminopeptidases Proteins 0.000 description 1
- RJUHZPRQRQLCFL-IMJSIDKUSA-N Asn-Asn Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CC(N)=O)C(O)=O RJUHZPRQRQLCFL-IMJSIDKUSA-N 0.000 description 1
- AYOAHKWVQLNPDM-HJGDQZAQSA-N Asn-Lys-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O AYOAHKWVQLNPDM-HJGDQZAQSA-N 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- 239000011547 Bouin solution Substances 0.000 description 1
- 101100512078 Caenorhabditis elegans lys-1 gene Proteins 0.000 description 1
- 101100315624 Caenorhabditis elegans tyr-1 gene Proteins 0.000 description 1
- 102000005367 Carboxypeptidases Human genes 0.000 description 1
- 108010006303 Carboxypeptidases Proteins 0.000 description 1
- 108010058699 Choline O-acetyltransferase Proteins 0.000 description 1
- 102100023460 Choline O-acetyltransferase Human genes 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 108090000317 Chymotrypsin Proteins 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 101500007657 Crotalus durissus terrificus Crotoxin chain gamma Proteins 0.000 description 1
- 208000025962 Crush injury Diseases 0.000 description 1
- UYYZZJXUVIZTMH-AVGNSLFASA-N Cys-Glu-Phe Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O UYYZZJXUVIZTMH-AVGNSLFASA-N 0.000 description 1
- 125000000030 D-alanine group Chemical group [H]N([H])[C@](C([H])([H])[H])(C(=O)[*])[H] 0.000 description 1
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- QXDXIXFSFHUYAX-MNXVOIDGSA-N Glu-Ile-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CCC(O)=O QXDXIXFSFHUYAX-MNXVOIDGSA-N 0.000 description 1
- ILWHFUZZCFYSKT-AVGNSLFASA-N Glu-Lys-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O ILWHFUZZCFYSKT-AVGNSLFASA-N 0.000 description 1
- WGYHAAXZWPEBDQ-IFFSRLJSSA-N Glu-Val-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O WGYHAAXZWPEBDQ-IFFSRLJSSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 101500025567 Homo sapiens Saposin-C Proteins 0.000 description 1
- 108090000604 Hydrolases Proteins 0.000 description 1
- 102000004157 Hydrolases Human genes 0.000 description 1
- 208000035154 Hyperesthesia Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- ZURHXHNAEJJRNU-CIUDSAMLSA-N Leu-Asp-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O ZURHXHNAEJJRNU-CIUDSAMLSA-N 0.000 description 1
- YQFZRHYZLARWDY-IHRRRGAJSA-N Leu-Val-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCCN YQFZRHYZLARWDY-IHRRRGAJSA-N 0.000 description 1
- WVJNGSFKBKOKRV-AJNGGQMLSA-N Lys-Leu-Ile Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O WVJNGSFKBKOKRV-AJNGGQMLSA-N 0.000 description 1
- SITLTJHOQZFJGG-UHFFFAOYSA-N N-L-alpha-glutamyl-L-valine Natural products CC(C)C(C(O)=O)NC(=O)C(N)CCC(O)=O SITLTJHOQZFJGG-UHFFFAOYSA-N 0.000 description 1
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 1
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 1
- MBLBDJOUHNCFQT-LXGUWJNJSA-N N-acetylglucosamine Natural products CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO MBLBDJOUHNCFQT-LXGUWJNJSA-N 0.000 description 1
- 108010010224 NK-lysin Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010029174 Nerve compression Diseases 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 208000005890 Neuroma Diseases 0.000 description 1
- 208000010886 Peripheral nerve injury Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- JLKVWTICWVWGSK-JYJNAYRXSA-N Tyr-Lys-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 JLKVWTICWVWGSK-JYJNAYRXSA-N 0.000 description 1
- GVNLOVJNNDZUHS-RHYQMDGZSA-N Val-Thr-Lys Chemical compound [H]N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(O)=O GVNLOVJNNDZUHS-RHYQMDGZSA-N 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 208000002552 acute disseminated encephalomyelitis Diseases 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 201000007930 alcohol dependence Diseases 0.000 description 1
- 206010053552 allodynia Diseases 0.000 description 1
- KOSRFJWDECSPRO-UHFFFAOYSA-N alpha-L-glutamyl-L-glutamic acid Natural products OC(=O)CCC(N)C(=O)NC(CCC(O)=O)C(O)=O KOSRFJWDECSPRO-UHFFFAOYSA-N 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 230000001713 cholinergic effect Effects 0.000 description 1
- 229960002376 chymotrypsin Drugs 0.000 description 1
- 230000001886 ciliary effect Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 230000007515 enzymatic degradation Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 210000003414 extremity Anatomy 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 239000000834 fixative Substances 0.000 description 1
- 210000002683 foot Anatomy 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 235000004554 glutamine Nutrition 0.000 description 1
- 108010055341 glutamyl-glutamic acid Proteins 0.000 description 1
- 150000002339 glycosphingolipids Chemical class 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 210000004209 hair Anatomy 0.000 description 1
- 230000002008 hemorrhagic effect Effects 0.000 description 1
- 210000000548 hind-foot Anatomy 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 230000030214 innervation Effects 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 208000018769 loss of vision Diseases 0.000 description 1
- 231100000864 loss of vision Toxicity 0.000 description 1
- 230000002132 lysosomal effect Effects 0.000 description 1
- 210000003712 lysosome Anatomy 0.000 description 1
- 230000001868 lysosomic effect Effects 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 108091005601 modified peptides Proteins 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 210000004457 myocytus nodalis Anatomy 0.000 description 1
- 229950006780 n-acetylglucosamine Drugs 0.000 description 1
- 210000004126 nerve fiber Anatomy 0.000 description 1
- 230000001474 neuritogenic effect Effects 0.000 description 1
- 230000016273 neuron death Effects 0.000 description 1
- 230000004031 neuronal differentiation Effects 0.000 description 1
- 230000004112 neuroprotection Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000001473 noxious effect Effects 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid group Chemical group C(CCCCCCC\C=C/CCCCCCCC)(=O)O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 210000002856 peripheral neuron Anatomy 0.000 description 1
- 210000005223 peripheral sensory neuron Anatomy 0.000 description 1
- 108010064486 phenylalanyl-leucyl-valine Proteins 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 210000004129 prosencephalon Anatomy 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000979 retarding effect Effects 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 210000001044 sensory neuron Anatomy 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 230000002739 subcortical effect Effects 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
- 230000001228 trophic effect Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 210000004885 white matter Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/475—Growth factors; Growth regulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Toxicology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Vascular Medicine (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Pain & Pain Management (AREA)
- Ophthalmology & Optometry (AREA)
- Psychology (AREA)
- Urology & Nephrology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Description
