Peptides with antagonistic activity against CXC chemokine receptor 4 (CXCR4)

Abstract

The invention relates to a peptide comprising an amino acid sequence X6X7X8X9X10X11X12 according to SEQ ID NO: 1, or its pharmacologically acceptable salts, derivatives and / or conjugates, wherein X6 is G or A, X7 is R or A, X8 is R or A, X9 is T or A, X10 is R or A, X11 is L or A, X12 is C or A, with the proviso that one of the amino acids at position X6, X7, X8, X9, X10, X11 or X12 may be alanine, wherein the peptide has a total length in the range of 7 to 30 amino acids, and wherein a peptide consisting of the amino acid sequence KRRPAKAWSGRRTRLCC according to SEQ ID NO: 2 is excluded. The invention further relates to a medicament comprising a peptide according to SEQ ID NO: 1 and to a use for the manufacture of a medicament.

Description

The invention relates to peptides, their use in the manufacture of a pharmaceutical product, and pharmaceutical products. The polypeptides are suitable for the treatment of diseases associated with CXCR4 involvement. The CXC chemokine receptor 4 (CXCR4) is a G protein-coupled receptor (GPCR) involved in immune cell transport, homeostasis, and tissue repair. The endogenous ligand for CXCR4 is CXC motif chemokine 12 (CXCL12), also known as stromal-derived factor 1 (SDF-1). Both CXCR4 and CXCL12 are frequently upregulated in inflammatory conditions and contribute to disease progression, particularly in chronic diseases. Furthermore, CXCR4 is upregulated in many cancers, especially cancer stem cells, contributing to their survival, proliferation, and migration, and acts as a co-receptor for HIV binding and entry into human cells. In addition to the endogenous ligand CXCL12, the cytokine MIF (macrophage migration inhibitory (MIF) factor) and ubiquitin also bind to CXCR4. Hayn, M. et al., Proc. Natl. Acad. Sci. USA 118, e2023776118 (2021), describe how the G protein-coupled receptor 15 ligand (GPR15LG) competes with an antibody specific for CXCR4. Meyrath M. et al., bioRxiv 2024 “ACKR5 / GPR182 is a scavenger receptor for the atypical chemokine CXCL17, GPR15L and various endogenous peptides” (doi: 10.1101 / 2024.06.01.596940) describe a peptide GPR15L(1-17) of the N-terminus of the G-protein-coupled receptor 15 ligand (GPR15LG) which binds to the G-protein-coupled receptor 182 (GPR182). Since CXCR4 is involved in tumor growth and metastatic spread, as well as in inflammatory processes, CXCR4 antagonists from various classes of substances, such as antibodies, small molecules, proteins, and peptides, are being investigated in numerous studies. Tahirovic et al. (2019), Expert Opinion on Therapeutic Patents (doi: 10.1080 / 13543776.2020.1707186) provide an overview of patent applications from 2010 to 2018 concerning molecule- (small molecule) and peptide-based CXCR4 modulators. Martin et al., J Leukoc Biol. 2021; 109:953-967 , describe the clinical use of CXCR4 inhibitors, including small molecules, peptides and antibodies, such as balixafortide (POL6326, Polyphor), mavorixafor (X4P-001, X4 Pharmaceuticals), motixafortide (BL-8040, Bio-LineRx), LY2510924 (Eli Lilly), and ulucuplumab (Bristol-Myers Squibb).Although many CXCR4 antagonists such as CXCR4 antibodies, peptide inhibitors and small molecule compounds are being investigated in preclinical studies, only a few have reached the clinical trial phase. Plerixafor (AMD3100) is a bicyclamen compound used in autologous stem cell transplantation to release stem cells from the bone marrow into the bloodstream. Wang et al., Pharmacological Research 159 (2020) 105010, describe its mechanism of action and therapeutic applications. McDermott et al., J Clin Invest. 2023;133(19):e164918, describe the use of plerixafor in the treatment of WHIM (an acronym for symptoms warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome. Motixafortide is a synthetic cyclic peptide consisting of 14 amino acids that acts as a selective antagonist of CXCR4. Sheridan M. Hoy, Drugs (2023) 83:1635-1643 describes the development of motixafortide that led to its approval. M. Hidalgo et al., Annals of Oncology 30 (Supplement 11): xi33-xi47, 2019 describe the use of motixafortide in a multicenter phase IIa trial in combination with pembrolizumab and chemotherapy in patients with metastatic pancreatic adenocarcinoma. Mavorixafor is a small-molecule, selective antagonist of the CXCR4 receptor that increases the mobilization and transport of white blood cells from the bone marrow. Dale et al., Blood. 2020;136(26):2994-3003 , describe the use of mavorixafor in a phase 2 study for the treatment of WHIM syndrome. Furthermore, peptides with antagonistic activity against CXCR4 are known. Buske et al., Oncotarget, Vol. 6, No. 34, 2015, describe EPI-X4 (Endogenous Peptide Inhibitor of CXCR4), a fragment of human serum albumin, as a CXCR4 antagonist. Harms et al., Acta Pharmaceutica Sinica B 2021; 11(9):2694-2708, describe the EPI-X4 derivative JM#21 as a potent CXCR4 antagonist. Zhou et al., Biochemistry 2000, 39, 3782-3787, describe a peptide antagonist of CXCR4 derived from the N-terminus of the viral chemokine vMIP-II. WO 2009 / 004054 A2 and WO 2014 / 198834 A1 describe peptide fragments of the protein human circulating antiviral albumin fragment (ALB-408), their use as CXCR4 antagonists, and their therapeutic and diagnostic uses. A general disadvantage of using chemokine antagonists is that chemokines, as signaling molecules, are involved in a multitude of physiological processes. Therefore, the use of an antagonist can affect an unpredictable number of physiological processes and lead to numerous side effects and sequelae. Many CXCR4 inhibitors suffer from undesirable side effects, the development of resistance, and limited therapeutic index. In particular, effective and selective inhibition of the CXCR4 receptor without impairing normal immune function poses a challenge. Therefore, there is a need for alternatives to existing CXCR4 inhibitors. The object of the present invention was to provide inhibitors for CXCR4 that can meet the therapeutic goals with fewer side effects. This problem is solved by the peptide according to claim 1. The problem is further solved by a medicament according to claim 6 and by a use of the peptide according to claim 9. Preferred embodiments of the invention are disclosed in the dependent claims and the description, wherein described or shown features, individually or in any combination, can constitute an object of the invention unless the context clearly indicates otherwise. The present invention relates to a peptide comprising an amino acid sequence X6X7X8X9X10X11X12 according to SEQ ID NO: 1, or its pharmacologically acceptable salts, derivatives and / or conjugates, wherein X6 is G or A, X7 is R or A, X8 is R or A, X9 is T or A, X10 is R or A, X11 is L or A, X12 is C or A, with the proviso that one of the amino acids at position X6, X7, X8, X9, X10, X11 or X12 may be alanine, wherein the peptide has a total length in the range of 7 to 30 amino acids, and wherein a peptide consisting of the amino acid sequence KRRPAKAWSGRRTRLCC according to SEQ ID NO: 2 is excluded. It was surprisingly found that binding of the peptide to the CXC chemokine receptor 4 (CXCR4) led to effective inhibition of the CXCL12-dependent signaling at CXCR4. The peptides act as CXCR4 antagonists. Peptides derived from the endogenous protein G protein-coupled receptor 15 ligand (GPR15LG) have been shown to exhibit antagonistic activity and inhibitory ability against CXCR4, and in particular, can display improved specificity. Specific binding and inhibition of CXCR4 can be provided, thereby enabling improved therapeutic outcomes with fewer side effects. The development of novel CXCR4 antagonists can especially advance personalized medicine and cancer therapies.Peptide inhibitors that specifically bind to and inhibit the CXCR4 receptor can be used to treat or prevent diseases in which CXCR4 plays a key role. This includes combating HIV infections, treating various cancers by inhibiting tumor metastasis, improving the efficacy of stem cell transplants, and their potential application in the treatment of autoimmune