CA2081312A1 - Cyclic peptides and their use - Google Patents
Cyclic peptides and their useInfo
- Publication number
- CA2081312A1 CA2081312A1 CA002081312A CA2081312A CA2081312A1 CA 2081312 A1 CA2081312 A1 CA 2081312A1 CA 002081312 A CA002081312 A CA 002081312A CA 2081312 A CA2081312 A CA 2081312A CA 2081312 A1 CA2081312 A1 CA 2081312A1
- Authority
- CA
- Canada
- Prior art keywords
- cyclic peptides
- cyclic
- peptides according
- contain
- immune
- 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.)
- Abandoned
Links
- 108010069514 Cyclic Peptides Proteins 0.000 title claims abstract description 42
- 102000001189 Cyclic Peptides Human genes 0.000 title claims abstract description 42
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 20
- 230000027455 binding Effects 0.000 claims abstract description 10
- 230000004913 activation Effects 0.000 claims abstract description 5
- 230000037361 pathway Effects 0.000 claims abstract description 3
- 230000002401 inhibitory effect Effects 0.000 claims abstract 2
- 201000010099 disease Diseases 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- 241000282414 Homo sapiens Species 0.000 claims description 10
- 150000001413 amino acids Chemical class 0.000 claims description 10
- 108010002842 labaditin Proteins 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 241000196324 Embryophyta Species 0.000 claims description 5
- 239000000463 material Substances 0.000 claims description 5
- 241000221017 Euphorbiaceae Species 0.000 claims description 4
- 241000124008 Mammalia Species 0.000 claims description 4
- 125000000539 amino acid group Chemical group 0.000 claims description 4
- 230000003171 anti-complementary effect Effects 0.000 claims description 4
- 230000001363 autoimmune Effects 0.000 claims description 4
- 208000025747 Rheumatic disease Diseases 0.000 claims description 3
- 230000004154 complement system Effects 0.000 claims description 3
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- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 230000000552 rheumatic effect Effects 0.000 claims description 3
- 230000009885 systemic effect Effects 0.000 claims description 3
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- 108010016626 Dipeptides Proteins 0.000 claims description 2
- 241000221089 Jatropha Species 0.000 claims description 2
- UYKREHOKELZSPB-JTQLQIEISA-N Trp-Gly Chemical compound C1=CC=C2C(C[C@H](N)C(=O)NCC(O)=O)=CNC2=C1 UYKREHOKELZSPB-JTQLQIEISA-N 0.000 claims description 2
- 239000013543 active substance Substances 0.000 claims description 2
- 238000004458 analytical method Methods 0.000 claims description 2
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- 208000022098 hypersensitivity pneumonitis Diseases 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
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- 125000004122 cyclic group Chemical group 0.000 abstract description 10
- 230000000295 complement effect Effects 0.000 abstract description 7
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
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- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
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- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
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- 239000006228 supernatant Substances 0.000 description 2
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 description 2
- RMARCXQAHOJNRB-KBUPBQIOSA-N (1r,4ar,7r,8ar)-7-(3-hydroxyprop-1-en-2-yl)-1,4a-dimethyl-2,3,4,5,6,7,8,8a-octahydronaphthalen-1-ol Chemical compound C1C[C@@H](C(=C)CO)C[C@H]2[C@](C)(O)CCC[C@@]21C RMARCXQAHOJNRB-KBUPBQIOSA-N 0.000 description 1
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- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- LYCVKHSJGDMDLM-LURJTMIESA-N His-Gly Chemical compound OC(=O)CNC(=O)[C@@H](N)CC1=CN=CN1 LYCVKHSJGDMDLM-LURJTMIESA-N 0.000 description 1
- 208000024781 Immune Complex disease Diseases 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241001048891 Jatropha curcas Species 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- GDBQQVLCIARPGH-UHFFFAOYSA-N Leupeptin Natural products CC(C)CC(NC(C)=O)C(=O)NC(CC(C)C)C(=O)NC(C=O)CCCN=C(N)N GDBQQVLCIARPGH-UHFFFAOYSA-N 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 238000012565 NMR experiment Methods 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 108010038807 Oligopeptides Proteins 0.000 description 1
- 102000015636 Oligopeptides Human genes 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 206010057249 Phagocytosis Diseases 0.000 description 1
- 108010067445 RA V Proteins 0.000 description 1
- 108010010225 RA VII Proteins 0.000 description 1
- VXVGFMUNENQGFW-UHFFFAOYSA-N Rubia akane RA-V Natural products C1=CC(OC)=CC=C1CC(N(C)C(=O)C(C)NC(=O)C(C)NC(=O)C(N(C1=O)C)C2)C(=O)NC(C)C(=O)N(C)C1CC(C=C1)=CC=C1OC1=CC2=CC=C1O VXVGFMUNENQGFW-UHFFFAOYSA-N 0.000 description 1
- MBQKTLYFUYNAPZ-UHFFFAOYSA-N Rubia akane RA-VII Natural products C1=CC(OC)=CC=C1CC(N(C)C(=O)C(C)NC(=O)C(C)NC(=O)C(N(C1=O)C)C2)C(=O)NC(C)C(=O)N(C)C1CC(C=C1)=CC=C1OC1=CC2=CC=C1OC MBQKTLYFUYNAPZ-UHFFFAOYSA-N 0.000 description 1
- 240000009235 Rubia cordifolia Species 0.000 description 1
- 229920002684 Sepharose Polymers 0.000 description 1
- 241000270295 Serpentes Species 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 108700011201 Streptococcus IgG Fc-binding Proteins 0.000 description 1
- 102400000368 Surface protein Human genes 0.000 description 1
- 101710120037 Toxin CcdB Proteins 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 206010047115 Vasculitis Diseases 0.000 description 1
- 229920000392 Zymosan Polymers 0.000 description 1
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- 150000001408 amides Chemical group 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 244000309464 bull Species 0.000 description 1
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- 229940079593 drug Drugs 0.000 description 1
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- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
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- 210000003743 erythrocyte Anatomy 0.000 description 1