WO 00/12553 PCT/US99/19378 CYCLIC PROSAPOSIN-DERIVED PEPTIDES AND USES THEREOF Field of the Invention The present invention relates to neurotrophic and analgesic peptides. More 5 particularly, the invention relates to cyclic peptides derived from the active region of saposin C which have neurotrophic and analgesic effects. Background of the Invention Neurotrophic factors are proteins or peptides capable of affecting the survival, target innervation and/or function of neuronal cell populations (Barde, Neuron 2:1525 10 1534, 1989). The efficacy of neurotrophic factors both in vitro and in vivo have been well-documented. For example, nerve growth factor (NGF) acts as atrophic factor for forebrain cholinergic, peripheral and sensory neurons (Hefti et al., Neurobiol. Aging 10:515-533, 1989) and can reverse naturally-occurring as well as physical traumatic injuries to peripheral nerves (Rich et al., J Neurocytol. 16:261-268, 1987). Brain 15 derived neurotrophic factor (BDNF) is a trophic factor for peripheral sensory neurons, dopaminergic neurons of the substantia nigra, central cholinergic neurons and retinal ganglia (Henderson et al., Restor. Neurol. Neurosci. 5:15-28, 1993). BDNF has been shown to prevent naturally-occurring cell death both in vitro and in vivo (Hofer et al., Nature 331:262-262, 1988). Ciliary neurotrophic factor (CNTF) promotes survival of 20 chicken embryo ciliary ganglia in vitro and supports survival of cultured sympathetic sensory and spinal motor neurons (Ip et al., J. Physiol. Paris 85:122-130, 1991). Demyelination is a defect common to a number of central nervous system (CNS) disorders, the most prevalent being multiple sclerosis (MS). MS, a chronic disorder which may lead to total disability, is characterized by damage to the myelin sheath, while leaving the axons 25 mostly intact. There is currently no effective treatment for MS. Other central nervous system disorders involving demyelination include acute disseminated encephalomyelitis, amyotrophic lateral sclerosis, acute hemorrhagic leukodystrophy, progressive multifocal leukoencephalitis, metachromatic leukodystrophy and adrenal leukodystrophy. The peripheral nervous system (PNS) can also be afflicted with demyelination, such as that occurring in Guillain-Barre 30 syndrome (Pathologic Basis of Disease, Robbins et al. eds., W.B. Saunders, Philadelphia, 1979, pp. 1578-1582). -1- WO 00/12553 PCT/US99/19378 Peripheral nerve injuries and peripheral neuropathies, such as those resulting from diabetes or chemotherapy, comprise the most prevalent peripheral nervous system disorders. Current treatments for peripheral nervous system disorders only treat the symptoms, not the cause of the disease. 5 Neuropathic pain results from nerve injury, such as a nerve compression or crush and traumatic injury to the spinal cord, and is often long-lasting or chronic. Most traumatic nerve injuries also cause the formation of neuromas, in which pain occurs as a result of aberrant nerve regeneration. In addition, cancer-related neuropathic pain results when tumor growth compresses adjacent nerves, brain or spinal cord. Neuropathic pain 10 is also associated with diseases including diabetes and alcoholism. In most cases, neuropathic pain is resistant to current drugs. These drugs also have serious side-effects. U.S. Patent Application Serial No. 08/611,307 provides a method for alleviating or preventing neuropathic pain by administering to an individual an effective amount of an active fragment of prosaposin. 15 Prosaposin is the precursor of a group of four small heat-stable glycoproteins which are required for hydrolysis of glycosphingolipids by lysosomal hydrolases (Kishimoto et al., J. Lipid Res. 33:1255-1267, 1992). Prosaposin is proteolytically processed in lysosomes, generating saposins A, B, C and D (O'Brien et al., FASEB 1. 5:301-308, 1991). O'Brien et al. (Proc. Natl. Acad. Sci. U.S.A. 91:9593-9596, 1994), 20 U.S. Patent No. 5,571,787 and published PCT Application No. WO95/03821 disclose that prosaposin, saposin C stimulate neurite outgrowth and promote increased myelination. In addition, U.S. Patent Nos. 5,571,787, 5,696,080, 5,714,459 and published PCT application No. WO95/03821 disclose that a 22-mer peptide (CEFLVKEVTKLIDNNKTEKEIL; SEQ ID NO: 1) consisting of amino acids 8-29 of 25 human saposin C stimulates neurite outgrowth. These references also disclose that an 18-mer peptide (YKEVTKLIDNNKTEKEL; SEQ ID NO: 2) contained within the active 22-mer of saposin C (with V replaced by Y) also promotes neurite outgrowth and is capable of crossing the blood brain barrier. O'Brien et al. (FASEB J 9:681-685, 1995) show that the 22-mer stimulates choline acetyltransferase activity and prevented 30 neuronal cell death. The active neuritogenic fragment was localized to a linear 12-mer sequence located within the amino terminus of saposin C (LIDNNKTEKEIL; SEQ ID -2- WO 00/12553 PCT/US99/19378 NO: 3) (O'Brien et al., FASEBJ. 9:681-685, 1994). Liepinsh et al. (Nature Struct. Biol. 4:793-795) indicated that the loop conformation of a neurotrophically active peptide segment of NK-lysin (residues 17-30) could be mimicked by a circular peptide. A major obstacle to the in vivo therapeutic use of peptides is their susceptibility 5 to proteolytic degradation. The present invention provides cyclic prosaposin peptidomimetics which have good resistance to proteolytic degradation and are capable of crossing the blood brain barrier. Summary of the Invention One embodiment of the present invention is a cyclic neurotrophic and analgesic 10 peptide having between about 11 and 25 amino acids, and including the sequence
XIX
2
X
3
NNX
4 TXsX 6 XTXs, wherein X 1 is a hydrophobic amino acid (alanine, leucine, isoleucine, valine, tyrosine, tryptophan, phenylalanine or methionine); X 2 is a hydrophobic amino acid, X 3 is aspartic acid, glutamic acid, lysine or arginine; N is asparagine, X 4 is any amino acid; T is threonine; X 5 is glutamic acid or aspartic acid; X6 15 is any amino acid, X7, is a hydrophobic amino acid; and X 8 is a hydrophobic amino acid. Preferably, the peptide has the amino acid sequence shown in SEQ ID NO: 5 or 6. The present invention also provides a composition comprising the peptide described above in a septum sealed vial, formulated with a controlled release material, in lyophilized form, in liposomal form, in a form suitable for topical administration or in 20 unit dosage form. Another embodiment of the present invention is a method for inducing myelination or inhibiting demyelination in a mammal, comprising administering to a mammal afflicted with demyelination a pharmaceutically effective demyelination inhibiting amount of a cyclic peptide having between about 11 and 25 amino acids, and 25 including the sequence XIX 2
X
3
NNX
4 TXsX6X 7 Xs, wherein X 1 is a hydrophobic amino acid (leucine, isoleucine, valine, tyrosine, tryptophan, phenylalanine or methionine); X 2 is a hydrophobic amino acid, X 3 is aspartic acid, glutamic acid, lysine or arginine; N is asparagine, X 4 is any amino acid; T is threonine; X 5 is glutamic acid or aspartic acid; X 6 is any amino acid, X 7 is a hydrophobic amino acid; and Xs is a hydrophobic amino acid. 30 In one aspect of this preferred embodiment, the demyelination is due to multiple sclerosis, ischemic injury or traumatic injury. Preferably, the administration is WO 00/12553 PCT/US99/19378 intravenous, intramuscular, intradermal. subcutaneous, intracranial, intracerebrospinal or topical. Advantageously, the peptide is administered in a pharmaceutically acceptable carrier. In another aspect of this preferred embodiment, the peptide is enclosed in a lamellar structure. Preferably, the peptide has the sequence shown in SEQ ID NOS: 5 or 5 6. In another aspect of this preferred embodiment, the mammal is a human. The present invention also provides a method for inhibiting neural degeneration or promoting neurite outgrowth in neural tissue, comprising: contacting neural tissue susceptible to such degeneration with an effective neural degeneration-inhibiting amount of a cyclic peptide having between about 11 and 25 amino acids, and including the 10 sequence XIX 2
X
3
NNX
4 TXsX 6
X
7 Xs, wherein X, is a hydrophobic amino acid (leucine, isoleucine, valine, tyrosine, tryptophan, phenylalanine or methionine); X 2 is a hydrophobic amino acid, X 3 is aspartic acid, glutamic acid, lysine or arginine; N is asparagine, X 4 is any amino acid; T is threonine; X 5 is glutamic acid or aspartic acid; X 6 is any amino acid, X 7 is a hydrophobic amino acid; and X 8 is a hydrophobic amino acid. 15 Preferably, the peptide has the amino acid sequence shown in SEQ ID NOS: 5 or 6. Preferably, the administration is intravenous, intramuscular, intradermal. subcutaneous, intracranial, intracerebrospinal or topical. Advantageously, the peptide is administered in a pharmaceutically acceptable carrier. In another aspect of this preferred embodiment, the peptide is enclosed in a lamellar structure. Preferably, the mammal is a human. 20 Still another embodiment of the invention is a method for treating neuropathic pain in a mammal in need thereof, comprising the step of administering to a mammal suffering from neuropathic pain an amount of a cyclic peptide effective to inhibit neuronal degeneration, wherein said peptide peptide has between about 11 and 25 amino acids, and including the sequence XIX 2
X
3
NNX
4 TXsX 6
X
7
X
