Peptides endowed with antiinflammatory activity

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai

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530324, A61K 3816, C07K 1435

Patent

active

058563059

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP95/04566 filed Nov. 20, 1995.


BACKGROUND OF THE INVENTION

1. Field of the Invention
The present invention relates to peptide derivatives of heat shock proteins, and to the use thereof in the treatment of inflammatory pathologies.
2. Description of the Related Art
The heat shock proteins (hereinfrom "HSP") are produced by cells under stress conditions, especially by mycobacteria. Procaryotes such as mycobacteria, express high HSP levels, some of which, e.g. a 65 kD protein, are immuno-dominant antigens, thus their use as vaccine was J. Immunol., 17, 351 (l987)!. WO 89/12455 gives a hint about the use of a protein of such class or a fragment thereof, specifically referring to a 65 kD protein, as a vaccine against non-viral infections and to induce an immune response.
Specific proteins within the same class were described as useful in different pathologies. For example, WO 90/10449 relates to the use of a HSP of 65 kD as a diagnostic agent and in the treatment of the insulin-independent diabetes. The same protein was found to posses a mycobacterial-specific epitope envolved in the pathogenesis of the
The HSP sequence weighing 10 kD is disclosed by Baird, P. N. et al., J. Gen. Microb., 135, 931-939 (1989) which describes it as coming from Mycobacterium tuberculosis BGC, while Mehra, V. et al., J. Exp. Med., 175, 275-284 (1992) discloses a homologous protein having the same weight from Mycobacterium leprae. Barnes, P. F. et al., J. Immun., 148, 1835-1840 (1992) discloses a 10 kD protein coming from Mycobacterium tuberculosis as highly immuno-reactive antigen hypothetically useful as anti-tuberculotic vaccine. Hartman, D. J. et al., Proc. Natl. Acad. Sci. USA, 89, 3394-3398 (1992) identified, in the mammal, a protein homologous to the 10 kD proteins described in the literature above mentioned.


SUMMARY OF THE INVENTION

It has been now found that peptides of 25 amino acids having a sequence corresponding to or with a homology of at least 25% with the 1-25 fragment of the HSP from Mycobacterium tubercolosis, are endowed with antiinflammatory activity.
Therefore, the invention relates to a peptide of 25 amino acids having a homology .gtoreq.25% with the following amino acid sequence I (Sequence Id No. 1): Asn Glu Ala Glu Thr Thr Thr Ala Ser-OH wherein the N-terminus is optionally acylated.
A preferred emboidment is a 1-25 peptide having the amino acid sequence I.
Said peptides are useful in the treatment of inflammatory pathologies, especially in the treatment of rheumatoid arthritis.
The peptides of the invention are prepares by conventional chemical methods of peptide synthesis. A method is the one in solid phase originally developed by Merrifield, R. B. (Biochemistry 1964, 3, page 1385; The Peptide 1979, 2, page 1-284, E. Gross and J. Meienhofer Ed.). Alternatively, the synthesis may be carried out, always in solid phase, applying the flow method and using Fmoc-amino acids optionally protected "Solid phase peptide synthesis--a practical approach", IRL PRESS, Oxford, 1989!. In the latter case a commercially available automatic or semiautomatic synthetizer (e.g., MILLIGEN.RTM. 9050) is used, and the solid support may be one of the resins suitable to this synthetic method (e.g., NOVASYN.RTM. resins of Novabiochem, or PEPSYN.RTM. resins of Milligen KA). Usually, these resins contain norleucine residues (as internal reference amino acid) to which the reversible anchoring agent for the peptide to be prepared may then be linked. The anchorage agent may be, for example, p-hydroxymethyl-phenoxyacetic acid. In this case, among the commercially available resins, the ones just containing the protected derivative of the first amino acid linked by an ester bond to the resin may be employed.
Generally, in any case the peptide synthesis is carried out through a series of deprotection cycles with 20% piridine in dimethylformamide (DMF), repeated short washings with DMF, acylation and again repeated washings with DMF, according to the standard procedures provided by the synthetizer manufact

REFERENCES:
Tisch R and McDevitt, HO. Proc. Natl. Acad. Sci. USA 91:437-438, Jan. 1994.
Wraith DC, et al., Cell, 59:247-255, 1989.
Winfield JB, Arthritis and Rheumatism, 32:1497-1503, Dec. 1989.
Thomas, CL. Tabor's Cylopedic Medical Dictionary. FA Davis Co., Philadelphia, PA., 1981.

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