DE4342846A1 - Peptide(s) or their derivs. binding to tumour-necrosis factor alpha - Google Patents

Abstract

Claimed are peptides or peptide derivs. of the formula R1-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-R2 whereby Xaa1 = Ala, Arg, Ile, Leu, Lys, Met, Phe, Ser, Tyr, Val or a bond Xaa2 = L- or D-Ala, Arg, Asn, His, Lys or Pro, Xaa3 = Arg or Lys Xaa4 = Arg, Lys or Pro Xaa5 = Trp or Tyr Xaa6 = Phe, Trp or Tyr Xaa7 = Cys, Ile, Leu, Met, Phe, Trp, Tyr or a bond R1 = H, an amino protective gp. or at least one further amino acid (AA) R2 = -OH, a carboxyl protective gp. or at least one other AA. Also claimed is a prodn. method for these peptides by (i) transformation of a N- alpha -protected w-amino- alpha -AA with a dialdehyde in the presence of a reducing agent and (ii) cleavage of the protective gps. of the side chains and possibly of the N- or C- terminus. Pref. is CH3-CO-Ala-Lys-Arg-Pro-Trp-Trp-Tyr-NH2.

Description

The invention relates to peptides or peptide derivatives that are specific to the human tumor necrosis factor alpha (TNF α) or its receptors tie. The invention also includes the use of these peptides or peptide derivatives as TNF α antagonists and diagnostics for TNF α.

State of the art

The human tumor necrosis factor alpha (TNF α) is a protein from the Group of cytokines. It is primarily used as an answer to Tissue damage, bacterial endotoxins, viruses and other cytokines from activated macrophages produced. He is an important regulator in the Immune defense and inflammatory processes by protecting the organism Protects tissue breakdown and infections. It also promotes reconstruction of damaged tissue. TNF α was developed by E. CARSWELL et al. (1975) Proc Natl Acad Sci USA 72: 3666-3700 discovered in mouse serum. There the factor shows cytostatic and cytotoxic in certain tumors Effects that assume a function as an endogenous, tumorizid factor to let.

The structure of the human TNF α and the expression of the TNF α coding DNA is described in the publications by PENNICA et al. (1984) Nature 312: 724-729; by MARMENOUT et al. (1985) Europ J Biochem 152: 515- 522; by WANN et al. (1985) Science 228: 149-154; and by SHIRAI et al. (1985) Nature 313: 803-806.

In addition to the protective functions, TNF α is available in a variety of pathological processes involved in which an increased TNF α level sometimes causes life-threatening conditions. This is how TNF α plays the following clinical pictures play an important role: septic shock, Cachexia, cerebral malaria, graft-versus-host reaction (graft against Host reaction), arthritis, premature birth, osteoporosis and multiple sclerosis. (For an overview is instructive: BEUTLER and CERAMI (1989) Ann Rev Immunol 7: 625-655; and BONAVISTA and GRANGER (eds) (1990) "Tumor Necrosis Factor: Structure, Mechanism of Action, Role in Disease and Therapy ", Kerger, Basel).  

Since TNF α is involved in a variety of pathogenic conditions, TNF α are Antagonists of great therapeutic importance. TNF α works over two Membrane receptors with 55 kD and 75 kD (kD = Kilo-Dalton = molecular mass) to its target cells (HOHMANN et al. (1989) J Biol Chem 264: 14927- 14934).

Little is known about the mechanisms of signal transmission inside the cell known. The previous attempts to inhibit the effect of TNF α focus on blocking the interaction of TNF α and its Receptors. This can be done either by binding an inhibitor to TNF α or happen to the receptors. There are examples of both strategies. The inhibition of the toxic effects of TNF α is not by binding toxic TNF α mutants and monoclonal antibodies to the TNF α Receptors reached (J.-I. YAMAGISHI et al. (1990) Prot Engin 3: 713-719 and T. ESPEVIK et al. (1990) J Exp Med 171: 415-426).

The TNF α mutants and the monoclonal antibodies are relatively large Molecules and therefore only of limited suitability for therapeutic use because they penetrate tissues only with difficulty and also have a high biological Possess half-life. Antibodies often continue to form through their Fc portion disturbing immune complexes. Anti-idiotype antibodies also occur. Cross reactions with "self" structures can lead to an autoimmune disease to lead.