8 , wherein X, is a 25 hydrophobic amino acid (leucine, isoleucine, valine, tyrosine, tryptophan, phenylalanine or methionine); X 2 is a hydrophobic amino acid, X 3 is aspartic acid, glutamic acid, lysine or arginine; N is asparagine, X 4 is any amino acid; T is threonine; X 5 is glutamic acid or aspartic acid; X 6 is any amino acid, X 7 is a hydrophobic amino acid; and X 8 is a hydrophobic amino acid. Preferably, the administering step is intravenous, 30 intramuscular, intradermal, subcutaneous, intracranial, intracerebrospinal, topical or oral. Advantageously, the peptide has the amino acid sequence shown in SEQ ID NOS: 5 or -4- WO 00/12553 PCT/US99/19378 6. Advantageously, the peptide is administered in a pharmaceutically acceptable carrier. In another aspect of this preferred embodiment, the peptide is enclosed in a lamellar structure. Preferably, the mammal is a human. The present invention also provides a cyclic peptide having between about 11 and 5 25 amino acids, and including the sequence XIX 2
X
3
NNX
4 TXsX 6
XX
8 , wherein X 1 is a hydrophobic amino acid (leucine, alanine isoleucine, valine, tyrosine, tryptophan, phenylalanine or methionine); X 2 is a hydrophobic amino acid, X 3 is aspartic acid, glutamic acid, lysine or arginine; N is asparagine, X 4 is any amino acid; T is threonine; X 5 is glutamic acid or aspartic acid; X 6 is any amino acid, X 7 is a hydrophobic amino acid; 10 and Xs is a hydrophobic amino acid, for use in inducing myelination or inhibiting demyelination in a mammal. Preferably, the peptide has the sequence shown in SEQ ID NOS: 5 or 6. Another embodiment of the invention is a cyclic peptide having between about 11 and 25 amino acids, and including the sequence X 1
X
2
X
3
NNX
4 TXsX 6
X
7
X
8 , wherein X, is 15 a hydrophobic amino acid (leucine, alanine isoleucine, valine, tyrosine, tryptophan, phenylalanine or methionine); X 2 is a hydrophobic amino acid, X 3 is aspartic acid, glutamic acid, lysine or arginine; N is asparagine, X 4 is any amino acid; T is threonine; X 5 is glutamic acid or aspartic acid; X 6 is any amino acid, X 7 is a hydrophobic amino acid; and X 8 is a hydrophobic amino acid for use in inhibiting neural degeneration or 20 promoting neurite outgrowth. Preferably, the peptide has the sequence shown in SEQ ID NOS: 5 or 6. The present invention also provides a cyclic peptide having between about 11 and 25 amino acids, and including the sequence XIX 2
X
3
NNX
4 TXsX 6
X
7
X
8 , wherein X! is a hydrophobic amino acid (leucine, alanine isoleucine, valine, tyrosine, tryptophan, 25 phenylalanine or methionine); X 2 is a hydrophobic amino acid, X 3 is aspartic acid, glutamic acid, lysine or arginine; N is asparagine, X 4 is any amino acid; T is threonine; X 5 is glutamic acid or aspartic acid; X 6 is any amino acid, X 7 is a hydrophobic amino acid; and X 8 is a hydrophobic amino acid for use in treatment of neuropathic pain. Preferably, the peptide has the sequence shown in SEQ ID NOS: 5 or 6 30 Detailed Description of the Preferred Embodiment -5- WO 00/12553 PCT/US99/19378 The present invention provides cyclic saposin C-derived peptides having between about 11 and 25 amino acids, and including the consensus sequence
XIX
2
X
3
NNX
4 TXsX 6
XX
8 (SEQ ID NO: 4), wherein X, is a hydrophobic amino acid (alanine, leucine, isoleucine, valine, tyrosine, tryptophan, phenylalanine or methionine); 5 X 2 is a hydrophobic amino acid, X 3 is aspartic acid, glutamic acid, lysine or arginine; N is asparagine, X 4 is any amino acid; T is threonine; X 5 is glutamic acid or aspartic acid; X 6 is any amino acid, X 7 is a hydrophobic amino acid; and Xg is a hydrophobic amino acid. In a preferred embodiment, the peptide has the sequence: cyclo-[LLDNNKTEKLY] (SEQ ID NO: 5) or cyclo-[LIDNNATEEIL] (SEQ ID NO: 6). Due to their 10 constrained structures, these cyclic prosaposin peptidomimetics are significantly more resistant to enzymatic degradation and are capable of crossing the blood brain barrier to a greater extent than corresponding linear peptides. The cyclic peptides of the invention are equally as effective or more effective in stimulating neurite outgrowth than a known highly-active linear prosaposin peptidomimetic ("prosaptide") having the sequence 15 TXLIDNNATEEILY, wherein X is D-alanine (SEQ ID NO: 7) (Example 1). Moreover, the cyclic peptides of the invention are more effective than prosaptide in preventing neural cell death in vitro (Example 2). These cyclic peptides lack free amino- and carboxy-terminal ends. Thus, they are more resistant to degradation in vivo by aminopeptidases and carboxypeptidases which degrade peptides from the amino-and carboxy-termini. 20 Cyclic saposin C-derived peptides comprising the active 11-mer region (SEQ ID NO: 4), and neurotrophic analogs thereof, have utility in promoting functional recovery after toxic, traumatic, ischemic, degenerative and inherited lesions to the peripheral and central nervous system. In addition, these peptides stimulate myelination and counteract the effects of demyelinating diseases. These peptides stimulate the outgrowth of neurons, promote 25 myelination, promote neuroprotection and prevent programmed cell death in neuronal tissues in mammals, preferably humans. The peptides of the invention can also be used to treat various neuropathies including, but not limited to, motor, sensory, peripheral, taxol-induced and diabetic neuropathies. As used herein, a neuropathy is a functional disturbance or pathological change in the peripheral nervous system and is characterized clinically by sensory 30 or motor neuron abnormalities. The peptides are also useful as analgesics, particularly for the -6- WO 00/12553 PCT/US99/19378 treatment of neuropathic pain in a mammal, preferably a human, which can develop days or months after a traumatic injury and is often long-lasting or chronic. The second asparagine residue within the native prosaposin sequence (corresponding to second "N" in SEQ ID NO: 4 ) is known to be glycosylated with N-acetylglucosamine 5 which may provide some resistance to proteolytic degradation. The synthetic modification of this asparagine residue within the instant non-native saposin C-derived peptides by standard methods (i.e. Merrifield synthesis) with various carbohydrates, preferably glucose, is also within the scope of the present invention. One embodiment of the present invention is a method of facilitating neurite 10 outgrowth or increased myelination in differentiated or undifferentiated neural cells by administering to the cells an effective, neurite outgrowth or myelin-facilitating amount of a saposin C-derived peptide encompassing the active cyclic 11-mer region shown in SEQ ID NO:4. Saposin C-derived cyclic peptide analogs of the invention can differ from saposin C 15 sequences or SEQ ID NOS: 4-6, for example, by replacement of one or more lysine and/or arginine residues; replacement of one or more tyrosine and/or phenylalanine residues, deletion of one or more phenylalanine residues and/or conservative replacement of one or more amino acids within the peptide. The replacement or deletion of lysine/arginine and tyrosine/phenylalanine residues will reduce the susceptibility of peptide degradation by trypsin 20 and chymotrypsin, respectively. The cyclic neurotrophic and myelinotrophic peptide sequences of the invention preferably have up to about 50 amino acids; more preferably, up to about 30 amino acids; and most preferably, between about 11 and 25 amino acids and include therein the sequence shown in SEQ ID NO: 4. Additional variations of these peptide sequences contemplated for use in the present 25 invention include minor insertions, deletions and substitutions. For example, conservative amino acid replacements are contemplated. Such replacements are, for example, those that take place within a family of amino acids that are related in the chemical nature of their side chains. The families of amino acids include the basic charged amino acids (lysine, arginine, histidine); the acidic charged amino acids (aspartic acid, glutamic acid); the non-polar amino 30 acids (alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan); the uncharged polar amino acids (glycine, asparagine, glutamine, cysteine, serine, threonine, -7- WO 00/12553 PCT/US99/19378 tyrosine); and the aromatic amino acids (phenylalanine, tryptophan and tyrosine). In particular, it is generally accepted that conservative amino acid replacements consisting of an isolated replacement of a leucine with an isoleucine or valine, or an aspartic acid with a glutamic acid, or a threonine