- -1 ethyl acet Chemical compound 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
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- 238000000605 extraction Methods 0.000 description 1
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 1
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- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 108010036413 histidylglycine Proteins 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- RMARCXQAHOJNRB-UHFFFAOYSA-N ilicic alcohol Natural products C1CC(C(=C)CO)CC2C(C)(O)CCCC21C RMARCXQAHOJNRB-UHFFFAOYSA-N 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- GDBQQVLCIARPGH-ULQDDVLXSA-N leupeptin Chemical compound CC(C)C[C@H](NC(C)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C=O)CCCN=C(N)N GDBQQVLCIARPGH-ULQDDVLXSA-N 0.000 description 1
- 108010052968 leupeptin Proteins 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
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- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 230000000897 modulatory effect Effects 0.000 description 1
- 230000031978 negative regulation of complement activation Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
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- 238000010647 peptide synthesis reaction Methods 0.000 description 1
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- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- MBQKTLYFUYNAPZ-FEZMQHRXSA-N ra vii Chemical compound C1=CC(OC)=CC=C1C[C@H](N(C)C(=O)[C@H](C)NC(=O)[C@@H](C)NC(=O)[C@@H](N(C1=O)C)C2)C(=O)N[C@@H](C)C(=O)N(C)[C@H]1CC(C=C1)=CC=C1OC1=CC2=CC=C1OC MBQKTLYFUYNAPZ-FEZMQHRXSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
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- 210000001519 tissue Anatomy 0.000 description 1
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- 231100000827 tissue damage Toxicity 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- TUBWTFZPLDUNIL-HJJYVODLSA-N tpc-a Chemical compound O.O.O.O.O.C1=CC(OC)=CC=C1C[C@H](N(C)C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](N(C1=O)C)C2)C(=O)N[C@H](C)C(=O)N(C)[C@@H]1CC(C=C1)=CC=C1OC1=CC2=CC=C1O.C1=CC(OC)=CC=C1C[C@H](N(C)C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](N(C1=O)C)C2)C(=O)N[C@H](C)C(=O)N(C)[C@@H]1CC(C=C1)=CC=C1OC1=CC2=CC=C1O.C1=CC(OC)=CC=C1C[C@H](N(C)C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](N(C1=O)C)C2)C(=O)N[C@H](C)C(=O)N(C)[C@@H]1CC(C=C1)=CC=C1OC1=CC2=CC=C1O.C1=CC(OC)=CC=C1C[C@H](N(C)C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](N(C1=O)C)C2)C(=O)N[C@H](C)C(=O)N(C)[C@@H]1CC(C=C1)=CC=C1OC1=CC2=CC=C1O TUBWTFZPLDUNIL-HJJYVODLSA-N 0.000 description 1
- 108010058119 tryptophyl-glycyl-glycine Proteins 0.000 description 1
- 241001446247 uncultured actinomycete Species 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/64—Cyclic peptides containing only normal peptide links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- 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)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Pain & Pain Management (AREA)
- Pulmonology (AREA)
- Rheumatology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
The present invention deals with a novel class of cyclic peptides with a selective IgG-binding activity and an inhibitory effect on the classical activation pathway of complement. These peptides may be pharmaceutically applied in compositions with an anti-inflammatory potential and further be used to enrich IgG from blood serum or plasma, to deplete plasma or serum from IgG, and/or to quantitate IgG levels in e.g. body fluids.
Description
WO 91/16~5 2 0 ~ PCT/~L91/0 ' :~
i Cyclic meptides and their use.
~ .
~ The present inven~ion with a novel class of - peptides and their application.
It is known that simple oligopeptides maj dis-. play diverse and potent biological acti-ities including antibiotic, antitumor, antiviral as well as im~uno-, suppressive activities. Thus far, cyclic peptides were mostly of microbial and more in particular of fungus origin. These so-called c~closporins are known as immunosuppressive compour.ds and sre used to p.event .'1 10 grsft rejection after organ trsnsplantation. Disadvant-sges of cyclospo-ins are the r insolubil~;~ in wacer and ~, their toxicitS, p~rt cula-l- for the k dneys.
Active pep~ides oriE natir, from highe- vl~^,ts ars ve-y rare. ~ecer.~l~, c~.clic o7~_ape?~ des here .~ 15 isolated from the roots of Rubia cordifolia and ~. aKane i~ (Rubiaceae). The cyclic hexapeptide was reportec to . possess antitumor activity in a mouse leukemia model (Itokawa, H., Takeya, Koichi, Mori, ~., Kikodoro, S., and Ysmamoto, H. ~1984a) Studies on antitumour cyclic hexapeptides RA obtained from Rubiae radix, Rubiaceae (IV): Quantitative determination of RA-VII and RA-V in commercial Rubia radix and collected plants, Plan~a Med.
~1, 313-316 & Ito',:ahD, Y.., TakQ~ ., Mor , ~., Hamanaka, T,, Sonobe T,, and Mihara, K, (1984D) Isolation and antitumour activity o~ cyclic hexapeptides isolated from Rubiae Radix. Chem. Pharm. Bull. 32 284- :
290). Both cyclosporins snd the Rubia peptides are for the major part composed of non-proteinogenic amino .~i acids.
3 Proteins and perhaps also peptides may bind to the Fc-portion of immunoglobulins. A surface protein from Staphylococcus aureus (protein A) was shown to bind . ~ IgG and to enhance complement activation ~ia the -~ ~ classical pathway (CP) (Masuda, S., Sakurai, S. & Kondo, :~ 35 I. (1975j Simple and effective method for selecting ~:
~;' ' .
i .. : ' WO91/16~ l 3~ PCT/~L91/0~ ~
i Cyclic meptides and their use.
~ .
~ The present inven~ion with a novel class of - peptides and their application.
It is known that simple oligopeptides maj dis-. play diverse and potent biological acti-ities including antibiotic, antitumor, antiviral as well as im~uno-, suppressive activities. Thus far, cyclic peptides were mostly of microbial and more in particular of fungus origin. These so-called c~closporins are known as immunosuppressive compour.ds and sre used to p.event .'1 10 grsft rejection after organ trsnsplantation. Disadvant-sges of cyclospo-ins are the r insolubil~;~ in wacer and ~, their toxicitS, p~rt cula-l- for the k dneys.