and fibrotic diseases. In particular, it was demonstrated that, compared to the approved CXCR4 antagonist plerixafor, a wider dosage range and a better tolerability profile could be achieved. A further advantage is that the peptide hardly interacts with GPR15. Of particular benefit is the fact that the peptide can be used in combination with heparin because it does not bind to heparin. Thus, an effective, selective, and safe alternative to known CXCR4 inhibitors can be provided. In other words, the invention comprises peptides with the motif GRRTRLC according to SEQ ID NO: 3, wherein one of the amino acids can be replaced by alanine. Thus, one of the amino acids can be arginine at position X8 or alanine at position X10. In embodiments, none of the amino acids at positions X6 to X12 are alanine, and the peptide comprises the motif GRRTRLC according to SEQ ID NO: 3. It has been shown that the specificity of binding to CXCR4 was increased when the peptide comprises the motif GRRTRLC. In embodiments, the peptide comprises an amino acid sequence X1X2X3X4X5GRRTRLCX13X14X15 according to SEQ ID NO: 4, wherein X1 is alanine (A) or a deletion, X2 is selected from lysine (K), alanine (A) or a deletion, X3 is alanine (A) or a deletion, X4 is selected from tryptophan (W), alanine (A) or a deletion, X5 is selected from serine (S), alanine (A) or a deletion, X13 is cysteine ​​(C) or alanine (A), X14 is histidine (H) or alanine (A), and X15 is selected from arginine (R), alanine (A), or a deletion. These peptides showed good binding to CXCR4. In preferred embodiments, X4 is selected from tryptophan (W) and alanine (A), and X5 is selected from serine (S) and alanine (A). It has been shown that binding to CXCR4 can be increased if at least one of the amino acids at position X2, X4, X5, X13, X14, or X15 is alanine. In embodiments, one or more, for example two, three, four, five, or six, in particular two, three, or four, of the amino acids at position X2, X4, X5, X13, X14, or X15 are alanine. In embodiments, one or two of the amino acids at position X2, X4, X5, X13, X14, or X15 are alanine. In embodiments, one of the amino acids at position X2, X4, X13, X14, or X15 is alanine, in particular X2, X4, or X15. For example, the peptides AAAWSGRRTRLCCHR according to SEQ ID NO: 7, AKAASGRRTRLCCHR according to SEQ ID NO: 8 and AKAWSGRRTRLCCHA according to SEQ ID NO: 11, in which the amino acid at positions X2, X4 or X15 alanine is a better binding than the peptide AKAWSGRRTRLCCHR according to SEQ ID NO: 6, containing arginine (R) of the naturally occurring sequence of the protein. Preferably, the amino acids at positions X4 and X5 are not deleted, but rather X4 is selected from tryptophan (W) and alanine (A), and X5 is selected from serine (S) and alanine (A). In principle, the amino acids at positions X1, X2, and X3 can be deleted, for example, in the peptide WSGRRTRLCCHR according to SEQ ID NO: 14. Improved binding to CXCR4 was observed when the amino acids at positions X1, X2, and X3, particularly at positions X1 and X2, were not deleted. Thus, peptides with the motif AX4X5GRRTRLCX13X14X15 according to SEQ ID NO: 5 may be preferred, where X4 is selected from tryptophan (W), alanine (A) or a deletion, X5 is selected from serine (S), alanine (A) or a deletion, X13 is cysteine ​​(C) or alanine (A), X14 is histidine (H) or alanine (A), and X15 is selected from arginine (R), alanine (A) or a deletion. In embodiments, the peptide is a polypeptide with a number of amino acids in the range of ≥ 10 to ≤ 25 amino acids, preferably in the range of ≥ 12 to ≤ 20 amino acids, preferably in the range of ≥ 13 to ≤ 16 amino acids, and particularly in the range of ≥ 14 to ≤ 15 amino acids. Peptides with a length of 13 to 16, and in particular 14 or 15 amino acids, showed good binding to CXCR4. In embodiments, the peptide has or consists of one of the following amino acid sequences: AKAWSGRRTRLCCHR according to SEQ ID NO: 6, AAAWSGRRTRLCCHR according to SEQ ID NO: 7, AKAASGRRTRLCCHR according to SEQ ID NO: 8, AKAWSGRATRLCCHR according to SEQ ID NO: 9, AKAWSGRRTALCCHR according to SEQ ID NO: 10, AKAWSGRRTRLCCHA according to SEQ ID NO: 11, KAWSGRRTRLCCHR according to SEQ ID NO: 12, AWSGRRTRLCCHR according to SEQ ID NO: 13, WSGRRTRLCCHR according to SEQ ID NO: 14, AKAWSGRRTRLCCH according to SEQ ID NO: 15, AKAWSGRRTRLCC according to SEQ ID NO: 16, and AKAWSGRRTRLC according to SEQ ID NO: 17, or homologs, isomers, or functional derivatives of the aforementioned peptides, which have at least exhibit 70% to 95% sequence homology. Preferably, the peptide is selected from the group of peptides comprising or consisting of one of the following amino acid sequences: AKAWSGRRTRLCCHR according to SEQ ID NO: 6, AAAWSGRRTRLCCHR according to SEQ ID NO: 7, AKAASGRRTRLCCHR according to SEQ ID NO: 8, AKAWSGRRTRLCCHA according to SEQ ID NO: 11, KAWSGRRTRLCCHR according to SEQ ID NO: 12, AWSGRRTRLCCHR according to SEQ ID NO: 13, WSGRRTRLCCHR according to SEQ ID NO: 14, and AKAWSGRRTRLCCH according to SEQ ID NO: 15, or homologs, isomers, or functional derivatives of the aforementioned peptides, exhibiting at least 70% to 95% sequence homology. These peptides showed binding to CXCR4 with an IC50 value below 3 µM. In preferred embodiments, the peptide is selected from the group of peptides comprising or consisting of one of the following amino acid sequences: AKAWSGRRTRLCCHR according to SEQ ID NO: 6, AAAWSGRRTRLCCHR according to SEQ ID NO: 7, AKAASGRRTRLCCHR according to SEQ ID NO: 8, AKAWSGRRTRLCCHA according to SEQ ID NO: 11, KAWSGRRTRLCCHR according to SEQ ID NO: 12, and AWSGRRTRLCCHR according to SEQ ID NO: 13, or homologs, isomers, or functional derivatives of the aforementioned peptides, exhibiting at least 70% to 95% sequence homology. These peptides showed binding to CXCR4 with an IC50 value below 2 µM. In further preferred embodiments, the peptide is selected from the group of peptides comprising or consisting of one of the following amino acid sequences: AAAWSGRRTRLCCHR according to SEQ ID NO: 7, AKAASGRRTRLCCHR according to SEQ ID NO: 8, AKAWSGRRTRLCCHA according to SEQ ID NO: 11, KAWSGRRTRLCCHR according to SEQ ID NO: 12, and AWSGRRTRLCCHR according to SEQ ID NO: 13, or homologs, isomers, or functional derivatives of the aforementioned peptides, exhibiting at least 70% to 95% sequence homology. These peptides showed binding to CXCR4 with an IC50 value of 1.5 µM or less. Methods for the synthetic production of peptides are known in the prior art. These methods include, for example, chemical syntheses, recombinant production, or hybrid processes for the production of peptides. The peptides can be present or usable in the form of their salts. Existence in salt form can increase the solubility of the peptide in a solvent. This can, for example, facilitate oral administration or absorption of the peptides. Pharmaceutically acceptable salts are preferred. In preferred embodiments, pharmaceutically acceptable salts comprise non-toxic salts of the compounds according to the invention, for example, in the form of alkali and alkaline earth salts, or salts such as sodium, potassium, lithium, calcium, magnesium, zinc, manganese, or ammonium salts, or salts selected from the group comprising chlorides, bromides, iodides, hydrochlorides, hydrobromides, sulfates, hydrogen sulfates, phosphates, or nitrates. The peptides can be present or usable in the form of derivatives or conjugates. In embodiments, the peptide derivatives are selected from N-methylated, amidated, acetylated, phosphorylated, pegylated, or glycosylated peptide derivatives, albumin-bound peptides, peptides containing one or more D-amino acids or beta-amino acids, cyclic peptide variants, peptidomimetics, or are fusion proteins, wherein the peptide is part of the fusion protein, in particular a bifunctional peptide. The peptide may include chemical modifications. Modifications to the free N- and C-termini are particularly preferred, for example, acetylation of the last and / or first amino acid, or amidation of the N-terminus. Such modifications can increase the peptide's stability. To further increase stability, one or more of the naturally occurring