with a serine, or a similar conservative replacement of an amino 5 acid with a structurally related amino acid will not significantly affect the properties of the peptide. The cyclic saposin C-derived sequences including SEQ ID NO: 4 can be modified to attain various objectives such as increased activity and stability. Other amino acids can be present outside this consensus sequence including native saposin C sequence, conservative substitutions of these native sequences, or unrelated peptide sequences to achieve objectives 10 such as increased binding, hydrophobicity, hydrophilicity and the like. Sequences outside the active neurotrophic region are not typically required for activity. Thus, in most instances, the subject peptide will be active regardless of the identity of these sequences. Again, any such peptide can be screened for such activity using the protocols described herein. The ability of any such cyclic peptide to stimulate neurite outgrowth, prevent neural 15 cell death, promote myelination, inhibit demyelination, alleviate neuropathic pain and treat sensory neuropathy can easily be determined by one of ordinary skill in the art using the procedures described in Examples 1-9. Methods for assaying the abilities of these peptides to promote myelination and to inhibit demyelination are set forth in Examples 3 and 4 hereinbelow. 20 A typical minimum amount of the peptides of the invention for the neurotrophic activity in cell growth medium is usually at least about 5 ng/ml. This amount or more of the cyclic synthetic peptides of the invention for in vitro use is contemplated. Typically, concentrations in the range of 0.1 tg/ml to about 10 pg/ml of these peptides will be used. Effective amounts for any particular tissue can be determined in accordance with Example 1. 25 The neural cells can be treated in vitro or ex vivo by directly administering the peptides of the invention to the cells. This can be done, for example, by culturing the cells in growth medium suitable for the particular cell type, followed by addition of the peptide to the medium. When the cells to be treated are in vivo, typically in a vertebrate, preferably a mammal, the composition can be administered by one of several techniques. Most preferably, 30 the composition is injected directly into the blood or tissue in sufficient quantity to give the desired local concentration of peptide. In the peptides lacking lysine and arginine residues, -8- WO 00/12553 PCT/US99/19378 proteolytic degradation is reduced. The smaller peptides (i.e., 20-mer or less) will most likely cross the blood brain barrier and enter the central nervous system for treatment of CNS disorders (see Banks et al., Peptides, 13:1289-1294, 1992). The peptides of the invention may also be esterified with fatty acids to form peptide 5 fatty acid esters using conventional acid-catalyzed esterification. Alternatively, the last amino acid added in the synthetic procedure is itself a commercially available esterified amino acid which obviates the need for the esterification reaction. Fatty acids contemplated for use in formation of peptide esters include lauric, myristic, palmitic, stearic, oleic and linoleic. The subject peptides may also be acetylated by inclusion of commercially available 10 acetylated lysine, arginine or asparagine residues during the synthetic procedure. These modified peptides retain the activity of the parent compound. Such modifications will facilitate the ability of the peptide to cross the blood brain barrier due to increased hydrophobicity. For treatment of neural disorders, direct intracranial injection or injection into the 15 cerebrospinal fluid may also be used in sufficient quantities to give the desired local concentration of neurotrophin. In both cases, a pharmaceutically acceptable injectable carrier is used. Such carriers include, for example, phosphate buffered saline and Ringer's solution. Alternatively, the composition can be administered to peripheral neural tissue by direct local injection or by systemic administration. Various conventional modes of administration are 20 contemplated, including intravenous, intracerebrospinal, intramuscular, intradermal, subcutaneous, intracranial, intranasal, epidural, topical and oral. For use as an analgesic, administration by direct intramuscular or intravenous injection is preferred. The peptide compositions of the invention can be packaged and administered in unit dosage form, such as an injectable composition or local preparation in a dosage amount 25 equivalent to the daily dosage administered to a patient or as a controlled release composition. A septum sealed vial containing a daily dose of the active ingredient in either PBS or in lyophilized form is an example of a unit dosage. Appropriate daily systemic dosages of the peptides of the invention based on the body weight of the vertebrate for treatment of neural diseases, demyelination or as an analgesic in general or for treatment of 30 neuropathic pain are in the range of from about 0.01 to about 10,000 gtg/kg. More preferably, daily systemic dosages are between about 0.1 and 1,000 tg/kg. Most preferably, -9- WO 00/12553 PCT/US99/19378 daily systemic dosages are between about 10 and 100 tg/kg. Thus, for the typical 70 kg human, dosages can be between about 0.7 and 700,000 tg daily; more preferably between about 7 and 70,000 tg daily; and most preferably between about 700 and 7,000 tg/kg. Daily dosages of locally administered material will be about an order of magnitude less. Oral 5 administration is also contemplated. In one preferred embodiment of the invention, the neurotrophic peptides are administered locally to neural cells in vivo by implantation thereof For example, polylactic acid, polygalactic acid, regenerated collagen, multilamellar liposomes and many other conventional depot formulations is expressly contemplated in the present invention. Infusion 10 pumps, matrix entrapment systems and combination with transdermal delivery devices are also contemplated. The peptides may also be encapsulated within a polyethylene glycol conformal coating as described in U.S. Patent No. 5,529,914 prior to implantation. The neurotrophic peptides of the invention may also be enclosed in micelles or liposomes. Liposome encapsulation technology is well known. Liposomes may be targeted 15 to specific tissue, such as neural tissue, through the use of receptors, ligands or antibodies capable of binding the targeted tissue. The preparation of these formulations is well known in the art (Radin et al., Meth. Enzymol., 98:613-618, 1983). There are currently no commercially available pharmaceuticals capable of promoting full functional regeneration and restoration of the structural integrity of neural systems. This 20 is particularly true of the CNS. Regeneration of peripheral nerves through the use of neurotrophic factors is within the scope of the invention. Moreover, neurotrophic factors can be therapeutically useful in the treatment of neurodegenerative diseases associated with the degeneration of neural populations or specific areas of the brain. The principal cause of Parkinson's disease is the degeneration of dopaminergic neurons of the substantia nigra. 25 Since antibodies against prosaposin immunohistochemically stain the dopaminergic neurons of the substantia nigra in human brain sections, the neurotrophic peptides of the invention may be therapeutically useful in the treatment of Parkinson's disease. Retinal neuropathy, an ocular neurodegenerative disorder leading to loss of vision in the elderly, is also treatable using the peptides of the invention. 30 It has long been believed that in order to reach neuronal populations in the brain, neurotrophic factors would have to be administered intracerebrally since these proteins do not -10- WO 00/12553 PCT/US99/19378 cross the blood brain barrier. U.S. Patent No.5,571,787 discloses that an iodinated neurotrophic 18-mer fragment derived from saposin C crosses the blood brain barrier. Peptides of the present invention having up to about 22 amino acids will also cross this barrier and can thus be administered intravenously, with greater transport occurring for shorter 5 peptides. Other neuronal populations, such as motor neurons, can also be treated by intravenous injection, although direct injection into the cerebrospinal fluid is also envisioned as an alternate route. Cells may be treated to facilitate myelin formation or to prevent demyelination in the manner described above in vivo, ex vivo or in vitro. Diseases resulting in demyelination of 10 nerve fibers including MS, acute disseminated leukoencephalitis, progressive multifocal leukoencephalitis, metachromatic leukodystrophy and adrenal leukodystrophy can be slowed or halted by administration of the neurotrophic peptides of the invention to the cells affected by the disease. Reversal of demyelination diseases or other neural damage is also contemplated. 