Active pep~ides oriE natir, from highe- vl~^,ts ars ve-y rare. ~ecer.~l~, c~.clic o7~_ape?~ des here .~ 15 isolated from the roots of Rubia cordifolia and ~. aKane i~ (Rubiaceae). The cyclic hexapeptide was reportec to . possess antitumor activity in a mouse leukemia model (Itokawa, H., Takeya, Koichi, Mori, ~., Kikodoro, S., and Ysmamoto, H. ~1984a) Studies on antitumour cyclic hexapeptides RA obtained from Rubiae radix, Rubiaceae (IV): Quantitative determination of RA-VII and RA-V in commercial Rubia radix and collected plants, Plan~a Med.
~1, 313-316 & Ito',:ahD, Y.., TakQ~ ., Mor , ~., Hamanaka, T,, Sonobe T,, and Mihara, K, (1984D) Isolation and antitumour activity o~ cyclic hexapeptides isolated from Rubiae Radix. Chem. Pharm. Bull. 32 284- :
290). Both cyclosporins snd the Rubia peptides are for the major part composed of non-proteinogenic amino .~i acids.
3 Proteins and perhaps also peptides may bind to the Fc-portion of immunoglobulins. A surface protein from Staphylococcus aureus (protein A) was shown to bind . ~ IgG and to enhance complement activation ~ia the -~ ~ classical pathway (CP) (Masuda, S., Sakurai, S. & Kondo, :~ 35 I. (1975j Simple and effective method for selecting ~:
~;' ' .
i .. : ' WO91/16~ l 3~ PCT/~L91/0~ ~
2 -.;-~, protein A deficient mutants by cosedimentation with sensitized sheep erythrocytes. Infection and Immunity 12, 24~-251: Van Dijk, H. & Van Bohemen, C.G. (1978) Indirect plaque-forming cells detected by use of normal mouse serum I. Normal mouse serum plaque-forming cells are IgA-producers. Cellular Immunlogy 38, 124-130).
Protein A and an analogue isolated from Streptococcus ; strain G148 (protein G) are used to isolate IgG from serum and plasma (Bjorck, L & Kronvall, G. (1984) Purif-ication and some properties of Streptococcal protein G, a novel IgG-biundine reagent. J. Immunol. 133, 969-973).
Leupeptin (a tripaptide from actinomycete fermen~ation) and singlQ amino acids can interfere with complement activation via the CP andior the alternative pathwa; (AP) (Takada, Y., .~rimoto, Y, Mineda, H. & Taka-da, .~.. (1978) Inhibition of the classical ar.~ alterna-~l tive pathwa~s by amino acids and their derivatives.
s~, Immunology 34, 509-515). -~ It has now been found by us that there are ;, 20 cyclic peptides with IgG-binding properties. This is to il say that cyclic peptides which are isolated from e.g.
the latex of specific plants or which may be prepared synthetically or semi-synthetically, were find to bind to human but also to rabbit and mouse IgG but not to Ig~7 and IgA in in vitro systems for Is~-binding. The peptides were isolated and ldentified on the basis of thelr selective inhibition of complement activation via the CP (Kosasi, S., Van der Sluis, W.G., Boelens, R., 't Hart, L.A. & Labadie, R.P. ~1989) Labaditin, a novel cyclic decapeptide from the latex of Jatropha multifida 1. (Euphorbiaceae) FEBS let~ers Z56, 91-96). AP activ-ation was not or only s-lightly affected by these peptides. It was shown that the anticomplemçntary activity of the peptides is mediated by an interference with Clq-acceptor sites on the IgG molecules they bind - to. Tnis means that the cyclic peptides combine protein A-like IgF-binding activitv with leupeptin- and amino ;~,~ . . .
;~ - .... .. .
.;~ ' . ~ . :^
wu Yl/ ln~ r~ l / :'~L~I/UWW
,~ ,~ ":
acid-like anticomplementary behavior. Such combined activity has never been described in literature, not for ' proteins but neither for linear peptides and particularly not for c~clic peptides. The anti-''.! 5 complementary activity of the novel cyclic peptides is mechanistically different from that of the linear peptide AA 27~-290, which represents a major part cf the Clq-acceptor site on IgG (Prystowski, M.B., Kehoe, J.M., ;~
& Erickson, B.W. (1981) Inhibition cf the classical ' ~ 10 complement pathway by synthetic peptides from the second-'i constant comain of the hea~.; chzin Or IgG. Bioche~istry '~ 21, p, 6349-6358). The latter does not bind to igG but '' prevents cocple~ent sctivstion by competing hith IsG for binding to C;. The an~ico~?lementary acti-ity is also different from the leupep~in-induced 2.-~ amino acid-induced complement inhibi;ion which is no: 'base~ on '~ binding to lgG.
'~ An advantage of our novel peptides over other cyclic peptides, such as cyclosporins, is their extreme solubility in water (up to 1000 mg per ml) and their . non-toxic behavior, at least in mice. They also differ from cyc.osporins and the Rubia peptides in the fact that they are built up fro~ proteinogenic (= proteinic) amino acids. ' Therefore, the cyclic peptides all ~o the invention consist preferably of proteinic a~ino acids.
Thls means that'such amino ~cids do not have to be modified, e.g. by methyl groups. It should be noted that the known cyclosporins contain methylated or derived proteinic amino acids.
' Structural analysis of the cyclic peptides of the present invention reveals that said cyclic peptides contain preferably the amino acid Trp and/or His, in particular the dipeptide groups Trp-Gly and/or His-Gly.
It is preferred tbat the cyclic peptides - according to the invention contain 8-12, preferably 9-11 amino acid residues.
~ ` ' ` ' .
~ .
.',ti ~,~`~' ' ' ' . . , ~O9l/16~5 2 ~ PCT/~Lgl/o~
In general, the cyclic peptides according to the invention contain at least 6 amino acid residues which are preferably selected from the group consis~ing of Ala, G~y, Val, Trp, Thr, Ile, Ser, and Leu.
Two important examples of cyclic peptides according to the present invention are characterized by the sequence Ala-Gly-Val-Trp-Thr-Val-Trp-Gly-Thr-Iie (Labaditin) and Ala-Ser-Ile-Leu-Gly-Leu-Gly-Trp-.~la-(Biobollein).
Of course, the cyclic peptides according to the present invention may be prepared according to classical peptide synthesis methods. However, they may also be isolated from plan~ material of the Euphorb aceae family, in pa-ticuiar the la-~x of Ja~ro?ha species.
The peptides accord r., to tr.e inven~ion ~a~ be ,j, used fo- various purposes such as for the preparation of pharmaceutical co~positions or for analysis, and/or :' separation standardization purposes.