Smaller molecules, such as antibody fragments or peptides, are therefore therapeutically far more suitable (R. SUTHERLAND et al. (1987) Cancer Res 47: 1627-1633 and M. WITLOW and D. FIPULA (1991) Methods 2: 97-105).

In addition, effective low-molecular TNF α-antagonists are not known.

task

The object of the invention is the production and use of peptides or their derivatives that do not belong to the group of antibodies or antibody fragments and TNF α mutants count. In particular, small molecules are of Interest that is easy to manufacture and good tolerance for humans  or have the animal. An effect as an antigen should be as complete as possible be excluded.

solution

The task is solved by peptides or peptide derivatives which do the following Own formula:

R₁-Xaa₁ · Xaa₂ · Xaa₃ · Xaa₄ · Xaa₅ · Xaa₆ · Xaa₇-R₂

it says
Xaa₁ for Ala, Arg, Ile, Leu, Lys, Met, Phe, Ser, Tyr, VaI or for a bond;
Xaa₂ for L-Ala, D-Ala, Arg, Asn, His, Lys or Pro,
Xaa₃ for Arg or Lys;
Xaa₄ for Arg, Lys or Pro;
Xaa₅ for Trp or Tyr;
Xaa₆ for Phe, Trp or Tyr;
Xaa₇ for Cys, Ile, Leu, Met, Phe, Trp, Tyr or for a bond;
R₁ for -H or an amino protecting group or at least one further amino acid and
R₂ for -OH or a carboxyl protecting group or at least one further amino acid.

It is preferred that one of the amino acid types tryptophan or Phenylalanine at most at two different positions in the sequence the formula occurs.

Explanation of terms

The abbreviations used in the text are determined by the rules that determined by the IUPAC-IUB commission for biochemical nomenclature (Biochemistry 11: 1726 (1972) and Biochem. J. 219: 345 (1984)). The following common abbreviations are used: Ala = alanine; Arg = arginine; His = histidine; Ile = isoleucine; Leu = leucine; Lys = lysine; Met = methionine; Phe = Phenylalanine; Pro = proline; Ser = serine; Trp = tryptophan; Tyr = tyrosine and Val = valine.  

The protective group of the radical R 1 can consist of:
Alkyl, aryl, alkylaryl, aralkyl, alkylcarbonyl or arylcarbonyl groups with 1 to 10 carbon atoms, naphthoyl, naphthylacetyl, naphthylpropionyl, benzoyl group or an acyl group with 1 to 7 carbon atoms are preferred.

The protective group of the rest R₂ can consist of:
An alkoxy or aryloxy group having 1 to 10 carbon atoms or from an amino group.

Further protecting groups - for both R₁ and R₂ - are in Houben-Weyl (1974) Georg Thieme Verlag, 4th edition described. The description of the Protecting groups in the cited references are part of the disclosure.

The sequence of the peptide or peptide derivative according to the invention can be terminal and / or C-terminal end instead of a protective group other frame amino acid sequences. These others Frame amino acid sequences are for the binding of the invention Peptides or peptide derivatives are not essential, but they can be carriers of other functions, such as chelates or cytostatic or include cytotoxic sequences. Such frame amino acid Sequences occur in nature. It can be, for example, the sequences of the. arranged between the hypervariable regions variable range of an antibody. These sequences are called "Frame work" (frame sequences) called. As a frame amino acid Sequences are still non-split signal sequences of one secreted eukaryotic protein known, the protein in one Bacterium is expressed. Such signal sequences sometimes have none Influence on the function of the subsequent protein. It is also possible coupling peptides or peptide derivatives according to the invention in series, with frame amino acid sequences between the individual sequences are arranged.

To decide in individual cases whether a particular peptide according to the invention or peptide derivative with at least one frame amino acid sequence and / or at least one protective group on the subject of the invention counts is a comparison between

• (i) this peptide or peptide derivative with frame amino acid Sequence and / or with protecting group and  
• (ii) the same peptide without a frame amino acid sequence and without Protecting group

to employ. Both molecules should be essentially the same Functions in binding (see example 2.1.) And inhibition (see example 2.2.).

The amino acids listed are L-amino acids with the exception of expressly identified D-amino acid D-alanine.