amino acids of the L-form can be replaced by the corresponding D-form. End-to-end cyclization of the peptide can also increase its stability. In embodiments, the peptides can be modified at the N-terminal end, in the side chain, and / or at the C-terminal end. One or more of the amino acids in a peptide can be modified, for example, by binding to a carbohydrate group, a hydroxyl group, a phosphate group, a farnesyl group, an isofarnesyl group, palmitoyl, geranylgeranyl, lauryl, a fatty acid group, an acetyl group, an amide group, or a polyethylene glycol group. Preferred modified derivatives of the peptide are selected from amidated, acetylated, phosphorylated, pegylated, or glycosylated peptide derivatives, or the peptide can be bound to albumin, such as bovine serum albumin, oval albumin, or mouse serum albumin. Binding to albumin can preferably be effected by carbodiimide or formaldehyde. This can enhance binding to substrates such as nylon membranes or glass slides.Albumin-conjugated peptides may offer improved applications in diagnostics, as research reagents, and therapeutics, for example, as probes. Modification of therapeutic peptides with polyethylene glycol (PEG) may be associated with a prolonged circulatory half-life. The incorporation of D-amino acids or amidations can increase the stability of the peptide. For example, hydrophobic groups such as carbobenzoxyl, dansyl, or t-butyloxycarbonyl groups can be added at the N-terminus. Similarly, an acetyl group or a 9-fluorenylmethoxycarbonyl group can be added at the N-terminus. Furthermore, a hydrophobic group, t-butyloxycarbonyl, or an amido group can preferably be added at the C-terminus. In particular, the D-isomer of one or more of the peptide's amino acids can be used instead of the usual L-isomer. Such chemical modifications can serve to increase the stability, bioavailability, and / or binding behavior of the peptides. Cyclic variants can be produced by disulfide bonding of cysteine ​​or by means of a linker, for example, an alkyl linker. Cyclic variants can, in particular, be dimeric peptides consisting of two identical monomeric peptides, where the dimeric peptides may be linked together via a cysteine ​​bridge or linkers that may be formed between the monomeric peptides. Cyclization can increase the plasma half-life or proteolytic stability, or lead to improved bioavailability or specific release profiles. The peptides may additionally contain N- and / or C-terminal amino acid sequences. In embodiments, the peptide is part of a fusion protein, in particular a bifunctional peptide. The term "bifunctional" peptide refers to a chemical entity with two or more structural domains exhibiting different biological functions and dual activity. A bifunctional peptide may refer to a peptide comprising two peptide motifs with different functions. A bifunctional peptide may include a peptide described herein with CXCR4-inhibiting function and an additional motif for inhibiting other signaling pathways, in particular CXCL12 or CXCR7, or exhibiting inverse agonist properties. For the purposes of this application, peptidomimetics refer to non-peptidic molecules that exhibit similar biological effects, preferably with the same specificity and activity, as the peptide. Peptidomimetics are, in particular, low-molecular-weight organic compounds whose essential structural elements are modeled on a peptide. In further embodiments, the conjugate is a peptide-antibody conjugate, wherein the peptide is bound to an antibody or an antibody fragment. Preferred antibody fragments are artificially produced fusion proteins consisting of a light (VL) and a heavy chain (VH) of an immunoglobulin, commonly referred to as "scFv" antibodies, short for "single chain variable fragment". Peptides coupled to antibodies or antibody fragments such as scFv are designed, for example, for targeted tumor treatment or immunomodulation. In preferred embodiments, the peptide is labeled with a fluorescent dye, a radioactive marker, an enzymatic marker such as biotin, luciferase or alkaline phosphatase, magnetic nanoparticles, carbon nanotubes, Raman dyes, stable isotopes such as 13C or 15N, azide or alkyne groups, polyethylene glycol, a thiol or maleimide. Fluorescent dyes are preferably selected from the group comprising fluorescein, rhodamine, eosin, xanthene dyes, cyan dyes (Cy3, Cy5, Cy7), commercially available Alexa Fluor® dyes or Atto dyes, boronipyrromethene (Bodipy) dyes, and quantum dots. The peptide may be labeled with a fluorophore dendrimer, a polymer structure with multiple fluorescent centers, thereby achieving signal enhancement. Quantum dots are semiconducting nanocrystals, typically with a diameter of 2 to 10 nanometers (10⁻⁵ atoms), that can convert an incoming light spectrum into a different frequency of energy emission. These artificial crystals are so finely ground that quantum mechanical effects occur. Radioactive markers or radioisotopes are preferably selected from the group comprising gold, gadolinium, lanthanides, 18 fluorine, 125 iodine (125I), 35 sulfur (35S), 64 copper (64Cu), 99m technetium (99mTc), 111 indium (111In) and tritium (3H). In embodiments, the peptide is labeled with an enzymatic marker. Enzymatic markers are preferably selected from biotin, luciferase, or alkaline phosphatase. Advantages of the biotin / streptavidin system include the ability to use biotinylated peptides with labeled streptavidin complexes, such as enzyme conjugates, fluorescent, or gold-labeled streptavidins. Peptides can be coupled with luciferase to generate bioluminescent signals. Labeling with alkaline phosphatase allows such labeled peptides to be used in enzyme immunoassays. In various embodiments, the peptide is labeled with non-fluorescent markers such as magnetic nanoparticles, carbon nanotubes, Raman dyes, or stable isotopes. Peptides labeled with magnetic nanoparticles are particularly suitable for magnetic resonance imaging (MRI) or targeted cell enrichment. Peptides labeled with carbon nanotubes can be coupled to other peptides to generate optical or electrical signals. Peptides labeled with Raman dyes are particularly suitable for sensitive detection techniques. Peptides labeled with stable isotopes such as 13C or 15N are particularly suitable for mass spectrometry analyses such as SILAC (stable isotope labeling by / with amino acids in cell culture). In some embodiments, the peptide is labeled with chemical or structural markers such as azide or alkyne groups, polyethylene glycol, a thiol, or maleimide. The introduction of azide or alkyne groups, so-called click chemistry components, allows for specific reactions of the labeled peptide with fluorescent, radioactive, or nanomaterials. Polyethylene glycol provides a label that can improve stability and solubility. Labeling with specific thiols or maleimides can be used for highly selective labeling of cysteine-rich peptides. In some embodiments, the peptide is labeled with a radioactive marker. Radioactively labeled peptides are particularly easy to detect. Isotopes frequently used as radioactive markers include, for example, iodine-125 (125I), sulfur (35S), and tritium (3H). Radiopharmaceutical or optically labeled peptides are particularly suitable for imaging applications in diagnostics, such as in the detection of CXCR4 tumor overexpression. Fluorescently or radioactively labeled peptides are particularly suitable for theranostic or dual applications with combined therapeutic and diagnostic functions, such as monitoring treatment response or as biomarkers in personalized medicine. Theranostics refers to diagnostics performed alongside therapy. Key elements of theranostic diagnosis include characterizing the stage of the disease and monitoring the progress of treatment. The peptides are suitable as pharmaceutical agents in drugs. The compounds are particularly suitable for the manufacture of pharmaceuticals by combining them with at least one carrier or excipient to create a suitable dosage form. Another subject matter relates to a medicinal product or a pharmaceutical or diagnostic composition comprising as its active ingredient a peptide comprising