,' The use of the cyclic peptides according to the 7 20 invention may - in general - be used for IgG-binding and ~ anticomplementary activity in mammals including human m beings.
:! .
,~i The present invention also relates to the ~! application mentioned above. The present. invention further relates to a method for trestlng diseases such as inflammstory diseases including rheumaticas well as other systemic or local-auto-immuné, and immune complex-related diseases including extrinsic allergic alveolitis in mammals including human beings wherein a cyclic peptide as defined in the above is used as an active substance.
The present invention further rçlates to `i, pharmaceutical compositions for treating diseases such ~;~ as inflammatory diseases including rheumatic as well as ,~j 35 other systemic or local auto-immune, and immune complex-`~ related diseases including extrinsic allergic alveo-~ litis, said compositions conta ning a cyclic peptide as , ,~ :"'.
:;~, c, WO91JI6~5 5 2 0 ~ ~ 312 PCT/~L9t/0~ ~
defined in the above.
In general, the peptides according to the invention may be applied in composition with an anti-inflammatory potential and further be used to enrich IgG
from blood serum or plasma to deplete plasma or serum from IgG, and/or to quantitate IgG levels in e.g. body liquids.
- With respect to the anticomplementary activity the following is remarked.
Complement is an important system in the body's ; defense against foreign invaders such as bacteria, virusses, and other micro-organisms. The activation of the complement cascsde by foreign materials leads to inflammation, opsonisation by C3b for phagocytosis, and l; the lysis of cells b- membrane damage. Complement can also be activated in diseases such as immune cc~leY.
j and/or auto-immune diseases and immuni ty states ~nere tissue damage may occur. It is believed that inhibition . of the complement cascade can prevent tissue injur-. .Abrief review on the C? and AP comple-ent inhibitors is , given in Ashgar, S,S., ~1984) Pharmalogical ~anipulation of Complement System, Pharmalogical Reviews 36, 223-224.
Up to now, a limited number of anticomplementory agents ~, are available. Of these agents only cobra venum facto-~e~ 25 ~CVF) gives rise to efficient complemer.~-de~lst on in vivo. The complement-depletion brought a~ou~ ~. CVr, however, is not selective but involves both the CP and ~ the AP complement activation. Therefore, the new C-'~ inhibitors according to the present invention for the treatment of auto-immune and other immune complex .,~ diseases are very important. The cyclic peptides according to the invention have specificity for the CP
and leave the AP unaffected. The latter is essential not only for the host's general defense potential but also .. :
ny ~ 35 for the elimination of certain types of immune complexes (Vogt, W., (i985) Drugs and the complement system.
Trends in Pharmocol. Sciences 6, 114-119). Probabl~. the , ~ .
'' .
~ ' ,:a~ -~-- .
WO91/16~ 2 0 8 ~ 312 PCT/~L91/0~ ~
best CP-inhibitors are substances which interfere with the binding of Cl to immune aggrc-ates.
Since the cyclic pept ~s according to the invention cause an inhibition of the classical complement pathway and leave the AP functionally intact, it may be assumed that the peptides will not interfere with the non-specific defense of the body agains-microbial infections and with processes as the AP-dependent elimin2tion of immune complexes from the circulation. This means that the cyclic peptides ; according to the invention are highly interesting sub-i stances that are suited to t.eat the deleter_ous e~ects of the CP-acti~ation in vivo as occ~rring in auto-immune diseases.
1~ It is a ve-y i~portan~ feature of the suDstances of the invention that no acute toxic effects can be sho~n in mice in concentrations up to ~ mg per anim21.
Peptides according to the invention could be beneficial } not only by local application (e.g. in vasculitis) but may also be of use upon oral or parenteral adm nistr-ation in the case of diseases such as mentioned above and in arthr~tis, hepatitis, glomerulo-nephritis etc. It , is expected that the cyclic peptides according to the present invention will not show chronic toxicit~, either.
The cyclic peprides ma- be used in the estim-ation of complement-activating human IgG's and analogues in other species by ELISA, the isolation of these antibodies and analogues by affinity chromatography, very similar to protein A-sepharose chromatography, and the selective removal of IgG from the circulating blood in immune complex diseases and cases of M. Kahler. This ~ could probably be achieved by plasmapheresis and passing -'~, the plasma over micro-carriers (beads) coated with cyclic peptides accordin-g to the invention, e.g.
~`~ labatidin or biobollein.
}.` . :
~fi ... . .
,' ~ - . , WO9t/16~; 2 0 i~ 13 ~ ~ PCT/~L9t/000~
,, ~ - .
The cyclic peptides according to the invention may be prepared according to standard procedures for the s~nthesis of cyclic (oligo) peptides. These procedures are well known to the man in art.
However, as noted above, the cyclic peptides according to the invention may be isolated from plant material, e.g. of the Euphorbiaceae family, in particular the latex of the genus Jatropha, e.g.
Jatropha multifida L.
The isolation of the cyclic peptides according to the invention is based on their modulatory effec~s on specific im~unological parsmeters in vitro. Relevant experiments are carried out according ~o standard pro-cedures.
Below an example is given o, the isolz-l~n cf two important cyclic peptides according to tne invent on, i.e. labaditin and biobollein.
Immunomodulatory constituents were isolated from the latex of Jatropha multifida accordin~ to the following fractonation scheme:
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",, crud~ (S rr~ :
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pol~amid~ CC
J: Me~H:H20 0 100 ! -- 7-- 32 1~0:0 ~`` ~
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.
; ~ sepka~e~ LH 20 : rnv~iliCol mullilid~l I
: 7 rrg g~ucosid~ 1 1 -; 13 rrg labadi~in blob~neln . ca~echin ~: ep;ca!echin (rninor al~ounls) ;.
~ ~ . ;,. ..
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~ : ~ LAST ADDED Sr.~
~, . .
-,'~',`~:
W091/t6~5 ~ ~g~ 3 ~ 2 PCT/~L91/0 ,; 8 According to the above scheme the crude latex ~5 ml) was mixed with 25 ml of demineralized water. After extraction of the supernatant with n-hexane, the super-natant was lyophillized, yielding a solid (500 mg). The solid material was dissolved in a small amount of water and subsequently separated on a polyaaide column. By elution with 500 ml portions of different methanol-water mixtures, i.e. (O : lOO), (l : 4), (2 : 3), (3 : 2) and ; (lOO : O) successively, five fractions (I-V) were obtained. These fractions were tested for modulatory effects on both CP and AP activation of human complement, and on the production of rea~ctive oxygen species (ROS) by zymosan-stimulated human polymorpho-nuclear neu~rophilis (PM~') monitored as chemi-l~ luminescence. Fraction IV was found to possess significant ac~ivity.