The expression: "It is preferred that one of the amino acid types Tryptophan or phenylalanine at two different positions at most occurs in the sequence of the formula. "states that in the Peptide or peptide derivative according to the invention via the sequence Xaa₁ to Xaa₇ the amino acid type tryprophan, phenylalanine or thyrosine at most two positions of sequence 1 to 7 is located.

benefits

The peptides or peptide derivatives according to the invention have conventional TNF α binding molecules and TNF α antagonists some Benefits. The peptides or peptide derivatives according to the invention are small Molecules that have little to no antigen activity. There is no education of Fc complexes, which can otherwise be observed with antibodies. Also the complement system is not activated. Because the big immune complexes cannot arise, the target molecules and those according to the invention remain Peptides or peptide derivatives are soluble, provided the target molecule is previously dissolved Form.

The peptides or peptide derivatives are easily attached to other molecules, such as diagnostics or cytotoxic molecules can be coupled. So chelating agents are central Metal atom (for example gadolinium) as diagnostics and cis- Diamine dichloroplatin is known as a cytotoxic substance. Further Uses also result from the publications: EP publication 0 502 595; DE-publications DE-OS 40 25 788 and DE-OS 41 07 570; Farther R. SUTHERLAND (1987) Cancer Res 47: 1627-1633; and M. WHITLOW and D. FlLPULA (1991) Methods 2: 97-105; and Römpps Chemie-Lexikon / Otto- Albrecht Neumüller, Volume 2, pages 855 to 856, 8th edition, 1981, Stuttgart, (ISBN 3-440-04512-9). Due to the molecular size of the peptides or  Peptide derivatives is a targeted reaction with one of the functional groups of the peptide or peptide derivative according to the invention possible.

Furthermore, the peptides or peptide derivatives according to the invention are light producible. Such short peptides or peptide derivatives can be obtained using a Technique can be produced by professionals in the field of peptide synthesis is known. A summary of many of these techniques can be found in J.M. STEWART and J.D. YOUNG, San Francisco, 1969; and J. MEIERHOFER, Hormonal Proteins and Peptides, Vol. 2 p 46, Academic Press (New York), 1973 for the solid phase method and E. SCHRODER and K.LUBKE, The Peptides, Vol. 1, Academic Press (New York) 1965 for the liquid phase Method can be looked up. The steps of the synthesis are in EP-OS 0 097 031. The general process steps from the European publications can be analogous to the synthesis of here described peptides or peptide derivatives according to the invention transferred. Further literature on solid phase synthesis are: Solid Phase Synthesis, E. ATHERTON and R.C. SHEPPARD (1989) IRL Press, ISBN 1-85221-133-4 and Amino Acid and Peptide Synthesis, J. JONES, Oxdford Science Publication (1992) ISBN 0-19-855668-3.

The peptides or peptide derivatives according to the invention can be according to the Example 1.4. produce.

Further advantages over antibodies or their fragments are in better shelf life. The molecules are more stable and do not need any other proteins to be stabilized.

Furthermore, the peptides or peptide derivatives have a better one Tissue mobility as antibodies or their fragments. This makes them suitable itself as a therapeutic.

Further embodiments regarding the amino acid Sequences

Preferred peptides or peptide derivatives according to the invention are those which include the following formula:

R₁-Xaa₁ · Xaa₂ · Xaa₃ · Xaa₄ · Xaa₅ · Xaa₆ · Xaa₇-R₂

it says
Xaa₁ for Ala, Leu, Ile, Phe, Arg or for a bond;
Xaa₂ for Lys, L-Ala, D-Ala, Pro or His
Xaa₃ for Arg;
Xaa₄ for Pro or Arg;
Xaa₅ for Trp or Tyr;
Xaa₆ for Trp, Phe or Tyr;
Xaa₇ for Tyr, Trp, Met, Ile, Leu, Phe, Cys or for a bond;
R₁ for -H or an amino protecting group or at least one further amino acid and
R₂ for -OH or a carboxyl protecting group or at least one further amino acid.

It is preferred that one of the amino acid types tryptophan or Phenylalanine at most at two different positions in the sequence the formula occurs.

More preferred are peptides or peptide derivatives according to the invention which include the following formula:

R₁-Xaa₁ · Xaa₂ · Xaa₃ · Xaa₄ · Xaa₅ · Xaa₆ · Xaa₇-R _2,

it says
Xaa₁ for Ala, Leu, Ile, Phe or Arg;
Xaa₂ for Lys or D-Ala;
Xaa₃ for Arg;
Xaa₄ for Pro;
Xaa₅ for Trp;
Xaa₆ for Trp;
Xaa₇ for Tyr;
R₁ for -H or an amino protecting group or at least one further amino acid and
R₂ for -OH or a carboxyl protecting group or at least one further amino acid.