15 The compositions of the present invention can be used in vitro as research tools for studying the effects of neurotrophic factors and myelin facilitating materials. However, more practically, they have an immediate use as laboratory reagents and components of cell growth media for facilitating growth and maintaining neural cells in vitro. The peptides of the invention are synthesized on a solid support using established 20 methods and Fmoc chemistry using an automated solid-phase protocol well known in the art (Traeciak et al., Tetrahedron Lett. 33:4557-4561, 1992) on a Protein Technologies Symphony peptide synthesizer. The cyclized peptides were cleaved from the solid support using TFA/water/triisopropylsilane (95:2.5:2.5). The peptides were purified using reverse phase HPLC on a C-18 column eluting with 0.3% trifluoroacetic acid (TFA) in acetonitrile. 25 Mass spectral analysis of the peptides shown in SEQ ID NOS: 5 (peptide A) and 6 (peptide B) confirmed that cyclic peptides had been synthesized [SEQ ID NO: 5: M-F1333 (expected), 1333 (observed); SEQ ID NO: 6 MI-H1127 (expected), 1127 (observed)]. The following examples are illustrative and are not intended to limit the scope of the present invention. 30 Example 1 Stimulation of neurite outgrowth in vitro -11- WO 00/12553 PCT/US99/19378 NS20Y neuroblastoma cells were grown in DMEM containing 10% fetal calf serum (FCS). Cells were removed with trypsin and plated in 30 mm petri dishes onto glass coverslips. After 20-24 hours, the medium was replaced with 2 ml DMEM containing 0.5% FCS plus various concentrations of the peptide A, peptide B or TX14(A). Cells were cultured 5 for an additional 24 hours, washed with PBS and fixed with Bouin's solution (saturated aqueous picric acid/formalin/acetic acid 15:5:1) for 30 minutes. Fixative was removed with PBS and neurite outgrowth was scored under a phase contrast microscope. Cells exhibiting one or more clearly defined neurites equal to or longer than one cell diameter were scored as positive. At least 200 cells were scored in different portions of each dish to determine the 10 percentage of neurite bearing cells and assays were performed in duplicate. All three peptides induced neurite outgrowth in NS20Y cells. The TIn (EDs 5 o), which is the concentration of peptide resulting in 50% increased neurite outgrowth, was 1.0 ng/ml for TX14(A) and for peptide B. The TIo for peptide A was 0.6 ng/ml. Thus, peptide B was as effective as TX14(A), while peptide A was more effective than TX14(A). This indicates 15 that the cyclized peptides of the present invention have excellent activity in comparison to an established standard "prosaptide". Example 2 Prevention of cell death in vitro NS20Y cells were plated as described in Example 1 and grown on glass coverslips in 20 0.5% fetal bovine serum for 2 days in the presence or absence of TX14(A), peptide A or peptide B Media was removed and 0.2% trypan blue in PBS was added to each well. Blue staining dead cells were scored as a percentage of the total on an inverted microscope, counting 400 cells in four areas of each well. The average error of duplicates was 5%. TX14(A), peptide A and peptide B reduced the number of trypan blue-positive (dead) cells. 25 The Tr 2
(ED
50 ) for prevention of neural cell death for TX14(A) was 1.0 ng/ml. Peptides A and B were more potent, with TI2 values of 0.6 ng/ml and 0.8 ng/ml, respectively. This indicates that the cyclic peptides have exceptional activity in rescuing neural cells from programmed cell death in comparison to a standard linear "prosaptide". Example 3 30 Ex vivo mvelination assay -12- WO 00/12553 PCT/US99/19378 Newborn mouse cerebellar explants are prepared according to Satomi (Zool. Sci., 9:127-137, 1992). Neurite outgrowth and myelination are observed over 22 days in culture, during the period when the newborn mouse cerebellum normally undergoes neuronal differentiation and myelination begins. A cyclic saposin C-derived peptide having between 11 5 and 25 amino acids and containing the sequence shown in SEQ ID NO: 4 (10 tg/ml) is added on the second day after preparation of the explants (three control and three treated explants), and outgrowth of neurites and myelination is assessed under a bright field microscope with a video camera. On the eighth day, cultures containing the peptides are thinner and more spread out than control cultures. On day 15, peptide-treated cultures contain many cells with 10 long projections at the periphery of the explant which are less prominent in untreated control cultures. Peptide-treated cultures contain significantly more myelinated axons in the subcortical white matter at 22 days compared to control explants. Thus, the peptides of the invention induce increased myelination in differentiating cerebellum ex vivo. Example 4 15 Prevention of demvelination The prevention of Schwann cell death is correlated with prevention of demyelination. Schwann cells contain an extensive myelin sheath. The addition of a cyclic saposin C-derived peptide having between 11 and 25 amino acids and containing the sequence shown in SEQ ID NO: 4 to Schwann cells in culture reduces Schwann cell death in a dose-dependent 20 manner and stimulates the incorporation of sulfatides, myelin-specific lipids, into Schwann cells. This indicates that the cyclic peptides of the invention can prevent demyelination due to Schwann cell death. Example 5 Use of peptides in treating traumatic ischemic CNS lesions 25 Humans with traumatic lesions to the spinal cord receive intracerebrospinal or direct injection of about 100 ptg/ml of a cyclic saposin C-derived peptide having between 11 and 25 amino acids and containing the sequence shown in SEQ ID NO: 4 in a sterile saline solution or in depot form to enable slow, continuous release of the peptide at the lesion site. Improvement is assessed by gain of motor nerve function (i.e. increased limb movement). 30 Treatments continue until no further improvement occurs. Example 6 -13- WO 00/12553 PCT/US99/19378 Use of peptides in treating demyelination disorders Patients diagnosed with early stage MS are given a cyclic saposin C-derived peptide having between 11 and 25 amino acids, and containing the sequence shown in SEQ ID NO: 4, by direct intravenous injection into the cerebrospinal fluid using the same dose range as in 5 Example 3. Dosages are repeated daily every 2-5 days, or weekly and improvement in muscle strength, musculoskeletal coordination and myelination (as determined by MRI) is observed. Example 7 Alleviation of neuropathic pain in Chung model rats 10 This example describes the effects of bolus intrathecal injection of a cyclic saposin C derived peptide having between 11 and 25 amino acids and containing the sequence shown in SEQ ID NO: 4 in the Chung experimental model of peripheral neuropathic pain. Each peptide is chemically synthesized, purified, dissolved in sterile PBS and buffered to neutral pH. The surgical procedure previously described by Kim et al. (Pain, 50:355, 1992) is 15 performed on male rats to induce an allodynic state. A spinal catheter is introduced two weeks after surgery, Five days later, the peptides are administered at 0.007, 0.07 and 0.7 pg/rat. Pressure thresholds are then determined using calibrated von Frey hairs. The longer the time taken for an animal to withdraw the paw in response to applied pressure, the less severe the neuropathic pain. The peptides significantly increase the threshold pressure, 20 indicating a significant alleviation ofneuropathic pain. Example 8 Treatment of sensory neuropathy Mice are administered taxol in order to induce sensory neuropathy. Taxol-treated mice are administered 50 ptg/kg, 100 pg/kg or 250 pg/kg of a cyclic saposin C-derived 25 peptide having between 11 and 25 amino acids and containing the sequence shown in SEQ ID NO: 4. The loss of thermal sensation is measured using a Hargreaves sensory testing apparatus as an indicator or sensory neuropathy. Each of the three doses of peptide is effective in preventing or retarding loss of thermal sensation in taxol-treated mice. Thus, the synthetic saposin C-derived peptides of the invention effectively inhibit sensory neuropathy. 