an amino acid sequence X6X7X8X9X10X11X12 according to SEQ ID NO: 1, or its pharmacologically acceptable salts, derivatives and / or conjugates, wherein X6 is G or A, X7 is R or A, X8 is R or A, X9 is T or A, X10 is R or A, X11 is L or A, X12 is C or A, with the proviso that one of the amino acids at position X6, X7, X8, X9, X10, X11 or X12 may be alanine, wherein the peptide has a total length in the range of 7 to 30 amino acids, and optionally pharmaceutically acceptable carriers, excipients and / or vehicles. For a further description of the peptide, reference is made to the preceding description. In embodiments, the drug product, pharmaceutical or diagnostic composition comprises as active ingredient a peptide comprising an amino acid sequence X1X2X3X4X5GRRTRLCX13X14X15 according to SEQ ID NO: 4, wherein X1 is alanine (A) or a deletion, X2 is selected from lysine (K), alanine (A) or a deletion, X3 is alanine (A) or a deletion, X4 is selected from tryptophan (W), alanine (A) or a deletion, X5 is selected from serine (S), alanine (A) or a deletion, X13 is cysteine ​​(C) or alanine (A), X14 is histidine (H) or alanine (A), and X15 is selected from arginine (R), alanine (A) or a deletion. In preferred embodiments, X4 is selected from tryptophan (W) and alanine (A) and X5 is selected from serine (S) and alanine (A). In preferred embodiments, the peptide has or consists of one of the following amino acid sequences: AKAWSGRRTRLCCHR according to SEQ ID NO: 6, AAAWSGRRTRLCCHR according to SEQ ID NO: 7, AKAASGRRTRLCCHR according to SEQ ID NO: 8, AKAWSGRATRLCCHR according to SEQ ID NO: 9, AKAWSGRRTALCCHR according to SEQ ID NO: 10, AKAWSGRRTRLCCHA according to SEQ ID NO: 11, KAWSGRRTRLCCHR according to SEQ ID NO: 12, AWSGRRTRLCCHR according to SEQ ID NO: 13, WSGRRTRLCCHR according to SEQ ID NO: 14, AKAWSGRRTRLCCH according to SEQ ID NO: 15, AKAWSGRRTRLCC according to SEQ ID NO: 16, and AKAWSGRRTRLC according to SEQ ID NO: 17, or homologs, isomers, or functional derivatives of the aforementioned peptides, which exhibit at least 70% to 95% sequence homology In embodiments, the drug product, pharmaceutical or diagnostic composition comprises as an active ingredient a peptide comprising an amino acid sequence or consisting of one of the following amino acid sequences: AKAWSGRRTRLCCHR according to SEQ ID NO: 6, AAAWSGRRTRLCCHR according to SEQ ID NO: 7, AKAASGRRTRLCCHR according to SEQ ID NO: 8, AKAWSGRRTRLCCHA according to SEQ ID NO: 11, KAWSGRRTRLCCHR according to SEQ ID NO: 12, and AWSGRRTRLCCHR according to SEQ ID NO: 13, or homologs, isomers or functional derivatives of the aforementioned peptides, which have at least 70% to 95% sequence homology. In embodiments, the drug product, pharmaceutical or diagnostic composition comprises derivatives of the peptide selected from N-methylated, amidated, acetylated, phosphorylated, pegylated or glycosylated peptide derivatives, albumin-bound peptide, peptides containing one or more D-amino acids or beta-amino acids, cyclic peptide variants, peptidomimetics, or fusion proteins, wherein the peptide is part of the fusion protein, in particular a bifunctional peptide, or wherein the conjugate is a peptide-antibody conjugate, wherein the peptide is bound to an antibody or antibody fragment. For a further description of the derivatives, reference is made to the preceding description. In embodiments, a diagnostic composition in particular comprises a peptide labeled with a fluorescent dye, a radioactive marker, an enzymatic marker such as biotin, luciferase or alkaline phosphatase, magnetic nanoparticles, carbon nanotubes, Raman dyes, stable isotopes such as 13C or 15N, azide or alkyne groups, polyethylene glycol, a thiol or maleimide, as described above. It has been shown that the peptides exhibit antagonistic activity and inhibitory ability towards CXCR4 and, in particular, can display good specificity. Specific binding and inhibition of CXCR4 can enable therapeutic outcomes with fewer side effects. Peptide inhibitors that specifically bind to and inhibit the CXCR4 receptor can be used to treat or prevent diseases in which CXCR4 plays a key role. A preferred subject matter is a medicinal product or a pharmaceutical or diagnostic composition for use in the therapeutic and / or prophylactic treatment or diagnosis of diseases selected from: CXCR4-associated diseases selected from the group comprising WHIM syndrome (Warts, hypogammaglobulinemia, infections, myelokathexis), Waldenström macroglobulinemia, acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), HIV infection, in particular infections with HIV-1, HIV-2, toxoplasmosis, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), myocardial infarction, atherosclerosis, stroke, type 2 diabetes mellitus, endometriosis, liver fibrosis and other fibroses, cancers, in particular cancers, which express the CRCX4 receptor, such as breast cancer, lung cancer,Prostate cancer, glioblastoma, colorectal cancer, pancreatic cancer, neuroendocrine tumors (NETs), non-Hodgkin lymphoma, multiple myeloma, and skin cancer; infections caused by bacteria and fungi, especially Pseudomonas, Candida, and S. aureus; infections with the SARS-CoV-2 coronavirus; dermatitis; pneumonia; asthma; impaired scar healing; cardiological disorders, especially heart failure; stroke, Parkinson's disease, and Alzheimer's disease; wounds, especially burn wounds, or to improve bone healing. For the purposes of the present invention, the term "prophylactic treatment" is understood to mean, in particular, that the compounds can be administered prophylactically before symptoms of a disease appear or before there is a risk of disease. Specifically, "prophylactic treatment" is understood to mean drug-based prevention. Preferred embodiments relate to the treatment of HIV infections, the treatment of various cancers by inhibiting tumor metastasis, the improvement of the efficacy of stem cell transplants, and potential application in the treatment of autoimmune and fibrotic diseases. Preferred embodiments relate to the treatment of HIV infections. In particular, the treatment of CXCR4-associated diseases selected from WHIM syndrome, Waldenström macroglobulinemia, AML, CLL, solid tumors, especially breast, lung, and prostate cancer, HIV, idiopathic pulmonary fibrosis, rheumatoid arthritis, and multiple sclerosis is preferred. Preferred embodiments relate to the treatment of various cancers by inhibiting tumor metastasis. The drug or pharmaceutical or diagnostic composition is particularly suitable for use in the prevention and treatment or diagnosis of metastases, inhibition of tumor cell migration and metastasis by CXCR4 blockade. Further preferred embodiments relate to improving the effectiveness of stem cell transplantations and the potential application in the treatment of autoimmune diseases and fibrotic diseases. It is particularly advantageous that heparin administration is not a contraindication for treatment with the peptide described here. The drug, or pharmaceutical or diagnostic composition, is especially suitable for use with heparin. It has been found that the peptide can continue to bind to CXCR4 even in the presence of heparin and is therefore usable even during heparin treatment, meaning that heparin does not need to be discontinued beforehand. The generic name "heparin" refers to endogenous polychararides that inhibit the coagulation cascade and are therefore widely used for anticoagulation and thrombosis prophylaxis.The term "heparin" here refers to the medicinally used, unfractionated heparin (also called standard heparin) as well as low molecular weight heparins with lower molecular weights produced by chemical or enzymatic cleavage and fractionation, which are also therapeutically usable. In preferred embodiments, the peptide is in the form of a combination of active ingredients, in particular in combination with other inhibitors, antibodies or viral / cellular therapies. In preferred embodiments, the drug product or pharmaceutical or diagnostic composition is intended for use in combination with chemotherapeutic agents, immunotherapeutic agents such as checkpoint inhibitors, chemokine