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:

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• Health & Medical Sciences (AREA)
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• Medicinal Chemistry (AREA)
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• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Pharmacology & Pharmacy (AREA)
• Public Health (AREA)
• Veterinary Medicine (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)

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Cited By (4)

• 1991
  • 1991-04-22 EP EP91908318A patent/EP0528835A1/en 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)

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