; From fraction I~' a novel c~c1i~ aecP?e~ de (labaditin) and a novel cyclic nonapeptide (biobollein) , were isolated, both of which show a strong inhibitcry- -.~, 20 effect on CP acitivity of human complemen~. The , isolation of labaditin and biobollein respectively is elucitsted here below.
Isolation of labaditin The concentrated MeOH : H20 (3 : 2) fraction (fraction IV) (42 mg) was dissolved in l;. NaHC03. The solution was exhaustively with ethyl acet&te. E~hyl - acetate extracts were combined.and the solves1t was e:ap-j orized under reduced pressure. The residue was dissolved ~ in 2 ml of MeOH and separated-by gel permeation over i' 3 Sephadex LH-20 ( 40 cm x l cm i.d.) with MeOH as eluting agent. Per fraction 300 drops were collected. Fractions 4, 5 and 6 showing one single spot on TLC were combined.
The MeOH was evaporated under reduced pressure.
' Subsequently, water was added and the solution was `~ 35 lyophillized, yielding 14 mg of a white solid.
,' . .
.~ .
. .
. . .~ .
,' .
. .
.. .
W091/16~5 PCT/~L91/O~K~
2~i3~2 - ~.uv Isolation of biobollein The MeOH : H20 (3 : 2~ fraction (fraction IV) (42 mg) was directly extracted with ethyl acetate. The ethyl acetate extracts were combined and the solvent was evaporated under reduced pressure. The residue was dissolved in 2 ml of MeOH and by adding 15 ml of acetone : water (1 : 1), a precipitate was obtained. The precipitate was dissolved in 2 ml of MeOH and separated over Sephadex LH-20 (column 40 cm x 1 cm i.d.) with MeOH
ss elutin~ agent. Per frsction 300 drops were collected.
Fractions 4, 5 and 6 showing two spots of TLC were combined and the solvent was removed under reduced pressure. The fraction cons ituents were separated by preparative TLC on silica gel 60 F 254, 1 mm (Merc~
Darmstsdt, FRG) with CHCl3 : MeOH ; H20 (13 10 : 2) as - eluent (saturated chamber), and were detected unde~
254 nm. The procedure yielded two white solid compounds, i.e. labsditin (14 mg) and biobollein (11 mg).
The structure of labaditin and biobollein was determined by means of the following procedures:
Amino acid an21ysis The amino acid composition wss determined with sn sutomat~c amino acid analyser (LK~ 4151 Alpha plus, Na-system 20 cm column) sfter hydrolysis ln 6 N HCL st 110 C for 48 hours and, for tryptophan determination, in ~ 6N HCL with 4X thioglycolic acid at 110 C for 24 hours.
,~ Th~n layer chromatogra~hy (TLC) Silica gel 60 F-254 TLC plates (Merc~, ~ Darmstadt, FRG) were used with CHCL3 : MeOH : H20 = 13 :
'~ - 30 10 : 2 as solvent system (saturated chamber). Spots were visualized under UV 254 nm and by spraying with vanilin-sulphuric acid followed by heating at 110 C for 5 min.
' NMR sPectroscoPY
.
For NMR experiments the purified peptide was dissolved in DMSO-d6 (conc. 30 mg/ml). For some exper- ~ -`~ iments 5% D20 was added to exchange amide protons. lH-`~ NMR spectra were recorded on a Bruker WM-300 spectro-meter at 303 and 338 K. Two-dimensional lH-NMR spectra ~rj were obtained at 303 X. For the COSY spectrum 257 ., .
.~. ' - ~ .
W091/16~5 2 ~ ~1312 PCT/~L91/00066 '''`'" 10 records of 2K data were recorded at 400 MHz on a Bruke.
MSL-400 apparatus. The phase sensitive NOESY expe.iment containing 350 records of 2X date was obtained 2- 600 MHz on a Bruker AM-600. The NOES~ data were multiplied with sinebell windows and Fourier transformed in both domains. The COSY spectrum was displayed in the absolute value mode.
FAB-MS measurement -For the FAB experiments a ZAB-2F VG instrument was used.
~J : ' :;'~ '' :.' ':~ ' .:
.~ .
`'': : ' ., .
~ ' . .
~'`` . ' 1. .
', ': , ':., . , ' `' ', ' ,............ .
Protein A and an analogue isolated from Streptococcus ; strain G148 (protein G) are used to isolate IgG from serum and plasma (Bjorck, L & Kronvall, G. (1984) Purif-ication and some properties of Streptococcal protein G, a novel IgG-biundine reagent. J. Immunol. 133, 969-973).
Leupeptin (a tripaptide from actinomycete fermen~ation) and singlQ amino acids can interfere with complement activation via the CP andior the alternative pathwa; (AP) (Takada, Y., .~rimoto, Y, Mineda, H. & Taka-da, .~.. (1978) Inhibition of the classical ar.~ alterna-~l tive pathwa~s by amino acids and their derivatives.
s~, Immunology 34, 509-515). -~ It has now been found by us that there are ;, 20 cyclic peptides with IgG-binding properties. This is to il say that cyclic peptides which are isolated from e.g.
the latex of specific plants or which may be prepared synthetically or semi-synthetically, were find to bind to human but also to rabbit and mouse IgG but not to Ig~7 and IgA in in vitro systems for Is~-binding. The peptides were isolated and ldentified on the basis of thelr selective inhibition of complement activation via the CP (Kosasi, S., Van der Sluis, W.G., Boelens, R., 't Hart, L.A. & Labadie, R.P. ~1989) Labaditin, a novel cyclic decapeptide from the latex of Jatropha multifida 1. (Euphorbiaceae) FEBS let~ers Z56, 91-96). AP activ-ation was not or only s-lightly affected by these peptides. It was shown that the anticomplemçntary activity of the peptides is mediated by an interference with Clq-acceptor sites on the IgG molecules they bind - to. Tnis means that the cyclic peptides combine protein A-like IgF-binding activitv with leupeptin- and amino ;~,~ . . .