Peptide derivatives according to the invention with the formula are more preferred

it says

From the group of the aforementioned peptide derivatives is that in SEQ ID NO 1 the most preferred compound, namely:

CH₃-CO-Ala₁ · Lys₂ · Arg₃ · Pro₄ · Trp₅ · Trp₆ · Tyr₇-NH₂.

Other embodiments regarding the residues

In addition to the modification of the amino acid sequence of the invention Peptides or peptide derivatives is also a variation of the radicals R₁ and R₂ possible. However, the residues need binding ability and inhibition not influence the effect of TNF α. Still let through Protecting group parameters such as stability, half-life, bioavailability and Clearly influence the penetration of the matrix or membranes.

Preferred peptides or peptide derivatives according to the invention in which the residues are:
R₁ for -H or an amino protecting group and
R₂ for -OH or a carboxyl protecting group.

More preferred are peptides or peptide derivatives according to the invention in which the residues are:
R₁ for -H or an acyl group and
R₂ for -OH or amino group.

Most preferred are peptides or peptide derivatives according to the invention in which the residues stand for:
R₁ for CH₃-CO- and
R₂ for an amino group.

Production process of the peptides according to the invention

The invention further comprises the production of the peptides according to the invention or peptide derivatives, where an N-α protected ω-amino-α-amino acid with implemented a dialdehyde in the presence of a reducing agent and then the protective groups of the side chains and, if appropriate, the Protective groups of the N-terminus and / or the C-terminus can be split off.

The invention also includes a method in which the peptides or peptide derivatives according to the invention are prepared by condensing the amino acids in a homogeneous phase or by the solid phase method, the carboxyl end of an amino acid to be coupled, its amino groups and optionally functional groups of the Carry a protective group, react with the free amino end of the amino acid to be coupled or the peptide fragment to be coupled in the presence of a condensation reagent, and
in the case of a non-terminal amino acid, the α-amino protective group of the coupled amino acid is then split off and further amino acids are coupled to the peptide chain to be synthesized according to the two steps described above, or
in the case of a terminal amino acid, the α-amino protective group of the coupled amino acid is subsequently split off, if appropriate and
after coupling the last amino acid in the case of the solid phase method, the peptide or peptide derivative is split off from the solid phase.

Use as a diagnostic

The peptides or peptide derivatives according to the invention can because of their Binding ability can be used as a diagnostic. Analogue The use of binding molecules is described in the publications EP- Publication 0 502 595; DE-publications 40 25 788 and 41 07 570 described.

Use as a therapeutic with coupled pharmaceutical reagent

The peptides or peptide derivatives according to the invention also have pharmacological effects when used with a pharmacologically active are connected to another part of the molecule (R. SUTHERLAND (1987) Cancer Res 47: 1627-1633; and M. WHITLOW and D. FlLPULA (1991), Methods 2: 97-105; and Römpps Chemie-Lexicon / Otto-Albrecht Neumüller, Volume 2, pages 855 to 856, 8th edition, 1981, Stuttgart, (ISBN 3-440-04512-9)).  

Use as a medicine

The peptides or peptide derivatives according to the invention have pharmacological properties and are therefore considered pharmaceutical Active substances can be used. The invention also includes a medicament which one of the peptides or peptide derivatives according to the invention or a mixture of which contains. Furthermore, a pharmaceutical belongs to the invention Composition comprising one of the peptides according to the invention or Peptide derivatives or a mixture of peptides according to the invention or Contains peptide derivatives, in the presence of pharmaceutically acceptable and acceptable auxiliaries and carriers. The invention also includes a pharmaceutical composition which is one of the pharmaceutically active, Peptides or peptide derivatives according to the invention or a mixture thereof and a pharmaceutically acceptable salt or pharmaceutically acceptable auxiliary and contains carriers.

In particular, the peptide derivatives according to the invention show the Sequence listing Nos. 1 to 6 inhibited TNF α activity.

The peptides or peptide derivatives according to the invention show inhibition (IC₅₀ value) of the cytotoxicity induced by TNF α at concentrations from 20 to 80 µmol / l. Higher concentrations are applicable without that Disrupt test system. The peptides according to the invention are thus or Peptide derivatives can be used in concentrations of 10 to 1000 µmol / l.

