EP0528835A1 - Zyklische peptide und ihre verwendung - Google Patents
Zyklische peptide und ihre verwendungInfo
- Publication number
- EP0528835A1 EP0528835A1 EP91908318A EP91908318A EP0528835A1 EP 0528835 A1 EP0528835 A1 EP 0528835A1 EP 91908318 A EP91908318 A EP 91908318A EP 91908318 A EP91908318 A EP 91908318A EP 0528835 A1 EP0528835 A1 EP 0528835A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- cyclic peptides
- peptides according
- cyclic
- gly
- trp
- 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.)
- Withdrawn
Links
- 108010069514 Cyclic Peptides Proteins 0.000 title claims abstract description 45
- 102000001189 Cyclic Peptides Human genes 0.000 title claims abstract description 45
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 19
- 230000027455 binding Effects 0.000 claims abstract description 10
- 230000002401 inhibitory effect Effects 0.000 claims abstract 2
- 201000010099 disease Diseases 0.000 claims description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
- 150000001413 amino acids Chemical class 0.000 claims description 8
- 241000196324 Embryophyta Species 0.000 claims description 7
- 241000282414 Homo sapiens Species 0.000 claims description 7
- 230000003171 anti-complementary effect Effects 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 6
- 230000001363 autoimmune Effects 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
- 208000027866 inflammatory disease Diseases 0.000 claims description 4
- 108010002842 labaditin Proteins 0.000 claims description 4
- 230000037361 pathway Effects 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 241000221089 Jatropha Species 0.000 claims description 3
- 208000025747 Rheumatic disease Diseases 0.000 claims description 3
- 230000004913 activation Effects 0.000 claims description 3
- 230000004154 complement system Effects 0.000 claims description 3
- 230000000552 rheumatic effect Effects 0.000 claims description 3
- 230000009885 systemic effect Effects 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 208000035939 Alveolitis allergic Diseases 0.000 claims description 2
- 108010016626 Dipeptides Proteins 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
- 201000001155 extrinsic allergic alveolitis Diseases 0.000 claims description 2
- 208000022098 hypersensitivity pneumonitis Diseases 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims 1
- 108010038745 tryptophylglycine Proteins 0.000 claims 1
- 102000004196 processed proteins & peptides Human genes 0.000 abstract description 17
- 230000024203 complement activation Effects 0.000 abstract description 8
- 210000002966 serum Anatomy 0.000 abstract description 7
- 210000002381 plasma Anatomy 0.000 abstract description 6
- 239000000203 mixture Substances 0.000 abstract description 3
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 2
- 210000001124 body fluid Anatomy 0.000 abstract 1
- 239000010839 body fluid Substances 0.000 abstract 1
- 125000004122 cyclic group Chemical group 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- 108010036941 Cyclosporins Proteins 0.000 description 6
- 229930182912 cyclosporin Natural products 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 5
- 239000004816 latex Substances 0.000 description 5
- 229920000126 latex Polymers 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 230000000295 complement effect Effects 0.000 description 4
- 238000002955 isolation Methods 0.000 description 4
- 241001103643 Rubia Species 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 230000007123 defense Effects 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- 208000024781 Immune Complex disease Diseases 0.000 description 2
- 241000221091 Jatropha multifida Species 0.000 description 2
- 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 2
- 241000699670 Mus sp. Species 0.000 description 2
- 108010038807 Oligopeptides Proteins 0.000 description 2
- 102000015636 Oligopeptides Human genes 0.000 description 2
- 241001107098 Rubiaceae Species 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 230000036039 immunity Effects 0.000 description 2
- 230000001506 immunosuppresive effect Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 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 2
- 108010052968 leupeptin Proteins 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 210000002925 A-like Anatomy 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 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
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241001048891 Jatropha curcas Species 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241001494479 Pecora Species 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
- 241001153838 Rubia argyi Species 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
- 206010052779 Transplant rejections Diseases 0.000 description 1
- 206010047115 Vasculitis Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
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- 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
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process 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
- 239000000969 carrier Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000007665 chronic toxicity Effects 0.000 description 1
- 231100000160 chronic toxicity Toxicity 0.000 description 1
- 239000004074 complement inhibitor Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 108010036413 histidylglycine Proteins 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 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
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 238000002616 plasmapheresis Methods 0.000 description 1
- 230000003389 potentiating effect Effects 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
- 241000894007 species Species 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
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- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity 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
- 238000002054 transplantation Methods 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
Definitions
- the present invention with a novel class of peptides and their application.