;~ - .... .. .
.;~ ' . ~ . :^
wu Yl/ ln~ r~ l / :'~L~I/UWW
,~ ,~ ":
acid-like anticomplementary behavior. Such combined activity has never been described in literature, not for ' proteins but neither for linear peptides and particularly not for c~clic peptides. The anti-''.! 5 complementary activity of the novel cyclic peptides is mechanistically different from that of the linear peptide AA 27~-290, which represents a major part cf the Clq-acceptor site on IgG (Prystowski, M.B., Kehoe, J.M., ;~
& Erickson, B.W. (1981) Inhibition cf the classical ' ~ 10 complement pathway by synthetic peptides from the second-'i constant comain of the hea~.; chzin Or IgG. Bioche~istry '~ 21, p, 6349-6358). The latter does not bind to igG but '' prevents cocple~ent sctivstion by competing hith IsG for binding to C;. The an~ico~?lementary acti-ity is also different from the leupep~in-induced 2.-~ amino acid-induced complement inhibi;ion which is no: 'base~ on '~ binding to lgG.
'~ An advantage of our novel peptides over other cyclic peptides, such as cyclosporins, is their extreme solubility in water (up to 1000 mg per ml) and their . non-toxic behavior, at least in mice. They also differ from cyc.osporins and the Rubia peptides in the fact that they are built up fro~ proteinogenic (= proteinic) amino acids. ' Therefore, the cyclic peptides all ~o the invention consist preferably of proteinic a~ino acids.
Thls means that'such amino ~cids do not have to be modified, e.g. by methyl groups. It should be noted that the known cyclosporins contain methylated or derived proteinic amino acids.
' Structural analysis of the cyclic peptides of the present invention reveals that said cyclic peptides contain preferably the amino acid Trp and/or His, in particular the dipeptide groups Trp-Gly and/or His-Gly.
It is preferred tbat the cyclic peptides - according to the invention contain 8-12, preferably 9-11 amino acid residues.
~ ` ' ` ' .
~ .
.',ti ~,~`~' ' ' ' . . , ~O9l/16~5 2 ~ PCT/~Lgl/o~
In general, the cyclic peptides according to the invention contain at least 6 amino acid residues which are preferably selected from the group consis~ing of Ala, G~y, Val, Trp, Thr, Ile, Ser, and Leu.
Two important examples of cyclic peptides according to the present invention are characterized by the sequence Ala-Gly-Val-Trp-Thr-Val-Trp-Gly-Thr-Iie (Labaditin) and Ala-Ser-Ile-Leu-Gly-Leu-Gly-Trp-.~la-(Biobollein).
Of course, the cyclic peptides according to the present invention may be prepared according to classical peptide synthesis methods. However, they may also be isolated from plan~ material of the Euphorb aceae family, in pa-ticuiar the la-~x of Ja~ro?ha species.
The peptides accord r., to tr.e inven~ion ~a~ be ,j, used fo- various purposes such as for the preparation of pharmaceutical co~positions or for analysis, and/or :' separation standardization purposes.
,' The use of the cyclic peptides according to the 7 20 invention may - in general - be used for IgG-binding and ~ anticomplementary activity in mammals including human m beings.
:! .
,~i The present invention also relates to the ~! application mentioned above. The present. invention further relates to a method for trestlng diseases such as inflammstory diseases including rheumaticas well as other systemic or local-auto-immuné, and immune complex-related diseases including extrinsic allergic alveolitis in mammals including human beings wherein a cyclic peptide as defined in the above is used as an active substance.
The present invention further rçlates to `i, pharmaceutical compositions for treating diseases such ~;~ as inflammatory diseases including rheumatic as well as ,~j 35 other systemic or local auto-immune, and immune complex-`~ related diseases including extrinsic allergic alveo-~ litis, said compositions conta ning a cyclic peptide as , ,~ :"'.
:;~, c, WO91JI6~5 5 2 0 ~ ~ 312 PCT/~L9t/0~ ~
defined in the above.
In general, the peptides according to the invention may be applied in composition with an anti-inflammatory potential and further be used to enrich IgG
from blood serum or plasma to deplete plasma or serum from IgG, and/or to quantitate IgG levels in e.g. body liquids.
- With respect to the anticomplementary activity the following is remarked.
Complement is an important system in the body's ; defense against foreign invaders such as bacteria, virusses, and other micro-organisms. The activation of the complement cascsde by foreign materials leads to inflammation, opsonisation by C3b for phagocytosis, and l; the lysis of cells b- membrane damage. Complement can also be activated in diseases such as immune cc~leY.
j and/or auto-immune diseases and immuni ty states ~nere tissue damage may occur. It is believed that inhibition . of the complement cascade can prevent tissue injur-. .Abrief review on the C? and AP comple-ent inhibitors is , given in Ashgar, S,S., ~1984) Pharmalogical ~anipulation of Complement System, Pharmalogical Reviews 36, 223-224.
Up to now, a limited number of anticomplementory agents ~, are available. Of these agents only cobra venum facto-~e~ 25 ~CVF) gives rise to efficient complemer.~-de~lst on in vivo. The complement-depletion brought a~ou~ ~. CVr, however, is not selective but involves both the CP and ~ the AP complement activation. Therefore, the new C-'~ inhibitors according to the present invention for the treatment of auto-immune and other immune complex .,~ diseases are very important. The cyclic peptides according to the invention have specificity for the CP
and leave the AP unaffected. The latter is essential not only for the host's general defense potential but also .. :
ny ~ 35 for the elimination of certain types of immune complexes (Vogt, W., (i985) Drugs and the complement system.
Trends in Pharmocol. Sciences 6, 114-119). Probabl~. the , ~ .
'' .
~ ' ,:a~ -~-- .
WO91/16~ 2 0 8 ~ 312 PCT/~L91/0~ ~
best CP-inhibitors are substances which interfere with the binding of Cl to immune aggrc-ates.
Since the cyclic pept ~s according to the invention cause an inhibition of the classical complement pathway and leave the AP functionally intact, it may be assumed that the peptides will not interfere with the non-specific defense of the body agains-microbial infections and with processes as the AP-dependent elimin2tion of immune complexes from the circulation. This means that the cyclic peptides ; according to the invention are highly interesting sub-i stances that are suited to t.eat the deleter_ous e~ects of the CP-acti~ation in vivo as occ~rring in auto-immune diseases.