The test results of this in vitro test show that the Peptides or peptide derivatives according to the invention as medicaments or for medical treatment can be used. These Test results can be changed from the in vitro test system to an in vivo System easily transferred, since the cytotoxicity test is a established experimental set-up acts to detect the TNF α activity serves (SECKINGER et al. (1990) J Biol Chem 264: 11966-11973).

The peptides or peptide derivatives according to the invention can therefore Treatment and prevention of septic shock, cachexia, cerebral Malaria, graft-versus-host response (graft versus host response), Arthritis, premature birth, osteoporosis, autoimmune diseases and multiple Serve sclerosis. The peptides or peptide derivatives of the invention can be used as  a TNF α inhibitor in mammals, especially humans, for treatment of the aforementioned diseases can be used.

The invention further provides

• (i) the use of one of the peptides or peptide derivatives according to the invention or their mixture for the manufacture of a medicament for treatment from septic shock, cachexia, cerebral malaria, graft versus host Reaction (graft versus host reaction), arthritis, premature birth, Osteoporosis, autoimmune diseases and multiple sclerosis;
• (ii) a method of treating septic shock, cachexia, cerebral Malaria, graft-versus-host response (graft versus host response), Arthritis, premature birth, osteoporosis, autoimmune diseases and multiple Sclerosis, which procedure is administration of a Peptide (derivative) amount according to the invention, the amount being the Disease suppressed, and the amount of peptide (derivative) one Given to patients in need of such a drug;
• (iii) a pharmaceutical composition for the treatment of septic Shock, cachexia, cerebral malaria, graft versus host response (Graft against host reaction), arthritis, premature birth, osteoporosis, Autoimmune diseases and multiple sclerosis, what treatment of one of the peptides or peptide derivatives according to the invention or their Mixture and at least one pharmaceutical auxiliary and / or Carrier comprises.

Different doses are suitable for the therapeutic effect. she depend, for example, on the peptides or peptide derivatives used, on the host, on the mode of administration and on the type and severity of the conditions to be treated.

In general, however, satisfactory results have been obtained in animals expect if the daily doses range from 100 µg to 100,000 µg per kg of body weight. For larger mammals, for example in humans, a recommended daily dose is in the range of 100 to 100,000 µg per kg body weight. A dose of 300 to 30,000 is preferred µg per kg body weight, more preferably a dose of 1000 to 10,000 µg per kg body weight, most preferably a dose of 2000 to 5000 µg per kg body weight. For example, this dose is conveniently in Partial doses administered up to four times a day. Satisfactory results are  to be expected if the peptides or peptide derivatives of the invention are subcutaneous or administered intra-venously.

The present invention provides pharmaceutical compositions which comprise one of the peptides or peptide derivatives according to the invention or a mixture thereof and at least one pharmaceutically acceptable carrier or additive. Such compositions can be prepared by known methods. Remington's Pharmaceutical Science, 15 ^th ed.Mack Publishing Company, East Pennsylvania (1980) should be noted.

Examples 1. Chemicals, proteins and cell lines 1.1. Chemicals for peptide synthesis

The Fmoc-protected amino acids are from Novabiochem (Switzerland) and Bachem (Bubendorf; Switzerland) available. Their manufacture is state of the art Technology. In the synthesis of peptides on polystyrene resin, the Amino acids in situ with PyBOP (Benzotriatol-1-yl-oxy tripyrrolidinophosphonium hexafluorophosphate) and NMM (N-methyl-morpholine) activated.

1.2. Tumor Necrosis Factor α (TNF α)

The production of the TNF α is in K. ASHMAN et al. (1989) Prot Engin 5: 387- 391. The human ¹²⁵I-labeled TNF α is from the company Amersham (Braunschweig) with a specific activity of 800 Ci / mmol available.

The extracellular domains of soluble human 55 kD and 75 kD TNF α- Receptors sp55 and sp75 are also found in the ASHMAN publication described. The marking with ¹²⁵I is in the publication L. HUSAON and F.C. HAY (1980) Practical Immunology, second ed. Oxford, page 96. described.

1.3. Cell lines

The murine fibroblast tumor cell line L929 is described in detail in the Publication: Seckinger et al. (1990) J Biol Chem 264: 11966-11973 described.

1.4. Production of the peptides or peptide derivatives

The synthesis of soluble peptide mixtures and peptides or Peptide derivatives is on a multiple peptide synthesizer (MPS) AMS 422 from ABIMED (Langenfeld) feasible (H. GAUSEPOHL et al. (1992) Peptide Research 5/6: 315-320).