- cyclic peptides were mostly of microbial and more in particular of fungus origin. These so-called cyclosporins are known as immunosuppressive compounds and are used to prevent graft rejection after organ transplantation. Disadvant ⁇ ages of cyclosporins are their insolubility in water and their toxicity, particularly for the kidneys.
- a surface protein from Staphylococcus aureus was shown to bind IgG and to enhance complement activation via the classical pathway (CP) (Masuda, S. , Sakurai, S. & Kondo , I. (1975) Simple and effective method for selecting protein A deficient mutants by cosedimentation with sensitized sheep erythrocytes . Infection and Immunity 12, 245-251; 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 Gl48 are used to isolate IgG from serum and plasma (Bj ⁇ rck, L & Kronvall, G. (1984) Purif- ication and some properties of Streptococcal protein G, a novel IgG-biunding reagent. J. Immunol. 133. 969 _ 973)-
- Leupeptin a tripeptide from actinomycete fermentation
- single amino acids can interfere with complement activation via the CP and/or the alternative pathway (AP)
- AP alternative pathway
- cyclic peptides with IgG-binding properties.
- cyclic peptides which are isolated from e.g. the latex of specific plants or which may be prepared synthetically or se i-synthetically, were find to bind to human but also to rabbit and mouse IgG but not to IgM and IgA in in vitro systems for IgG-binding.
- the peptides were isolated and identified on the basis of their selective inhibition of complement activation via the CP (Kosasi, S., Van der Sluis, W.G., Boelens, R. , 't Hart, L.A. & Labadie, R.P.
- the anti- complementary activity of the novel cyclic peptides is mechanistically different from that of the linear peptide AA 275-290, which represents a major part of the Clq-acceptor site on IgG (Prystowski, M.B. , Kehoe, J.M. , & Erickson, B.W. (1981) Inhibition of the classical complement pathway by synthetic peptides from the second constant comain of the heavy chain of IgG. Biochemistry 21, p. 6349-6358) . The latter does not bind to IgG but prevents complement, activation by competing with IgG for binding to Cl .
- the anticomplementary activity is also different from the leupeptin-induced and amino acid- induced complement inhibition which is not ' .based on binding to IgG .
- cyclic peptides all to the invention consist preferably of proteinic amino acids. This means that such amino * acids 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.
- cyclic peptides of the present invention 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 "H amino acid residues. In general, the cyclic peptides according to the invention contain at least 6 amino acid residues which are preferably selected from the group consisting of Ala, GLy, Val, Trp, Thr, lie, Ser, and Leu.
- cyclic peptides according to the present invention are characterized by the sequence Ala-Gly-Val-Trp-Thr-Val-Trp-Gly-Thr-Ile (Labaditin) and Ala-Ser-Ile-Leu-Gly-Leu-Gly-Trp-Ala- (Biobollein) .
- the cyclic peptides according to the present invention may be prepared according to classical peptide synthesis methods. However, they may also be isolated from plant material of the Euphorbiaceae family, in particular the latex of Jatropha species.
- the peptides according to the invention may be used for various purposes such as for the preparation: of pharmaceutical compositions or for analysis, and/or separation standardization purposes.
- cyclic peptides according to the ' invention may -" in general - be used for IgG-binding and anticomplementary activity in mammals including human beings .
- the present invention also relates to the application mentioned above.
- the present invention further relates to a method for treating diseases such as inflammatory diseases including rheumaticas well as other systemic or local- auto-immune, 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 relates to 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 alveo ⁇ litis, said compositions containing a cyclic peptide as defined in the above.
- 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 .