receptor inhibitors, particularly CXCR7, or genome-based therapies such as CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats), or as adjuvants for CAR-T cell therapies. Use as an adjuvant for CAR-T cell therapies is particularly preferred. In this context, the peptide can be used to enhance the efficacy of CAR-T cells against CXCR4-overexpressing tumors. The medicinal product may be in liquid, semi-solid, or solid dosage forms, such as solutions for injection, drops, syrups, sprays, suspensions, tablets, capsules, or in multiparticulate form, such as pellets or granules, and / or administered in these forms. Preparations in the form of tablets, coated tablets, capsules, or granules are preferred for oral administration. Preferred pharmaceutical formulations are selected from the group comprising tablets, solutions for injection, implants, or other dosage forms for systemic or local applications. A formulation in delivery systems such as liposomes, nanoparticles, biodegradable polymers or albumin-binding structures for targeted release is also preferred. The medicinal product may be sterilized. The medicinal product may contain suitable additives, carriers and / or excipients. The type of additives, carriers, and / or excipients depends on the desired route of administration. Oral preparations can be in the form of tablets, film-coated tablets, or capsules, including extended-release formulations, and can contain common excipients such as binders, fillers, lubricants, disintegrants like starch, or surfactants. Preferably, a tablet is water-soluble. Film-coated tablets are also preferred. Their core is preferably coated with a thin film of a film-forming agent. Oral liquid preparations can be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs, or sprays, etc., or can be supplied as a dry powder for reconstitution with water or another suitable carrier. Suitable carrier substances include, for example, organic or inorganic substances that are suitable for enteral (e.g., oral or rectal) or parenteral administration and do not react with the compounds, such as water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate and other fatty acid glycerides, gelatin, soy lecithin, carbohydrates such as lactose or starch, magnesium stearate, talc or cellulose. In other words, a peptide as described above is provided for use in the therapeutic and / or prophylactic treatment or diagnosis of diseases as described above. For further description of the peptides and diseases, please refer to the preceding description. Another aspect concerns the use of a peptide comprising an amino acid sequence X6X7X8X9X10X11X12 according to SEQ ID NO: 1, or its pharmacologically acceptable salts, derivatives and / or conjugates, wherein X6 is G or A, X7 is R or A, X8 is R or A, X9 is T or A, X10 is R or A, X11 is L or A, X12 is C or A, with the proviso that one of the amino acids at position X6, X7, X8, X9, X10, X11 or X12 may be alanine, wherein the peptide has a total length in the range of 7 to 30 amino acids, its pharmacologically acceptable salts, derivatives and / or conjugates, for the manufacture of a medicinal product, in particular for the manufacture of a medicinal product for the therapeutic and / or prophylactic treatment or diagnosis of diseases selected from: CXCR4-associated diseases selected from the group comprising WHIM syndrome (Warts, hypogammaglobulinemia, infections, myelokathexis), Waldenström macroglobulinemia, acute myeloid leukemia (AML),Chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), HIV infection, especially infections with HIV-1, HIV-2, toxoplasmosis, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), myocardial infarction, atherosclerosis, stroke, type 2 diabetes mellitus, endometriosis, liver fibrosis and other fibroses, cancers, especially cancers expressing the CRCX4 receptor, such as breast cancer, lung cancer, prostate cancer, glioblastoma, colorectal carcinoma, pancreatic carcinoma, neuroendocrine tumors (NETs), non-Hodgkin lymphoma, multiple myeloma and skin cancer; infections caused by bacteria and fungi, especially Pseudomonas, Candida, S. aureus; Infections with the coronavirus SARS-CoV-2; dermatitis; pneumonia; asthma; impaired scar healing; cardiological disorders, especially heart failure; stroke,Parkinson's disease, Alzheimer's disease; wounds, especially burn wounds, or to improve bone healing. For further description of the peptides, salts, derivatives, conjugates, drugs, and diseases, please refer to the description above. Preferred use is for the treatment or diagnosis of diseases involving the CXCR4-CXCL12 axis. CXCR4 and CXCL12 are significantly elevated, particularly in chronic inflammation. CXCL12 directs immune cells into tissues, where they accumulate, leading to tissue damage and inflammatory responses. Furthermore, CXCR4 is overexpressed on malignant cancer cells, contributing to cell survival and metastasis. In tumors, high expression of CXCL12 and CXCR4 is a predictor of a poorer prognosis. Preferred embodiments relating to uses, wherein the therapeutic and / or prophylactic treatment takes place in tumoral, urogenital or pulmonary microenvironments with a high CXCR4 / CXCL12 gradient. Unless otherwise stated, the technical and scientific terms used have the meanings that would be commonly understood by a person skilled in the art in the field to which this invention relates. Examples and figures that serve to illustrate the present invention are given below. Figure 1 shows the determination of the interactions of the peptide AKAWSGRRTRLCCHR (SEQ ID NO: 6) with that of the protein GPR15LG, a C-terminal peptide derivative, and plerixafor with the binding pocket of CXCR4. Values ​​represent three experiments in duplicates ± SEM. Figure 2 shows the determination of the interactions of the peptide AKAWSGRRTRLCCHR (SEQ ID NO: 6) with that of the protein GPR15LG, a C-terminal peptide derivative, and plerixafor with the N-terminus of CXCR4. Values ​​represent three experiments, in triplicates ± SEM. Fig. 3 Infection of CXCR4-expressing TZM-bl reporter cells by HIV-1 after treatment with the peptide AKAWSGRRTRLCCHR, the protein GPR15LG(1-57), the peptide derivative of the C-terminus of GPR15LG, and plerixafor. Values ​​represent one measurement for (GPR15LG(5-19) and GPR15LG-C without SD or three measurements for GPR15LG and plerixafor. Fig.4. Arrestin recruitment in the presence of the peptide AKAWSGRRTRLCCHR (SEQ ID NO: 6), the protein GPR15LG(1-57), the C-terminal peptide derivative of GPR15LG, and plerixafors. Values ​​represent three experiments, in triplicates ± SEM. Fig. 5. Arrestin recruitment plotted against the concentration for activation of the canonical receptor GPR15 in the presence of the peptide AKAWSGRRTRLCCHR (SEQ ID NO: 6), the protein GPR15LG(1-57), the C-terminal peptide derivative of GPR15LG, and plerixafors. Values ​​represent three experiments, in triplicates ± SEM. Fig. 6 The recruitment of arrestin plotted against the concentration for activation of CXCR7 / ACKR3 in the presence of the peptide AKAWSGRRTRLCCHR, the protein GPR15LG(1-57), the peptide derivative of the C-terminus of GPR15LG, and plerixafors. Values ​​represent three experiments, in triplicates ± SEM.Fig. 7 The migration of CD4+ T cells in the presence of different concentrations of the peptide AKAWSGRRTRLCCHR (SEQ ID NO: 6) without CXCL12. Values ​​represent an experiment in triplicates ± SEM. Fig. 8 The migration of CD4+ T cells in the presence of different concentrations of the peptide AKAWSGRRTRLCCHR (SEQ ID NO: 6) and 10 nM CXCL12. Values ​​represent an experiment in triplicates ± SD (agonism) or an experiment in duplicates ± SD (antagonism). Fig. 9 The amount of CXCR4 phosphorylated by 12.5 nM CXCL12 versus the concentration of the peptide AKAWSGRRTRLCCHR (SEQ ID NO: 6). Values ​​correspond to an experiment in triplicates ± SD. Fig. 10 The amount of ERK phosphorylated by 12.5 nM CXCL12 versus the concentration of the peptide AKAWSGRRTRLCCHR (SEQ ID NO: 6). Values ​​correspond to an experiment in triplicates ± SD. Fig. 11 The interaction of the peptide AKAWSGRRTRLCCHR (SEQ ID NO: 6) and the protein GPR15LG with