30 Example 9 Alleviation of neuropathic pain in diabetic rats -14- WO 00/12553 PCT/US99/19378 This example describes the effects of kg of a cyclic saposin C-derived peptide having between 11 and 25 amino acids and containing the sequence shown in SEQ ID NO: 4 by intraperitoneal administration in a rat model of diabetic neuropathy. Rats are made diabetic by a single intraperitoneal injection of streptozotocin (50 5 mg/kg body weight, freshly dissolved in 0.9% sterile saline) to ablate pancreatic P cells and induce insulin deficiency as described by Calcutt et al. (Pain, 68:293-299, 1996). Two days later, diabetes is confirmed in streptozotocin-injected rats by measuring blood glucose levels. Streptozotocin-injected animals with a blood glucose concentration below 15 mmol/1 were excluded from subsequent studies, according to the commonly accepted definition of non 10 fasting hyperglycemia in studies of diabetes in rats. Both diabetic and control rats are studied at 8 weeks by analyzing the behavioral response to the noxious chemical formalin as an indicator of allodynia (Calcutt et al., supra, 1996). Briefly, rats receive a subcutaneous injection of freshly-prepared formalin (50 pl of 0.5% solution in sterile saline) into the dorsal surface of the right hind paw. This 15 concentration of formalin induces sub-maximal behavioral responses in control rats and allows detection of hyperalgesia in diabetic rats during phases Q and 2 (Calcutt et al., Eur. J. Pharmacol., 285:189-197, 1995). Animals are transferred to an observation chamber constructed to allow continuous visualization of the paws. The number of flinches during one minute periods is counted at 5 minute intervals for the next 60 minutes by an observer who is 20 unaware of the treatment group of each animal. Phase 1 is defined as the initial measurement of flinching (1-2 and 5-6 minutes post injection); the Q (quiescent) phase as the measurements made at 10-11, 15-16 and 20-21 minutes; and Phase 2 as all subsequent measurements post-injection, as previously defined for studies of diabetic rats (see, for example, Malmberg et al., Neurosci. Lett., 161:45-48, 1993). Comparisons of activity during 25 each phase are made by summing the flinches at measurement points within the phase. diabetic rats five an abnormal flinch response. Diabetic rats are divided in two groups of four animals each which are administered saline or a cyclic saposin C-derived peptide having between 11 and 25 amino acids and containing the sequence shown in SEQ ID NO: 4, respectively. Two hours before treatment 30 with 0.5% formalin, the diabetic rats are treated with saline or 200 tg/kg peptide using intraperitoneal administration. Administration of peptide completely prevents the abnormal -15- WO 00/12553 PCT/US99/19378 flinch response in Phase 1 and ameliorates the response in Phase 2 by 70%. Thus, parenteral administration of peptide alleviates the pain from formalin injection and improves motor neuron function in a rat model of painful diabetic neuropathy. -16- WO 00/12553 PCT/US99/19378 SEQUENCE LISTING (1) GENERAL INFORMATION: (i) APPLICANT: MYELOS CORPORATION (ii) TITLE OF INVENTION: CYCLIC ANALGESIC AND NEUROTROPHIC PEPTIDES (iii) NUMBER OF SEQUENCES: 6 (iv) CORRESPONDENCE ADDRESS: (A) ADDRESSEE: Knobbe, Martens, Olson & Bear (B) STREET: 620 Newport Center Drive, 16th Floor (C) CITY: Newport Beach (D) STATE: CA (E) COUNTRY: U.S.A. (F) ZIP: 92660 (v) COMPUTER READABLE FORM: (A) MEDIUM TYPE: Diskette (B) COMPUTER: IBM Compatible (C) OPERATING SYSTEM: Windows (D) SOFTWARE: FastSEQ for Windows Version 2.0b (vi) CURRENT APPLICATION DATA: (A) APPLICATION NUMBER: (B) FILING DATE: (C) CLASSIFICATION: (vii) PRIOR APPLICATION DATA: (A) APPLICATION NUMBER: 60/098,359 (B) FILING DATE: 28-AUG-1998 (viii) ATTORNEY/AGENT INFORMATION: (A) NAME: Bartfeld, Neil S (B) REGISTRATION NUMBER: 39,901 (C) REFERENCE/DOCKET NUMBER: MYELOS.014PR (ix) TELECOMMUNICATION INFORMATION: (A) TELEPHONE: 619-235-8550 (B) TELEFAX: 619-235-0176 (C) TELEX: -17- WO 00/12553 PCT/US99/19378 (2) INFORMATION FOR SEQ ID NO: 1: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 21 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 1: Cys Glu Phe Leu Val Lys Glu Val Thr Lys Leu Ile Asp Asn Asn Lys 1 5 10 15 Thr Glu Lys Glu Lys 20 (2) INFORMATION FOR SEQ ID NO:2: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2: Tyr Lys Glu Val Thr Lys Leu Ile Asp Asn Asn Lys Thr Glu Lys Glu 1 5 10 15 Ile Leu (2) INFORMATION FOR SEQ ID NO:3: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 12 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3: -18- WO 00/12553 PCT/US99/19378 Leu Ile Asp Asn Asn Lys Thr Glu Lys Glu Ile Leu 1 5 10 (2) INFORMATION FOR SEQ ID NO:4: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 11 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Other (B) LOCATION: 1...2 (D) OTHER INFORMATION: A,L,I,V,Y,W,F OR M (A) NAME/KEY: Other (B) LOCATION: 3...3 (D) OTHER INFORMATION: D,E,K OR R (A) NAME/KEY: Other (B) LOCATION: 6...6 (D) OTHER INFORMATION: ANY AMINO ACID (A) NAME/KEY: Other (B) LOCATION: 8...8 (D) OTHER INFORMATION: D OR E (A) NAME/KEY: Other (B) LOCATION: 9...9 (D) OTHER INFORMATION: ANY AMINO ACID (A) NAME/KEY: Other (B) LOCATION: 10... 11 (D) OTHER INFORMATION: A,L,I,V,Y,W,F OR M (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4: Xaa Xaa Xaa Asn Asn Xaa Thr Xaa Xaa Xaa Xaa 1 5 10 -19- WO 00/12553 PCT/US99/19378 (2) INFORMATION FOR SEQ ID NO:5: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 11 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: cyclic (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5: Leu Leu Asp Asn Asn Lys Thr Glu Lys Leu Tyr 1 5 10 (2) INFORMATION FOR SEQ ID NO:6: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 11 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: cyclic (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6: Leu lie Asp Asn Asn Ala Thr Glu Glu lie Leu 1 5 10 -20-
Claims (33)
1. A cyclic peptide having between about 11 and 25 amino acids, and including the sequence XIX 2 X 3 NNX 4 TXsX 6 X 7 Xs, wherein X 1 is a hydrophobic amino acid (leucine, alanine isoleucine, valine, tyrosine, tryptophan, phenylalanine or 5 methionine); X 2 is a hydrophobic amino acid, X 3 is aspartic acid, glutamic acid, lysine or arginine; N is asparagine, X 4 is any amino acid; T is threonine; X 5 is glutamic acid or aspartic acid; X 6 is any amino acid, X 7 is a hydrophobic amino acid; and Xs is a hydrophobic amino acid.
2. The peptide of Claim 1, wherein the peptide has the amino acid 10 sequence shown in SEQ ID NO: 5 or 6.
3. A composition comprising the peptide of Claim 1, in a septum sealed vial.
4. A composition comprising the peptide of Claim 1, formulated with a controlled release material. 15
5. A composition comprising the peptide of Claim 1, in lyophilized form.
6. A composition comprising the peptide of Claim 1, in liposomal form.
7. A composition comprising the peptide of Claim 1, in a form suitable for topical administration.
8. A composition comprising the peptide of Claim 1, in unit dosage 20 form.
9. A method for inducing myelination or inhibiting demyelination in a mammal, comprising: administering to a mammal afflicted with demyelination a pharmaceutically effective demyelination inhibiting amount of a cyclic peptide having between about 11 25 and 25 amino acids, and including the sequence X 1 X 2 X 3 NNX 4 TXsX 6 X 7 Xs, wherein X, is a hydrophobic amino acid (leucine, isoleucine, valine, tyrosine, tryptophan, phenylalanine or methionine); X 2 is a hydrophobic amino acid, X 3 is aspartic acid, glutamic acid, lysine or arginine; N is asparagine, X 4 is any amino acid; T is threonine; X 5 is glutamic acid or aspartic acid; X 6 is any amino acid, X 7 is a 30 hydrophobic amino acid; and Xs is a hydrophobic amino acid.
10. The method of Claim 9, wherein said demyelination is due to multiple sclerosis, ischemic injury or traumatic injury. -21- WO 00/12553 PCT/US99/19378
11. The method of Claim 9, wherein said administration is selected from the group consisting of intravenous, intramuscular, intradermal. subcutaneous, intracranial, intracerebrospinal and topical.