The peptide synthesis, in which the peptide or peptide derivative via a Anchor group is fixed and is only split off at the end of the synthesis on polystyrene resin (batch size 50 µmol). DMF is used as the solvent  used. Double couplings are always carried out. Of the The machine's synthesis cycle consists of the splitting off of the Fmoc Protecting group with 20% piperidine (twice 15 minutes) and one then wash six times with DMF before the Amino acids are coupled (twice 15 minutes). Before the next one Fmoc cleavage is again washed six times with DMF.

During the reaction, the automat activates 200 µmol amino acid in 400 µl DMF by adding 200 µmol PyBOP in 220 µl DMF and 400 µmol NMM in 100 µl DMF.

The N-terminus of the peptides or peptide derivatives is determined by adding DMF / acetic anhydride / DIPA in a volume ratio of 7: 2: 1 acetylated (30 minutes stir).

For cleavage of the peptide or peptide derivative from the resin and for cleavage the side protection groups are 2 to 3 ml 90% TFA, 5% triisobytylsiolan, 5% Water and 5% phenol used. After five hours of incubation, the Peptides or peptide derivatives precipitated with approx. 35 ml ice-cold ether. Of the Precipitation is centrifuged off, the pellet (sediment) with 15 to 20 ml ice-cold ether resuspended and washed. Centrifuging and Washing is repeated five times before the peptides or peptide derivatives are in the smallest possible volume of 5% acetic acid. The peptides or peptide derivatives are then freeze-dried. The After cleavage, peptides or peptide derivatives lie at the C-terminal as an amide in front.

DIPA diisopropylethylamine
DMF dimethylformamide
Fmoc o-fluorenylmethoxycarbonyl
PyBOP benzotriatol-1-yl-oxy-tripyrrolidinophosphonium hexafluorophosphate
NMM N-methyl morpholine
TFA trifluoroacetic acid

2. Functional detection of binding and inhibition 2.1. Competitive binding test TNF α / TNF receptors

The peptides or peptide derivatives determined in the cytotoxic test are tested in a competition test to determine whether their TNF α-neutralizing effect is due to an interaction with the TNF receptors. For this, 10 ng / reaction vessel (well) of the soluble, recombinant part of the 55 kD or 75 kD receptor (in 50 μl 0.1 mol / l NaHCO₃, pH 9.6) are bound to a microtiter plate (Dynateck) (4 ° C overnight). After washing once (3 minutes with 200 µl PBS / 0.1% Tween 80), the binding sites that are still free are blocked for three hours at room temperature with incubation buffer (200 µl 6% Gelifundol®S from Biotest (Dreieich; Cat No. 1056061) , 0.1 Tween 80 in PBS). After washing once, 0.5 ng ¹²⁵I-TNF α and the respective competitor (peptide or peptide derivative) (after 10 minutes of preincubation) in 50 μl of incubation buffer are added and incubated for 2 hours at room temperature. The reaction vessels are washed three times and the bound activity is measured in the γ counter (count rate 73.1%). For the evaluation, the cpm values measured in the control buffer (without competitor) (cpm = counts per minute) are set to 100%.
PBS = Phosphate Buffered Saline
Tween = polyoxyethylene sorbitan monooleate.

2.2. Inhibition test of the cytotoxicity of TNF α

To show that the TNF α-binding is also functionally effective measured whether the cytotoxic effect of TNF α on TNF α-sensitive L929- Cells is inhibited by the peptides or peptide derivatives according to the invention (Seckinger et al. (1990) J Biol Chem 264: 11966-11973). Following IC₅₀ Values are achieved:  

Sequence listing

Claims (15)