CXCR4, each in the presence of 1 g / ml heparin and without heparin.Values ​​represent one experiment, in duplicates ± SD. Materials and methods Peptide production Peptides were produced in the research group of Dr. L. Ständker (Ulm Peptide Pharmaceuticals, University of Ulm). The peptides were synthesized by solid-phase peptide synthesis and purified by high-performance liquid chromatography (HPLC). Cell culture HEK293T and SupT1 cells were obtained from the American Type Culture Collection (ATCC). TZM-bl cells were obtained from the NIH AIDS Reagent Program. HEK293T and TZM-bl cells were cultured in Dulbecco's Modified Eagle Medium (DMEM), supplemented with 10% fetal calf serum (FCS), 100 units / mL penicillin, 100 µg / mL streptomycin, and 2 mmol / L L-glutamine. SupT1 cells were cultured in Roswell Park Memorial Institute Medium (RPMI), supplemented with 10% or 1% FCS, 100 units / mL penicillin, 100 µg / mL streptomycin, 2 mmol / L L-glutamine, and 1 mmol / L HEPES (Gibco). Competition with CXCR4 antibodies Competition with CXCR4 antibodies was performed on SupT1 cells. The ligand was serially diluted in cold PBS and then added to 5 × 10⁴ cells. For heparin assays, the ligand was pre-incubated with 1 µg / ml heparin for 30 minutes. APC-conjugated anti-human CXCR4 antibody against ECL-2 (clone 12G5, #555976, BD) or PE-conjugated anti-human CXCR4 antibody against the N-terminus (clone 1D9, #551510, BD) were diluted in PBS with 1% FCS and added immediately. After 90 minutes of incubation at 4 °C, unbound antibody was removed by two washes in PBS with 1% FCS. The cells were fixed in 2% paraformaldehyde and analyzed by flow cytometry. The mean fluorescence intensity (MFI) of the isotype staining was subtracted from all sample MFIs and the values ​​were normalized to full staining (100%) and unstained (0%). HIV-1 production and inhibitionVirus stocks of X4-tropic HIV-1 NL4-3-derived V3 variants were generated by transient transfection of HEK293T cells with proviral DNA. On day 1, 3.5 × 10^6 HEK293T cells were seeded into a T75 flask containing 20 ml of DMEM. On the following day, the cells were transfected with 15 µg of proviral plasmid DNA using TransIT-LT1® (Mirus Bio, Madison, WI, USA) according to the manufacturer's instructions in Opti-MEM. Four days post-infection, the flask supernatant was harvested and centrifuged to separate the virus stock from cell debris. The aliquoted stock was stored at -80 °C until use. Inhibition of viral infection was performed in TZM-bl reporter cells. For this purpose, 1 × 10^4 cells (in growth medium with 2.5% FCS) were pretreated with serially diluted inhibitors for 30 minutes at 37 °C. The cells were then inoculated with virus diluted in serum-free medium.Infection rates were determined after 3 days using the Gal-Screen system (Applied Biosystems). Viral control without medication was set to 100% to normalize the situation. β-Arrestin recruitment assay For transfection, 20,000 HEK293T cells were plated in 96-well Eppendorf microplates with reservoirs (Eppendorf Hamburg, Germany) (Cat. 0030 730.135). The following day, the cells were transiently transfected with 50 ng GPCR-LgBiT plasmid and 50 ng SmBiT-arrestin plasmid using TransIT-LT1® (Mirus Bio, Madison, WI, USA) according to the manufacturer's instructions in Opti-MEM. After another 24 hours, for antagonistic measurements, the entire medium was replaced with 100 µl of Opti-MEM and the reservoirs in the microplate were filled with PBS. The plates were incubated at 37°C for 30 minutes to stabilize the temperature before 25 µl of Nano-Glo Live Cell Reagent was added to each well and an initial baseline luminescence was recorded for 10 minutes on a Synergy H1 (Agilent, Santa Clara, CA, United States). Subsequently, 15 µl of serially diluted inhibitory compound or buffer control was added for a further 10 minutes.Finally, 10 µl of stimulating compounds were added and the kinetics were measured for 1 hour. For agonist measurements, the medium was changed to 110 µl of Opti-MEM, and after adding 25 µl of Nano-Glo Live reagent for 10 minutes, 15 µl of serially diluted stimulating ligand or buffer control was added for 1 hour. Baseline values ​​were averaged, and the change from the mean baseline value was calculated. The changes were then normalized to the mean buffer change for each time point, and the area under the curve was calculated. To normalize the antagonist measurement, the buffer area under the curve (AUC) was set to 0%, and the stimulating compound values ​​were set to 100%. For agonist measurements, the change from the buffer control was calculated. Example 1 Determination of the interaction of the peptide AKAWSGRRTRLCCHR with CXCR4 The binding of the peptide AKAWSGRRTRLCCHR according to SEQ ID NO: 6 to CXCR4 was investigated by competition with CXCR4 antibodies clone 12G5 from the receptor binding pocket and 1D9 against the N-terminus of CXCR4 as described above. For comparison, the protein GPR15LG(1-57), a peptide of the C-terminus of GPR15LG, and the approved CXCR4 inhibitor plerixafor were also tested (Table 1). AKAWSGRRTRLCCHRSEQ ID NO: 6GPR15LG(5-19) KRRPAKAWSGRRTRLCCHRVPSPNSTNLKGHHVRLCKPCKLEPEPRLWVVPGALPQVSEQ ID NO: 18GPR15LG(1-57) EPEPRLWVVPGALPQVSEQ ID NO: 19GPR15LG-C Figure 1 shows the results of the determination of the interactions of the peptide AKAWSGRRTRLCCHR (SEQ ID NO: 6) with that of the protein GPR15LG, the C-terminal peptide derivative, and plerixafor with the binding pocket of CXCR4. Figure 2 shows the results of the determination of the interactions of the peptide AKAWSGRRTRLCCHR (SEQ ID NO: 6) with that of the protein GPR15LG, the C-terminal peptide derivative, and plerixafor with the N-terminus of CXCR4. As can be seen in Figure 1, the peptide AKAWSGRRTRLCCHR, like GPR15LG and plerixafor, displaced the monoclonal anti-CXCR4 antibody clone 12G5 from the receptor's binding pocket. As can be seen in Fig. 2, the anti-CXCR4 antibody 1D9 was only weakly antagonized by the peptide AKAWSGRRTRLCCHR. The C-terminus GPR15LG-C did not interact with any of the binding sites. The results show that the peptide AKAWSGRRTRLCCHR (SEQ ID NO: 6) displaced the monoclonal anti-CXCR4 antibody 12G5 from the receptor binding pocket more effectively than the protein GPR15LG, with a half-maximal inhibitory concentration of 3.28 µg / ml compared to 8.23 ​​µg / ml for GPR15LG. The half-maximal inhibitory concentration of plerixafor was 192 ng / ml. As expected, the C-terminus did not interact with CXCR4. The monoclonal anti-CXCR4 antibody 1D9, which specifically binds to the free N-terminus of CXCR4, was also antagonized by the protein GPR15LG, while the peptide AKAWSGRRTRLCCHR had only a slight effect at its highest concentration. Due to its direct binding to the CXCR4 binding pocket, plerixafor does not antagonize 1D9. Example 2 Determination of the interaction of other peptides with CXCR4 The binding of the peptides listed in Table 2 to CXCR4 was investigated by competition with the CXCR4 antibody clone 12G5 from the receptor's binding pocket, as described above. Two short peptides and the peptide according to SEQ ID NO: 22 were tested as controls. The peptides and half-maximal inhibitory concentrations are summarized in Table 2 below. KRRPAKAWSGRRTRLCCHRVPSPNSTNLKGHHVRLCKPCKLEPEPRLWVVPGALPQV~5SEQ ID NO: 18GPR15LG(1-57) AKAWSGRRTRLCCHR1.8 ± 0.2SEQ ID NO: 6GPR15LG(5-19) AAAWSGRRTRLCCHR0.9 ± 0.3SEQ ID NO: 7GPR15LG(5-19) K2A AKAASGRRTRLCCHR1.2 ± 0.3SEQ ID NO: 8GPR15LG(5-19) W4A AKAWSGRATRLCCHR5.6 ± 4.0SEQ ID NO: 9GPR15LG(5-19) R8A AKAWSGRRTALCCHR4.4 ± 1.5SEQ ID NO: 10GPR15LG(5-19) R10A AKAWSGRRTRLCCHA1.5 ± 0.1SEQ ID NO: 11GPR15LG(5-19) R15A KAWSGRRTRLCCHR1.2 ± 0.2SEQ ID NO: 12GPR15LG(6-19) AWSGRRTRLCCHR1,2 ± 0,5SEQ ID NO: 13GPR15LG(7-19) WSGRRTRLCCHR3,0 ± 0,8SEQ ID NO: 14GPR15LG(8-19) AKAWSGRRTRLCCH2,7 ± 0,9SEQ ID NO: 15GPR15LG(5-18) AKAWSGRRTRLCC3,7 ± 1,1SEQ ID NO: 16GPR15LG(5-17) AKAWSGRRTRLC8,8 ± 4,4SEQ ID NO: 17GPR15LG(5-16) AKAWSGRN.D.SEQ ID NO: 20GPR15LG(5-11) RTRLCCHR20 ± 11SEQ ID NO: 21GPR15LG(12-19) AKAWSGAATALCCHRN.D.SEQ ID NO: 22GPR15LG-N GAGMotivdeletion As can be seen from Table 2, peptides with the motif GRRTRLC (SEQ ID NO: 3), where one of