12. The method of Claim 9, wherein said peptide is administered in a 5 pharmaceutically acceptable carrier.
13. The method of Claim 9, wherein said peptide is enclosed in a lamellar structure.
14. The method of Claim 9, wherein said peptide has the sequence shown in SEQ ID NOS: 5 or 6. 10
15. The method of Claim 9, wherein said mammal is a human.
16. A method for inhibiting neural degeneration or promoting neurite outgrowth in neural tissue, comprising: contacting neural tissue susceptible to such degeneration with an effective neural degeneration-inhibiting amount of a cyclic peptide having between about 11 15 and 25 amino acids, and including the sequence XIX 2 X 3 NNX 4 TXsX 6 X 7 Xs, wherein X, is a hydrophobic amino acid (leucine, isoleucine, valine, tyrosine, tryptophan, phenylalanine or methionine); X 2 is a hydrophobic amino acid, X 3 is aspartic acid, glutamic acid, lysine or arginine; N is asparagine, X 4 is any amino acid; T is threonine; X 5 is glutamic acid or aspartic acid; X 6 is any amino acid, X 7 is a 20 hydrophobic amino acid; and X 8 is a hydrophobic amino acid.
17. The method of Claim 16, wherein said administration is selected from the group consisting of intravenous, intramuscular, intradermal. subcutaneous, intracranial, intracerebrospinal and topical.
18. The method of Claim 16, wherein said peptide is administered in a 25 pharmaceutically acceptable carrier.
19. The method of Claim 16, wherein said peptide is enclosed in a lamellar structure.
20. The method of Claim 16, wherein said peptide has the amino acid sequence shown in SEQ ID NOS: 5 or 6. 30
21. The method of Claim 16, wherein said mammal is a human.
22. A method for treating neuropathic pain in a mammal in need thereof, comprising the step of administering to a mammal suffering from a neurodegenerative disease an amount of a cyclic peptide effective to treat neuropathic pain, wherein said peptide contains between about 11 and 25 amino acids, and includes the sequence -22- WO 00/12553 PCT/US99/19378 XIX 2 X 3 NNX 4 TXsX 6 X7Xs, wherein X, is a hydrophobic amino acid (leucine, isoleucine, valine, tyrosine, tryptophan, phenylalanine or methionine); X 2 is a hydrophobic amino acid, X 3 is aspartic acid, glutamic acid, lysine or arginine; N is asparagine, X 4 is any amino acid; T is threonine; Xs is glutamic acid or aspartic acid; 5 X 6 is any amino acid, X7 is a hydrophobic amino acid; and X 8 is a hydrophobic amino acid.
23. The method of Claim 22, wherein said administering step is selected from the group consisting of intravenous, intramuscular, intradermal, subcutaneous, intracranial, intracerebrospinal, topical and oral. 10
24. The method of Claim 22, wherein said peptide is administered in a pharmaceutically acceptable carrier.
25. The method of Claim 22, wherein said peptide is enclosed in a lamellar structure
26. The method of Claim 22, wherein said peptide has the amino acid 15 sequence shown in SEQ ID NOS: 5 or 6.
27. The method of Claim 22, wherein said mammal is a human.
28. A cyclic peptide having between about 11 and 25 amino acids, and including the sequence XIX 2 X 3 NNX 4 TXsX 6 X 7 Xs, wherein X 1 is a hydrophobic amino acid (leucine, alanine isoleucine, valine, tyrosine, tryptophan, phenylalanine or 20 methionine); X 2 is a hydrophobic amino acid, X 3 is aspartic acid, glutamic acid, lysine or arginine; N is asparagine, X 4 is any amino acid; T is threonine; Xs is glutamic acid or aspartic acid; X 6 is any amino acid, X 7 is a hydrophobic amino acid; and X 8 is a hydrophobic amino acid, for use in inducing myelination or inhibiting demyelination in a mammal. 25
29. The peptide of Claim 28, wherein said peptide has the sequence shown in SEQ ID NOS: 5 or 6.
30. A cyclic peptide having between about 11 and 25 amino acids, and including the sequence XIX 2 X 3 NNX 4 TXsX 6 X 7 Xs, wherein X, is a hydrophobic amino acid (leucine, alanine isoleucine, valine, tyrosine, tryptophan, phenylalanine or 30 methionine); X 2 is a hydrophobic amino acid, X 3 is aspartic acid, glutamic acid, lysine or arginine; N is asparagine, X 4 is any amino acid; T is threonine; X5 is glutamic acid or aspartic acid; X 6 is any amino acid, X 7 is a hydrophobic amino acid; and X 8 is a hydrophobic amino acid for use in inhibiting neural degeneration or promoting neurite outgrowth. -23- WO 00/12553 PCT/US99/19378
31. The peptide of Claim 30, wherein said peptide has the sequence shown in SEQ ID NOS: 5 or 6.
32. A cyclic peptide having between about 11 and 25 amino acids, and including the sequence XIX 2 X 3 NNX4TXsX 6 X 7 Xs, wherein X 1 is a hydrophobic 5 amino acid (leucine, alanine isoleucine, valine, tyrosine, tryptophan, phenylalanine or methionine); X 2 is a hydrophobic amino acid, X 3 is aspartic acid, glutamic acid, lysine or arginine; N is asparagine, X 4 is any amino acid; T is threonine; X 5 is glutamic acid or aspartic acid; X6 is any amino acid, X7, is a hydrophobic amino acid; and X 8 is a hydrophobic amino acid for use in treatment of neuropathic pain. 10
33. The peptide of Claim 32, wherein said peptide has the sequence shown in SEQ ID NOS: 5 or 6. -24-
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US9835998P | 1998-08-28 | 1998-08-28 | |
| US60/098359 | 1998-08-28 | ||
| PCT/US1999/019378 WO2000012553A1 (en) | 1998-08-28 | 1999-08-20 | Cyclic prosaposin-derived peptides and uses thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU5690599A true AU5690599A (en) | 2000-03-21 |
| AU751034B2 AU751034B2 (en) | 2002-08-08 |
Family
ID=22268937
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU56905/99A Ceased AU751034B2 (en) | 1998-08-28 | 1999-08-20 | Cyclic prosaposin-derived peptides and uses thereof |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP1105420A1 (en) |
| JP (2) | JP4528443B2 (en) |
| KR (1) | KR20010079695A (en) |
| CN (1) | CN1324367A (en) |
| AU (1) | AU751034B2 (en) |
| BR (1) | BR9913490A (en) |
| CA (1) | CA2341810A1 (en) |
| CZ (1) | CZ2001655A3 (en) |
| HU (1) | HUP0103265A3 (en) |
| IL (1) | IL141586A0 (en) |
| PL (1) | PL204359B1 (en) |
| WO (1) | WO2000012553A1 (en) |
| ZA (1) | ZA200102489B (en) |
Families Citing this family (34)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5571787A (en) | 1993-07-30 | 1996-11-05 | Myelos Corporation | Prosaposin as a neurotrophic factor |
| BR9913490A (en) * | 1998-08-28 | 2001-09-25 | Myelos Corp | Cyclic prosaposine and its uses |
| AUPQ084899A0 (en) * | 1999-06-08 | 1999-07-01 | University Of Melbourne, The | Neurotrophin agonists |
| IL137820A (en) * | 2000-08-10 | 2009-06-15 | S I S Shulov Inst For Science | Pharmaceutical composition for topical administration comprising an analgesic peptide |
| CN100366286C (en) * | 2003-04-28 | 2008-02-06 | 常州南云科技有限公司 | Saposin C-DOPS: A new anticancer drug |
| US9271932B2 (en) | 2006-04-28 | 2016-03-01 | Children's Hospital Medical Center | Fusogenic properties of saposin C and related proteins and peptides for application to transmembrane drug delivery systems |
| WO2008051818A2 (en) * | 2006-10-20 | 2008-05-02 | Children's Hospital Medical Center | Spontaneously forming ellipsoidal phospholipid unilamellar vesicles |
| CN103275187B (en) * | 2013-06-14 | 2014-10-29 | 四川合泰新光生物科技有限公司 | Analgesic peptide FI as well as genes and application thereof |