1. Peptides or peptide derivatives with the formula R₁-Xaa₁ · Xaa₂ · Xaa₃ · Xaa₄ · Xaa₅ · Xaa₆ · Xaa₇-R _2, stands here
Xaa₁ for Ala, Arg, Ile, Leu, Lys, Met, Phe, Ser, Tyr, Val or for a bond;
Xaa₂ for L-Ala, D-Ala, Arg, Asn, His, Lys or Pro,
Xaa₃ for Arg or Lys;
Xaa₄ for Arg, Lys or Pro;
Xaa₅ for Trp or Tyr;
Xaa₆ for Phe, Trp or Tyr;
Xaa₇ for Cys, Ile, Leu, Met, Phe, Trp, Tyr or for a bond;
R₁ for -H or an amino protecting group or at least one further amino acid and
R₂ for -OH or a carboxyl protecting group or at least one further amino acid. 2. peptides or peptide derivatives according to claim 1 with the formula R₁-Xaa₁ · Xaa₂ · Xaa₃ · Xaa₄ · Xaa₅ · Xaa₆ · Xaa₇-R _2, stands here
Xaa₁ for Ala, Leu, Ile, Phe, Arg or for a bond;
Xaa₂ for Lys, L-Ala, D-Ala, Pro or His;
Xaa₃ for Arg;
Xaa₄ for Pro or Arg;
Xaa₅ for Trp or Tyr;
Xaa₆ for Trp, Phe or Tyr;
Xaa₇ for Tyr, Trp, Met, Ile, Leu, Phe, Cys or for a bond;
R₁ for -H or an amino protecting group or at least one further amino acid and
R₂ for -OH or a carboxyl protecting group or at least one further amino acid. 3. peptides or peptide derivatives according to claim 1 or 2 with the formula R₁-Xaa₁ · Xaa₂ · Xaa₃ · Xaa₄ · Xaa₅ · Xaa₆ · Xaa₇-R₂, where
Xaa₁ for Ala, Leu, Ile, Phe or Arg;
Xaa₂ for Lys or D-Ala;
Xaa₃ for Arg;
Xaa₄ for Pro;
Xaa₅ for Trp;
Xaa₆ for Trp;
Xaa₇ for Tyr;
R₁ for -H or an amino protecting group or at least one further amino acid and
R₂ for -OH or a carboxyl protecting group or at least one further amino acid. 4. Peptide derivatives according to one of the preceding claims with the formula: it says 5. Peptide derivative according to claim 4 with the formula CH₃-CO-Ala₁ 3 · Lys₂ · Arg₃ · Pro₄ · Trp₅ · Trp₆ · Tyr₇-NH₂. 6. Peptides or peptide derivatives according to one of the preceding claims 1 to 3, wherein
R₁ for -H or an amino protecting group and
R₂ represents -OH or a carboxyl protecting group. 7. peptides or peptide derivatives according to claim 6, wherein the radicals are:
R₁ for -H or an acyl group and
R₂ for -OH or amino group. 8. peptide derivatives according to claim 7, wherein the radicals are:
R₁ for CH₃-CO- and
R₂ for an amino group. 9. Process for the preparation of peptides or peptide derivatives any one of the preceding claims, wherein an N-α protected ω-amino-α- amino acid with a dialdehyde in the presence of a reducing agent implemented and then the protective groups of the side chains and optionally the protective group of the N-terminus and / or the C-terminus be split off. 10. The method according to claim 9, in which the amino acids are condensed in a homogeneous phase or by the solid phase method, the carboxyl end of an amino acid to be coupled, the amino groups and optionally functional groups of the side chain carrying a protective group with the free amino -End of the amino acid to be coupled or the peptide fragment to be coupled reacts in the presence of a condensation reagent, and
in the case of a non-terminal amino acid, the α-amino protective group of the coupled amino acid is then split off and further amino acids are coupled to the peptide chain to be synthesized according to the two steps described above, or
in the case of a terminal amino acid, the α-amino protective group of the coupled amino acid is subsequently split off, if appropriate and
after coupling the last amino acid in the case of the solid phase method, the peptide or peptide derivative is split off from the solid phase. 11. peptides or peptide derivatives according to any one of claims 1 to 8 or produced according to one of claims 9 and 10 as a diagnostic. 12. Peptides or peptide derivatives according to one of claims 1 to 8 or produced according to one of claims 9 and 10 as a medicament, wherein the Peptides or peptide derivatives with a pharmacologically active one Molecular part are connected. 13. Peptides or peptide derivatives according to one of claims 1 to 8 or produced according to one of claims 9 and 10 as a medicament. 14. Pharmaceutical composition containing one of the peptides or Peptide derivatives according to one of claims 1 to 8 or produced according to one of claims 9 and 10 or a mixture thereof, in the presence of pharmaceutically acceptable and acceptable auxiliaries and carriers. 15. Use of one of the peptides or peptide derivatives after a of claims 1 to 8 or produced according to one of claims 9 and 10 for the manufacture of a medicament for the treatment of septic shock, Cachexia, cerebral malaria, graft-versus-host reaction, arthritis, premature birth, Osteoporosis, autoimmune diseases and multiple sclerosis.