the amino acids can be replaced by alanine, showed good binding to CXCR4, while several substitutions by alanine in the peptide of SEQ ID NO: 22 led to a loss of binding. Besides the peptide AKAWSGRRTRLCCHR (SEQ ID NO: 6), the peptides AAAWSGRRTRLCCHR (SEQ ID NO: 7), AKAASGRRTRLCCHR (SEQ ID NO: 8), AKAWSGRRTRLCCHA (SEQ ID NO: 11, (GPR15LG(5-19) R15A), KAWSGRRTRLCCHR (SEQ ID NO: 12), and AWSGRRTRLCCHR (SEQ ID NO: 13) showed low half-maximal inhibitory concentrations, with the latter showing a promising improvement in interaction with CXCR4. In particular, the peptides SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 11, in which position X2, X4, or X15 was replaced by alanine (A), showed a lower IC50 compared to the peptide SEQ ID NO: 6, which contained a fragment of the naturally occurring sequence of the protein. Example 3 Determination of the inhibition of CXCR4-tropic HIV-1 by the peptide AKAWSGRRTRLCCHR (SEQ ID NO: 6) The infection rates of HIV-1 infected cells were investigated by the beta-galactosidase reporter system after treatment with the peptide AKAWSGRRTRLCCHR (SEQ ID NO: 6) and the protein GPR15LG(1-57) (SEQ ID NO: 18), the peptide according to SEQ ID NO: 19 of the C-terminus of GPR15LG and the approved CXCR4 inhibitor plerixafor as described above, with beta-galactosidase being quantified and normalized three days after infection. Figure 3 shows the infection rates after treatment plotted against the concentration. As can be seen in Figure 3, the peptide AKAWSGRRTRLCCHR (SEQ ID NO: 6) inhibited the infection of CXCR4-expressing TZM-bl reporter cells by HIV-1 with greater effectiveness than the full protein GPR15LG. The C-terminus GPR15LG-C again showed no effect due to the lack of interaction with CXCR4. The greater effectiveness in inhibiting CXCR4-tropic HIV-1 with the receptor is attributed to the specific binding of plerixafor to the binding pocket of CXCR4. Without committing to a specific theory, it is assumed that the also greater effectiveness of the peptide AKAWSGRRTRLCCHR (SEQ ID NO: 6) compared to the protein GPR15LG(1-57) resulted from its stronger binding towards the binding pocket. Example 4 Determination of the interaction of CXCR4 with beta-arrestin-2 after treatment with the peptide AKAWSGRRTRLCCHR (SEQ ID NO: 6) The interaction of CXCR4 with beta-arrestin-2 was determined based on the β-arrestin recruitment assay according to the NanoBiT system (ProMega) as described above. The CXCL12-dependent recruitment of arrestin to CXCR4 was investigated in human embryonic kidney cells (HEK293T) transiently transfected with NanoBiT-based CXCR4 and arrestin expression plasmids after treatment with the peptide AKAWSGRRTRLCCHR (SEQ ID NO: 6), the protein GPR15LG(1-57) (SEQ ID NO: 18), the peptide (SEQ ID NO: 19) of the C-terminus of GPR15LG, and the approved CXCR4 inhibitor plerixafor. Upon interaction of BiT-tagged receptor and arrestin, substrate conversion occurs and luminescence is quantifiable. Figure 4 shows the recruitment of arrestin plotted against concentration. As can be seen in Figure 4, the peptide AKAWSGRRTRLCCHR (SEQ ID NO: 6), like the protein GPR15LG(1-57) and plerixafor, inhibited the CXCL12-dependent recruitment of arrestin to CXCR4. The C-terminus GPR15LG-C did not lead to the recruitment of arrestin due to the lack of interaction with CXCR4. Here, the peptide AKAWSGRRTRLCCHR inhibited the CXCL12-induced interaction of arrestin with the receptor more strongly than the original protein GPR15LG(1-57), but much less strongly than plerixafor. For plerixafor, it was shown that even low concentrations block CXCR4 signaling. However, this also leads to the attack and inhibition of off-target cells. The high efficacy of plerixafor in inhibiting CXCR4 through direct interaction with the binding pocket is therefore considered a possible cause for the frequently reported adverse effects in clinical practice. Currently, due to its broad range of side effects, plerixafor is only approved for the mobilization of hematopoietic stem cells. It is assumed that the peptides described here, such as the peptide AKAWSGRRTRLCCHR, as peptide agents with a wider dosage range, should exhibit a better tolerability profile and lower accumulation. Particularly in the therapy of frequently CXCR4 overexpressing cancer cells, which are sensitized to CXCR4 inhibition, the peptides described here are assumed to have an advantage over plerixafor with regard to the dose spectrum. Example 5 Determination of the effects of the peptide AKAWSGRRTRLCCHR (SEQ ID NO: 6) on CXCR7 and GPR15 In addition to CXCR4, the CXC motif chemokine receptor 7 (CXCR7), also renamed atypical chemokine receptor 3 (CKR3), is activated by CXCL12. The canonical receptor of the protein GPR15LG is GPR15. Therefore, the effect of the peptide AKAWSGRRTRLCCHR (SEQ ID NO: 6) on the activation of the canonical receptor GPR15 as well as the chemokine receptor CXCR7 was also determined using the β-arrestin recruitment assay in human embryonic kidney cells (HEK293T) transiently transfected with GPR15 or CXCR4 / ACKR3 and arrestin expression plasmids, as described above. Figure 5 illustrates the recruitment of arrestin plotted against the concentration for activation of the canonical receptor GPR15. As can be seen in Figure 5, the peptide AKAWSGRRTRLCCHR (SEQ ID NO: 6) interacted poorly with GPR15 compared to the protein GPR15LG and the C-terminal peptide GPR15LG-C. While the C-terminal peptide continued to signal GPR15, the peptide AKAWSGRRTRLCCHR (SEQ ID NO: 6) was only weakly agonistic. Figure 6 illustrates the recruitment of arrestin plotted against the concentration for CXCR7 / ACKR3 activation. As can be seen in Figure 6, the peptide AKAWSGRRTRLCCHR (SEQ ID NO: 6) and the protein GPR15LG, but not the C-terminal peptide GPR15LG-C, bound to CXCR7 / ACKR3 and recruited β-arrestin there. Here, the peptide AKAWSGRRTRLCCHR activated the receptor, similar to plerixafor. These results show that the peptide AKAWSGRRTRLCCHR (SEQ ID NO: 6) and plerixafor have similar effects on CXCR4, CXCR7, and GPR15. Accordingly, a similarity in mechanism is assumed, suggesting the possibility of therapeutic application of these peptides by blocking the signaling function of CXCR4, similar to the mechanism of plerixafor. Example 6 Determination of the antagonistic effect of the peptide AKAWSGRRTRLCCHR (SEQ ID NO: 6) on CXCR4 Furthermore, it was investigated whether the binding of the peptide AKAWSGRRTRLCCHR (SEQ ID NO: 6) to CXCL12 is agonistic (receptor-activating) or antagonistic (receptor-inhibiting). This was determined by examining the migration of primary CD4+ T cells towards CXCL12. For this purpose, primary CD4+ T cells were isolated from buffycoats and allowed to migrate towards CXCL12 for 4 hours at 37°C in a transwell migration assay, either in the presence of various concentrations of the peptide AKAWSGRRTRLCCHR (SEQ ID NO: 6) and 10 nM CXCL12, or without CXCL12. The total number of migrated cells was determined by measuring ATP concentrations (Cell Titer Glow, ProMega). Figure 7 illustrates the migration of CD4+ T cells in the presence of different concentrations of the peptide AKAWSGRRTRLCCHR without CXCL12. As can be seen in Figure 7, administration of the peptide AKAWSGRRTRLCCHR alone did not lead to T cell migration. Figure 8 illustrates the migration of CD4+ T cells in the presence of different concentrations of the peptide AKAWSGRRTRLCCHR and 10 nM CXCL12. As can be seen in Figure 8, the presence of CXCL12 led to migration. However, the addition of the peptide AKAWSGRRTRLCCHR increasingly inhibited CXCL12-directed T cell migration with increasing concentration. These results show that the peptide AKAWSGRRTRLCCHR (SEQ ID NO: 6) blocks CXCR4 signaling by CXCL12 and thus acts as a CXCR4 antagonist. Example 7 Determination of the antagonistic effect of the peptide AKAWSGRRTRLCCHR (SEQ ID NO: 6) on CXCR4 using phosphorylation assays The antagonistic effect of the peptide AKAWSGRRTRLCCHR (SEQ ID NO: 6) on CXCL12-mediated CXCR4 signaling was further investigated in a CXCR4 phosphorylation assay and an Erk phosphorylation assay. For this purpose, primary CD4+ T cells were isolated from