Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1997-04-14
2000-08-15
Woodward, Michael P.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 15, 514 16, 514 17, 514 18, 530327, 530328, 530329, 530330, 530332, 4242781, 4242801, A61K 3808, A61K 3810
Patent
active
061036978
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to new peptides, a method for the preparation of said peptides and a pharmaceutical preparation containing said peptides. The peptides according to the present invention are excellent as immunomodulating agents.
BACKGROUND OF THE INVENTION
There has been a longfelt need for new safe immunomodulatory agents in the treatment of many different diseases including malignant diseases, autoimmune diseases and asthma/allergy. Present immunomodulatory agents such as Cyclosporin A and steroids, are very potent immunosuppressive agents but also present severe side effects in a dose dependent manner. New immunomodulatory agents with higher specificity for the immune system, showing less side effects will be of great benefit in the treatment of diseases with a pathological immune response as an important component in the disease process.
PRIOR ART
Signalling between cells are to a major extent mediated by oligo- or polypeptide principles, including cytokines, neuropeptides and hormones. One possible way such a signal can be transmitted may involve oxidoreductase activity mediated by thiol-disulfide interaction of cysteine residues. This type of action can induce conformational changes of proteins which ultimately may result in a signal to the cell nuclei. Thus redox systems, based on oxidised or reduced cysteines, play important roles in initiating, maintaining and/or downregulating inflammatory responses. Redox systems that are characterized today are the thioredoxin (TR)/thioredoxin reductase (TRR) system (Holmgren et al, 1989, J.Biol.Chem, 264, 13963) and similar systems like the glutaredoxin/glutathione reductase (Bushweller et al., 1992, Biochemistry, 31, 9288) and the protein disulfide isomerase (PDI) systems (Noiva and Lennarz, 1992, J.Biol.Chem., 267, 3553). The TR/TRR system and related redox systems are potent regulators of different known immunological and inflammatory parameters, like IL-2R .alpha.-chain expression (Espinoz-Adelgado et al, 1992, J.Immunol., 149, 2961), modulation of expression of IFN-.gamma. activity (Deiss and Kimchi, 1991, Science, 252, 117), differentiation and effector function of lymphocytes (Yodoi and Uchiyama, 1992, Immunol. Today 13, 405-411), regulation of eosinophil effector functions (Balcewics et al, 1991, J. Immunol., 147, 2170), activation of glucocorticoid receptor (Grippo et al, 1985, J.Biol.Chem. 260, 93-97) and modulation of immune response during pregnancy (Clarke et al, 1991, J.Reprod.Fert., 93, 525).
The active site of TR includes a sequence with a -Cys-Gly-Pro-Cys- motif. Selected virus proteins, e.g. gene products coded from X regions of human T-cell leukaemia viruses (Shimotohno et al, 1985, P.N.A.S. 82, 302-306) and human immunoregulatory proteins may have cysteine-containing sequences which are homologous to such a -Cys-Gly-Pro-Cys- motif. We have considered that these proteins may either express oxidoreductase activity or can be substrates for such an activity or possibly act as inhibitors of such an activity.
Previously peptides based on the cysteine-rich TR active site sequence mentioned above have been produced and shown to exhibit biological activities similar to the native protein Another example of a cysteine-containing peptide with thioredoxin-like activity was obtained from hFSH-.beta.-(81-95) (Grasso et al, 1991, Molecular and Cellular Endocrinology 78, 163).
Analogs of thymic humoral factor .gamma.2 (ThF-.gamma.2) for use as immunomodulatory agents in pharmaceutical compositions are described in WO, A1, 9501182 (12.01.95). This document discloses two cyclic analogs; Leu-Glu-Cys-Gly-Pro-Cys-Phe-Leu (SEQ ID NO: 34) and Leu-Cys-Ala-Gly-Pro-Cys-Phe-Leu (SEQ ID NO: 35);, which are excluded from the present invention. However, this document does not reveal the active importance of cysteine-containing sequences.
We have prepared peptides with cysteine-containing motifs, selected from virus structural proteins e.g. retroviral transmembraneous protein p15E, and human proteins involved in regulation of in
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Bergstrand H.ang.kan
Eriksson Tomas
Karabelas Kostas
Lindvall Magnus
Sarnstrand Bengt
Astra Aktiebolag
Borin Michael
Woodward Michael P.
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