- 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 cascade by foreign materials leads to inflammation, opsonisation by C3b for phagocy osis, and the lysis of cells by membrane damage.
- Complement can also be activated in diseases such as immune com'plex and/or auto-immune diseases and immunity states where tissue damage may occur. It is believed that inhibition of the complement cascade can prevent tissue injury.
- a brief review on the CP and AP complement inhibitors is given in Ashgar, S.S., ?1984) Pharmalogical Manipulation of Complement System, Pharmalogical Reviews 36, 223-224.
- CVF cobra venu factor
- the complement-depletion brought about by CVF 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 for the elimination of certain types of immune complexes (Vogt, W. , (1985) Drugs and the complement system. Trends in Phar ocol. Sciences 6, 114-119) - Probably, the best CP-inhibitors are substances which interfere with the binding of Cl to immune aggregates.
- the cyclic pept_..es 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 against microbial infections and with processes as the AP- dependent elimination of immune complexes from the circulation.
- the cyclic peptides according to the invention are highly interesting sub ⁇ stances that are suited to treat the deleterious effects of the CP-activation in vivo as occurring in auto-immune diseases . It is a very important feature of the- substances of the invention that no acute toxic effects can be shown in mice in concentrations up to 5 - ⁇ -g per animal.
- 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 administr ⁇ ation in the case of diseases such as mentioned above and in arthritis, hepatitis, glomerulo-nephritis etc. It is expected that the cyclic peptides according to the present invention will not show chronic toxicity, either.
- the cyclic peptides may 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 according to the invention, e.g. labatidin or biobollein.
- the cyclic peptides according to the invention may be prepared according to standard procedures for the synthesis of cyclic (oligo) peptides.
- 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 effects on specific immunological parameters in vitro. Relevant experiments are carried out according to standard pro ⁇ cedures . Below an example is given of the isolation of two important cyclic peptides according to the invention, i.e. labaditin and biobolleiri.
- Immunomodulatory constituents were isolated from the latex of Jatropha multifida according to the following fractonation scheme:
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)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US51279690A | 1990-04-23 | 1990-04-23 | |
| US512796 | 1995-08-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0528835A1 true EP0528835A1 (de) | 1993-03-03 |
Family
ID=24040600
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP91908318A Withdrawn EP0528835A1 (de) | 1990-04-23 | 1991-04-22 | Zyklische peptide und ihre verwendung |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0528835A1 (de) |
| JP (1) | JPH05508391A (de) |
| AU (1) | AU7749491A (de) |
| CA (1) | CA2081312A1 (de) |
| WO (1) | WO1991016345A1 (de) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2248772C (en) * | 1996-03-13 | 2007-06-12 | John D. Lambris | Novel peptides which inhibit complement activation |
| AU2003275075A1 (en) | 2002-09-20 | 2004-04-08 | The Trustees Of The University Of Pennsylvania | Compstatin analogs with improved activity |
| EP2377877B1 (de) | 2005-11-28 | 2018-03-28 | The Trustees Of The University Of Pennsylvania | Potente Compstatin-Analoga |
| HUE047375T2 (hu) | 2011-09-07 | 2020-04-28 | Univ Pennsylvania | Javított farmakokinetikai tulajdonságokkal rendelkezõ compstatin analógok |
-
1991
- 1991-04-22 EP EP91908318A patent/EP0528835A1/de not_active Withdrawn
- 1991-04-22 AU AU77494/91A patent/AU7749491A/en not_active Abandoned
- 1991-04-22 JP JP3507949A patent/JPH05508391A/ja active Pending
- 1991-04-22 WO PCT/NL1991/000066 patent/WO1991016345A1/en not_active Application Discontinuation
- 1991-04-22 CA CA002081312A patent/CA2081312A1/en not_active Abandoned
Non-Patent Citations (1)
| Title |
|---|
| See references of WO9116345A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1991016345A1 (en) | 1991-10-31 |
| AU7749491A (en) | 1991-11-11 |
| JPH05508391A (ja) | 1993-11-25 |
| CA2081312A1 (en) | 1991-10-24 |
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