| BR112017022021B1 (en) | 2015-04-23 | 2021-07-06 | The Procter & Gamble Company | HAIR TREATMENT COMPOSITION |
| EP3423031B1 (en) | 2016-03-03 | 2021-09-08 | The Procter & Gamble Company | Aerosol antidandruff composition |
| EP3528899B1 (en) | 2016-10-21 | 2024-04-10 | The Procter & Gamble Company | Dosage of foam for delivering consumer desired dosage volume and surfactant amount in an optimal formulation space |
| EP3528898A1 (en) | 2016-10-21 | 2019-08-28 | The Procter and Gamble Company | Concentrated shampoo dosage of foam designating hair conditioning benefits |
| CN109843383A (en) | 2016-10-21 | 2019-06-04 | 宝洁公司 | For delivering the foam of the desired dose volume of consumer, amount of surfactant and scalp health dosage in optimal formulation space |
| US11129783B2 (en) | 2016-10-21 | 2021-09-28 | The Procter And Gamble Plaza | Stable compact shampoo products with low viscosity and viscosity reducing agent |
| US20180110688A1 (en) | 2016-10-21 | 2018-04-26 | The Procter & Gamble Company | Concentrated Shampoo Dosage of Foam for Providing Hair Care Benefits |
| EP3528895A1 (en) | 2016-10-21 | 2019-08-28 | The Procter & Gamble Company | Concentrated shampoo dosage of foam for providing hair care benefits |
| US11141361B2 (en) | 2016-10-21 | 2021-10-12 | The Procter And Gamble Plaza | Concentrated shampoo dosage of foam designating hair volume benefits |
| US11679073B2 (en) | 2017-06-06 | 2023-06-20 | The Procter & Gamble Company | Hair compositions providing improved in-use wet feel |
| US11141370B2 (en) | 2017-06-06 | 2021-10-12 | The Procter And Gamble Company | Hair compositions comprising a cationic polymer mixture and providing improved in-use wet feel |
| US11224567B2 (en) | 2017-06-06 | 2022-01-18 | The Procter And Gamble Company | Hair compositions comprising a cationic polymer/silicone mixture providing improved in-use wet feel |
| CN111201010A (en) | 2017-10-10 | 2020-05-26 | 宝洁公司 | Method for treating hair or skin with a personal care composition in foam form |
| JP2020536876A (en) | 2017-10-10 | 2020-12-17 | ザ プロクター アンド ギャンブル カンパニーＴｈｅ Ｐｒｏｃｔｅｒ ＆ Ｇａｍｂｌｅ Ｃｏｍｐａｎｙ | Compact shampoo composition containing amino acid-based anionic surfactant and cationic polymer |
| WO2019074989A1 (en) | 2017-10-10 | 2019-04-18 | The Procter & Gamble Company | Compact shampoo composition containing sulfate-free surfactants |
| EP3694607B1 (en) | 2017-10-10 | 2022-12-28 | The Procter & Gamble Company | Compact shampoo composition |
| US10912732B2 (en) | 2017-12-20 | 2021-02-09 | The Procter And Gamble Company | Clear shampoo composition containing silicone polymers |
| EP3813774A1 (en) | 2018-06-29 | 2021-05-05 | The Procter & Gamble Company | Low surfactant aerosol antidandruff composition |
| US12226505B2 (en) | 2018-10-25 | 2025-02-18 | The Procter & Gamble Company | Compositions having enhanced deposition of surfactant-soluble anti-dandruff agents |
| US11980679B2 (en) | 2019-12-06 | 2024-05-14 | The Procter & Gamble Company | Sulfate free composition with enhanced deposition of scalp active |
| EP4110474A1 (en) | 2020-02-27 | 2023-01-04 | The Procter & Gamble Company | Anti-dandruff compositions with sulfur having enhanced efficacy and aesthetics |
| CA3198853A1 (en) | 2020-11-23 | 2022-05-27 | The Procter & Gamble Company | Personal care compositions free of sulfated surfactants |
| CN116568263A (en) | 2020-12-04 | 2023-08-08 | 宝洁公司 | Hair care composition comprising malodor reducing material |
| US11771635B2 (en) | 2021-05-14 | 2023-10-03 | The Procter & Gamble Company | Shampoo composition |
| US11986543B2 (en) | 2021-06-01 | 2024-05-21 | The Procter & Gamble Company | Rinse-off compositions with a surfactant system that is substantially free of sulfate-based surfactants |
| JP2024544222A (en) | 2021-12-09 | 2024-11-28 | ザ プロクター アンド ギャンブル カンパニー | Sulfate-free personal cleansing composition with effective preservative properties - Patents.com |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL106106A0 (en) * | 1993-06-22 | 1993-10-20 | Interpharm Lab Ltd | Library of polymeric molecules and its preparation |
| US6271196B1 (en) * | 1996-03-05 | 2001-08-07 | Regents Of The University Of Ca | Methods of alleviating neuropathic pain using prosaposin-derived peptides |
| BR9913490A (en) * | 1998-08-28 | 2001-09-25 | Myelos Corp | Cyclic prosaposine and its uses |
-
1999
- 1999-08-20 BR BR9913490-0A patent/BR9913490A/en not_active IP Right Cessation
- 1999-08-20 CZ CZ2001655A patent/CZ2001655A3/en unknown
- 1999-08-20 CN CN99812627A patent/CN1324367A/en active Pending
- 1999-08-20 CA CA002341810A patent/CA2341810A1/en not_active Abandoned
- 1999-08-20 WO PCT/US1999/019378 patent/WO2000012553A1/en not_active Ceased
- 1999-08-20 HU HU0103265A patent/HUP0103265A3/en unknown
- 1999-08-20 EP EP99943903A patent/EP1105420A1/en not_active Withdrawn
- 1999-08-20 JP JP2000567569A patent/JP4528443B2/en not_active Expired - Fee Related
- 1999-08-20 AU AU56905/99A patent/AU751034B2/en not_active Ceased
- 1999-08-20 KR KR1020017002478A patent/KR20010079695A/en not_active Withdrawn
- 1999-08-20 IL IL14158699A patent/IL141586A0/en not_active IP Right Cessation
- 1999-08-20 PL PL346346A patent/PL204359B1/en not_active IP Right Cessation
-
2001
- 2001-03-27 ZA ZA200102489A patent/ZA200102489B/en unknown
-
2010
- 2010-02-19 JP JP2010034833A patent/JP2010150272A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| CA2341810A1 (en) | 2000-03-09 |
| WO2000012553A1 (en) | 2000-03-09 |
| PL204359B1 (en) | 2010-01-29 |
| KR20010079695A (en) | 2001-08-22 |
| JP4528443B2 (en) | 2010-08-18 |
| JP2002523518A (en) | 2002-07-30 |
| IL141586A0 (en) | 2002-03-10 |
| HUP0103265A3 (en) | 2002-09-30 |
| BR9913490A (en) | 2001-09-25 |
| JP2010150272A (en) | 2010-07-08 |
| HUP0103265A2 (en) | 2002-02-28 |
| CN1324367A (en) | 2001-11-28 |
| AU751034B2 (en) | 2002-08-08 |
| EP1105420A1 (en) | 2001-06-13 |
| PL346346A1 (en) | 2002-02-11 |
| CZ2001655A3 (en) | 2001-11-14 |
| ZA200102489B (en) | 2002-06-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU751034B2 (en) | Cyclic prosaposin-derived peptides and uses thereof | |
| CA2168029C (en) | Prosaposin and cytokine-derived peptides as therapeutic agents | |
| CA2248139C (en) | Methods of alleviating neuropathic pain using prosaposin-derived peptides | |
| US6458357B1 (en) | Retro-inverso neurotrophic and analgesic peptides | |
| US6849602B1 (en) | Compositions for alleviating neuropathic pain with prosaposin receptor agonists | |
| EP0979238A1 (en) | Method of alleviating neuropathic pain | |
| WO1998042746A9 (en) | Synthetic saposin c-derived neurotrophic peptides | |
| EP0971956A2 (en) | Synthetic saposin c-derived neurotrophic peptides | |
| EP1183266A1 (en) | Retro-inverso peptides derived from leukemia inhibitory factor | |
| MXPA01001966A (en) | Cyclic prosaposin-derived peptides and uses thereof | |
| US20020128193A1 (en) | Retro-inverso prosaposin-derived peptides and use thereof | |
| AU2002300005B2 (en) | Method of alleviating neuropathic pain | |
| AU4267297A (en) | Method of alleviating neuropathic pain |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FGA | Letters patent sealed or granted (standard patent) |