1~ It is a ve-y i~portan~ feature of the suDstances of the invention that no acute toxic effects can be sho~n in mice in concentrations up to ~ mg per anim21.
Peptides according to the invention could be beneficial } not only by local application (e.g. in vasculitis) but may also be of use upon oral or parenteral adm nistr-ation in the case of diseases such as mentioned above and in arthr~tis, hepatitis, glomerulo-nephritis etc. It , is expected that the cyclic peptides according to the present invention will not show chronic toxicit~, either.
The cyclic peprides ma- be used in the estim-ation of complement-activating human IgG's and analogues in other species by ELISA, the isolation of these antibodies and analogues by affinity chromatography, very similar to protein A-sepharose chromatography, and the selective removal of IgG from the circulating blood in immune complex diseases and cases of M. Kahler. This ~ could probably be achieved by plasmapheresis and passing -'~, the plasma over micro-carriers (beads) coated with cyclic peptides accordin-g to the invention, e.g.
~`~ labatidin or biobollein.
}.` . :
~fi ... . .
,' ~ - . , WO9t/16~; 2 0 i~ 13 ~ ~ PCT/~L9t/000~
,, ~ - .
The cyclic peptides according to the invention may be prepared according to standard procedures for the s~nthesis of cyclic (oligo) peptides. These procedures are well known to the man in art.
However, as noted above, the cyclic peptides according to the invention may be isolated from plant material, e.g. of the Euphorbiaceae family, in particular the latex of the genus Jatropha, e.g.
Jatropha multifida L.
The isolation of the cyclic peptides according to the invention is based on their modulatory effec~s on specific im~unological parsmeters in vitro. Relevant experiments are carried out according ~o standard pro-cedures.
Below an example is given o, the isolz-l~n cf two important cyclic peptides according to tne invent on, i.e. labaditin and biobollein.
Immunomodulatory constituents were isolated from the latex of Jatropha multifida accordin~ to the following fractonation scheme:
. ' .
~ji .
. ~ .
` .
;1 .
. ..
: :
.` .
., .
;~.~ . -.#
' :
' .
' .
-. SUBSTITUTE SHEET
., .
~ .
..;
... . . ~ . `., , - . ... . . ., .. ,. -,.. ,. . ... . . - ~ . - - .
WO 91/16345 2 0 S ~ 3 i 2 PCI~L91/00066 7/1 ;:
'' ;'''. " ' ;.
",, crud~ (S rr~ :
'~, . . :.
.. - ~a:er (25 r~) ,, , .
~, ~ su?erna~ -- p~ ?,~,ate ~ n-he~ar~
res- ue ~reeze dri~ : . :
~5.~-~ t;~) ' .'~, I , ~
pol~amid~ CC
J: Me~H:H20 0 100 ! -- 7-- 32 1~0:0 ~`` ~
t~r n~ .m) ~r nr) ~t,~
161 tn~ 30 r~T~9 93 m9 ~2 rng ~ tn~
~ I ...
.
; ~ sepka~e~ LH 20 : rnv~iliCol mullilid~l I
: 7 rrg g~ucosid~ 1 1 -; 13 rrg labadi~in blob~neln . ca~echin ~: ep;ca!echin (rninor al~ounls) ;.
~ ~ . ;,. ..
:
~ : ~ LAST ADDED Sr.~
~, . .
-,'~',`~:
W091/t6~5 ~ ~g~ 3 ~ 2 PCT/~L91/0 ,; 8 According to the above scheme the crude latex ~5 ml) was mixed with 25 ml of demineralized water. After extraction of the supernatant with n-hexane, the super-natant was lyophillized, yielding a solid (500 mg). The solid material was dissolved in a small amount of water and subsequently separated on a polyaaide column. By elution with 500 ml portions of different methanol-water mixtures, i.e. (O : lOO), (l : 4), (2 : 3), (3 : 2) and ; (lOO : O) successively, five fractions (I-V) were obtained. These fractions were tested for modulatory effects on both CP and AP activation of human complement, and on the production of rea~ctive oxygen species (ROS) by zymosan-stimulated human polymorpho-nuclear neu~rophilis (PM~') monitored as chemi-l~ luminescence. Fraction IV was found to possess significant ac~ivity.
; From fraction I~' a novel c~c1i~ aecP?e~ de (labaditin) and a novel cyclic nonapeptide (biobollein) , were isolated, both of which show a strong inhibitcry- -.~, 20 effect on CP acitivity of human complemen~. The , isolation of labaditin and biobollein respectively is elucitsted here below.
Isolation of labaditin The concentrated MeOH : H20 (3 : 2) fraction (fraction IV) (42 mg) was dissolved in l;. NaHC03. The solution was exhaustively with ethyl acet&te. E~hyl - acetate extracts were combined.and the solves1t was e:ap-j orized under reduced pressure. The residue was dissolved ~ in 2 ml of MeOH and separated-by gel permeation over i' 3 Sephadex LH-20 ( 40 cm x l cm i.d.) with MeOH as eluting agent. Per fraction 300 drops were collected. Fractions 4, 5 and 6 showing one single spot on TLC were combined.
The MeOH was evaporated under reduced pressure.
' Subsequently, water was added and the solution was `~ 35 lyophillized, yielding 14 mg of a white solid.
,' . .
.~ .
. .
. . .~ .
,' .
. .
.. .
W091/16~5 PCT/~L91/O~K~
2~i3~2 - ~.uv Isolation of biobollein The MeOH : H20 (3 : 2~ fraction (fraction IV) (42 mg) was directly extracted with ethyl acetate. The ethyl acetate extracts were combined and the solvent was evaporated under reduced pressure. The residue was dissolved in 2 ml of MeOH and by adding 15 ml of acetone : water (1 : 1), a precipitate was obtained. The precipitate was dissolved in 2 ml of MeOH and separated over Sephadex LH-20 (column 40 cm x 1 cm i.d.) with MeOH
ss elutin~ agent. Per frsction 300 drops were collected.
Fractions 4, 5 and 6 showing two spots of TLC were combined and the solvent was removed under reduced pressure. The fraction cons ituents were separated by preparative TLC on silica gel 60 F 254, 1 mm (Merc~
Darmstsdt, FRG) with CHCl3 : MeOH ; H20 (13 10 : 2) as - eluent (saturated chamber), and were detected unde~
254 nm. The procedure yielded two white solid compounds, i.e. labsditin (14 mg) and biobollein (11 mg).
The structure of labaditin and biobollein was determined by means of the following procedures:
Amino acid an21ysis The amino acid composition wss determined with sn sutomat~c amino acid analyser (LK~ 4151 Alpha plus, Na-system 20 cm column) sfter hydrolysis ln 6 N HCL st 110 C for 48 hours and, for tryptophan determination, in ~ 6N HCL with 4X thioglycolic acid at 110 C for 24 hours.
,~ Th~n layer chromatogra~hy (TLC) Silica gel 60 F-254 TLC plates (Merc~, ~ Darmstadt, FRG) were used with CHCL3 : MeOH : H20 = 13 :
'~ - 30 10 : 2 as solvent system (saturated chamber). Spots were visualized under UV 254 nm and by spraying with vanilin-sulphuric acid followed by heating at 110 C for 5 min.
' NMR sPectroscoPY
.
For NMR experiments the purified peptide was dissolved in DMSO-d6 (conc. 30 mg/ml). For some exper- ~ -`~ iments 5% D20 was added to exchange amide protons. lH-`~ NMR spectra were recorded on a Bruker WM-300 spectro-meter at 303 and 338 K. Two-dimensional lH-NMR spectra ~rj were obtained at 303 X. For the COSY spectrum 257 ., .
.~. ' - ~ .
W091/16~5 2 ~ ~1312 PCT/~L91/00066 '''`'" 10 records of 2K data were recorded at 400 MHz on a Bruke.
MSL-400 apparatus. The phase sensitive NOESY expe.iment containing 350 records of 2X date was obtained 2- 600 MHz on a Bruker AM-600. The NOES~ data were multiplied with sinebell windows and Fourier transformed in both domains. The COSY spectrum was displayed in the absolute value mode.
FAB-MS measurement -For the FAB experiments a ZAB-2F VG instrument was used.
~J : ' :;'~ '' :.' ':~ ' .:
.~ .
`'': : ' ., .
~ ' . .
~'`` . ' 1. .
', ': , ':., . , ' `' ', ' ,............ .
Claims (17)
1. Cyclic peptides having I??-binding properties.
2. Cyclic peptides according to claim 1, characterized by their anti-complementary activity.
3. Cyclic peptides according to claim 1 and 2, characterized by their selective inhibitory effect on the classical activation pathway of the complement system.
4. Cyclic peptides according to claim 1-3, characterized by their solubility in water.
5. Cyclic peptides according to claim 1-3, characterized in that they consist of proteinic amino acid.
6. Cyclic peptides according to claim 1-3, characterized in that they contain Trp and/or histidine.
7. Cyclic peptides according to claim 6, characterized in that they contain the dipeptide group Trp-Gly.
8. Cyclic peptides according to claim 1-3, characterized in that they contain at least 6 amino acid residues.
9. Cyclic peptides according to claim 8.
characterized in that they contain 8-12, preferably 9-11 amino acid residues.
characterized in that they contain 8-12, preferably 9-11 amino acid residues.
10. Cyclic peptides according to claim 1-3, characterized in that they contain residues from amino acids selected from the group consisting of Ala, Gly, Val, Trp, Thr, Ile, Ser and Leu.
11. Cyclic peptide according to claim 1-3, characterized by the sequence (Labaditin).
12. Cyclic peptide according to claim 1-3, characterized by the sequence (Biobollein).
13. Cyclic peptides according to claim 1-3, characterized in that they may be isolated from plant material of the Euphorbiaceae family, in particular plant material of the genus Jatropha.
14. Use of cyclic peptides as defined in any of claims 1-13 for the preparation of pharmaceutical compositions or for analysis, standarization and/or separation purposes.
15. Use of cyclic peptides as defined in any of claims 1-13 for IgG binding in mammals including human beings.
16. Methods for treating diseases such as inflammatory diseases including rheumatic, auto-immune and immune-complex related diseases in mammals including human beings wherein a peptide according to any of claims 1-13 is used as an active substance.
17. Pharmaceutical compositions for treating diseases such as inflammatory diseases including rheumatic as well as other systemic or local auto-immune and immune-complex related diseases including extrinsic allergic alveolitis, characterized in that they contain a cyclic peptide as defined in any of claims 1-13.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US51279690A | 1990-04-23 | 1990-04-23 | |
| US512,796 | 1990-04-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2081312A1 true CA2081312A1 (en) | 1991-10-24 |
Family
ID=24040600
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002081312A Abandoned CA2081312A1 (en) | 1990-04-23 | 1991-04-22 | Cyclic peptides and their use |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0528835A1 (en) |
| JP (1) | JPH05508391A (en) |
| AU (1) | AU7749491A (en) |
| CA (1) | CA2081312A1 (en) |
| WO (1) | WO1991016345A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0894002A4 (en) * | 1996-03-13 | 2001-11-14 | Univ Pennsylvania | Novel peptides which inhibit complement activation |
| SI1549333T1 (en) | 2002-09-20 | 2012-02-29 | Univ Pennsylvania | Compstatin analogues with improved activity |
| CA2971349C (en) | 2005-11-28 | 2020-09-08 | The Trustees Of The University Of Pennsylvania | Potent compstatin analogs |
| HUE047375T2 (en) | 2011-09-07 | 2020-04-28 | Univ Pennsylvania | Compstatin analogs with improved pharmacokinetic properties |
-
1991
- 1991-04-22 WO PCT/NL1991/000066 patent/WO1991016345A1/en not_active Application Discontinuation
- 1991-04-22 JP JP3507949A patent/JPH05508391A/en active Pending
- 1991-04-22 AU AU77494/91A patent/AU7749491A/en not_active Abandoned
- 1991-04-22 EP EP91908318A patent/EP0528835A1/en not_active Withdrawn
- 1991-04-22 CA CA002081312A patent/CA2081312A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| EP0528835A1 (en) | 1993-03-03 |
| JPH05508391A (en) | 1993-11-25 |
| AU7749491A (en) | 1991-11-11 |
| WO1991016345A1 (en) | 1991-10-31 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued | ||
| FZDE | Discontinued |
Effective date: 19941024 |