buffycoats and pretreated with the peptide AKAWSGRRTRLCCHR (SEQ ID NO: 6) for 10 minutes. Subsequently, the T cells were stimulated with 10 nM CXCL12 for 2 minutes and stained immunofluorescently. A control in pure buffer was considered the zero value (0% phosphorylation), and the values ​​were normalized to 100% with respect to CXCL12 phosphorylation in the absence of the peptide. Figure 9 shows the amount of phosphorylated CXCR4. Figure 10 shows the amount of phosphorylated ERK. As can be seen from Figures 9 and 10, the peptide AKAWSGRRTRLCCHR inhibited the CXCL12-dependent phosphorylation of CXCR4 and ERK. This confirms the antagonistic effect of the peptide AKAWSGRRTRLCCHR (SEQ ID NO: 6) on CXCL12-mediated CXCR4 signaling. Example 8 Determination of binding to CXCR4 in the presence of heparin On the cell surface, chemokines interact with glycosaminoglycans (GAGs) to bind near receptors and create concentration gradients. This facilitates receptor interaction. However, this interaction is inhibited in the presence of heparin, as used clinically. In the presence of heparin, GAG binding motifs are blocked, and GPR15LG can no longer displace 12G5 from CXCR4. Therefore, the binding of the peptide AKAWSGRRTRLCCHR (SEQ ID NO: 6) to CXCR4 was investigated by competition with the CXCR4 antibody clone 12G5 as described above, both in the presence of 1 g / ml heparin and without heparin. For comparison, the protein GPR15LG(1-57) was also tested in the presence of 1 g / ml heparin and without heparin. Figure 11 shows the results of the determination of the interaction of the peptide AKAWSGRRTRLCCHR (SEQ ID NO: 6) with CXCR4 versus that of the protein GPR15LG, both in the presence of 1 g / ml heparin and without heparin. As shown in Fig. 11, unlike the protein, the peptide AKAWSGRRTRLCCHR (SEQ ID NO: 6) was able to continue binding to CXCR4 and displacing the monoclonal antibody clone 12G5 even in the presence of heparin. While not committing to a specific theory, it is assumed that the peptide binds specifically to CXCR4 with only minimal interaction with GAGs. These results demonstrate that the peptides can be used even during heparin treatment, and that heparin does not need to be discontinued beforehand. Overall, the results show that the peptides described here, comprising an amino acid sequence according to SEQ ID NO: 1, are suitable for the manufacture of a drug for use in therapeutic and / or prophylactic treatment or for the diagnosis of CXCR4-associated diseases, such as HIV infections and cancer, by blocking the signaling function of CXCR4 similar to the mechanism of plerixafor, advantageously also in the presence of heparin. QUOTES INCLUDED IN THE DESCRIPTION This list of documents cited by the applicant was automatically generated and is included solely for the reader's convenience. The list is not part of the German patent or utility model application. The DPMA accepts no liability for any errors or omissions. Cited patent literature WO 2009 / 004054 A2

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[0007]

Claims

Peptide comprising an amino acid sequence X6X7X8X9X10X11X12 according to SEQ ID NO: 1, or its pharmacologically acceptable salts, derivatives and / or conjugates, wherein X6 is G or A, X7 is R or A, X8 is R or A, X9 is T or A, X10 is R or A, X11 is L or A, X12 is C or A, with the proviso that one of the amino acids at position X6, X7, X8, X9, X10, X11 or X12 may be alanine, wherein the peptide has a total length in the range of 7 to 30 amino acids, and wherein a peptide consisting of the amino acid sequence KRRPAKAWSGRRTRLCC according to SEQ ID NO: 2 is excluded. Peptide according to claim 1, wherein the peptide comprises an amino acid sequence X1X2X3X4X5GRRTRLCX13X14X15 according to SEQ ID NO: 4, wherein X1 is A or a deletion, X2 is selected from K, A or a deletion, X3 is A or a deletion, X4 is selected from W, A or a deletion, X5 is selected from S, A or a deletion, X13 is C or A, X14 is H or A, X15 is selected from R, A or a deletion. Peptide according to claim 1 or 2, wherein the peptide comprises or consists of one of the following amino acid sequences: AKAWSGRRTRLCCHR according to SEQ ID NO: 6, AAAWSGRRTRLCCHR according to SEQ ID NO: 7, AKAASGRRTRLCCHR according to SEQ ID NO: 8, AKAWSGRATRLCCHR according to SEQ ID NO: 9, AKAWSGRRTALCCHR according to SEQ ID NO: 10, AKAWSGRRTRLCCHA according to SEQ ID NO: 11, KAWSGRRTRLCCHR according to SEQ ID NO: 12, AWSGRRTRLCCHR according to SEQ ID NO: 13, WSGRRTRLCCHR according to SEQ ID NO: 14, AKAWSGRRTRLCCH according to SEQ ID NO: 15, AKAWSGRRTRLCC according to SEQ ID NO: 16, and AKAWSGRRTRLC according to SEQ ID NO: 17, or homologs, isomers, or functional derivatives thereof. the aforementioned peptides, which exhibit at least 70% to 95% sequence homology. Peptide according to any of the preceding claims, wherein the peptide is selected from the group of peptides comprising or consisting of one of the following amino acid sequences: AKAWSGRRTRLCCHR according to SEQ ID NO: 6, AAAWSGRRTRLCCHR according to SEQ ID NO: 7, AKAASGRRTRLCCHR according to SEQ ID NO: 8, AKAWSGRRTRLCCHA according to SEQ ID NO: 11, KAWSGRRTRLCCHR according to SEQ ID NO: 12, and AWSGRRTRLCCHR according to SEQ ID NO: 13, or homologs, isomers or functional derivatives of the aforementioned peptides, which have at least 70% to 95% sequence homology. Peptide according to any of the preceding claims, wherein the derivatives of the peptide are selected from N-methylated, amidated, acetylated, phosphorylated, pegylated or glycosylated peptide derivatives, albumin-bound peptide, containing peptides, one or more D-amino acids or beta-amino acids, cyclic peptide variants, peptidomimetics, or fusion proteins wherein the peptide is part of the fusion protein, in particular a bifunctional peptide, or wherein the conjugate is a peptide-antibody conjugate, wherein the peptide is bound to an antibody or an antibody fragment. A pharmaceutical or diagnostic composition comprising as an active ingredient a peptide comprising an amino acid sequence X6X7X8X9X10X11X12 according to SEQ ID NO: 1, or its pharmacologically acceptable salts, derivatives and / or conjugates, wherein X6 is G or A, X7 is R or A, X8 is R or A, X9 is T or A, X10 is R or A, X11 is L or A, X12 is C or A, with the proviso that one of the amino acids at position X6, X7, X8, X9, X10, X11 or X12 may be alanine, wherein the peptide has a total length in the range of 7 to 30 amino acids, or comprising a peptide according to any one of claims 2 to 5, and optionally pharmaceutically acceptable carriers, excipients and / or vehicles. A pharmaceutical or diagnostic composition according to claim 6, for use in the therapeutic and / or prophylactic treatment or diagnosis of diseases selected from: CXCR4-associated diseases selected from the group comprising WHIM syndrome (Warts, hypogammaglobulinemia, infections, myelokathexis), Waldenström macroglobulinemia, acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), HIV infection, in particular infections with HIV-1, HIV-2, toxoplasmosis, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), myocardial infarction, atherosclerosis, stroke, type 2 diabetes mellitus, endometriosis, liver fibrosis and other fibroses, cancers, in particular cancers which The CRCX4 receptor shows how breast cancer, lung cancer, prostate cancer, glioblastoma,Colorectal cancer, pancreatic cancer, neuroendocrine tumors (NETs), non-Hodgkin lymphoma, multiple myeloma and skin cancer; infections caused by bacteria and fungi, especially Pseudomonas, Candida, S. aureus; infections with the coronavirus SARS-CoV-2; dermatitis; pneumonia; asthma; impaired scar healing; cardiological disorders, especially heart failure; stroke, Parkinson's disease, Alzheimer's disease; wounds, especially burn wounds, or to improve bone healing. Drug or pharmaceutical or diagnostic composition according to claim 6 or 7, for use in combination with chemotherapeutic agents, immunotherapeutic agents, chemokine receptor inhibitors in particular CXCR7 or genome-based therapies such as CRISPR, or as adjuvants for CAR-T cell therapies. Use of a peptide comprising an amino acid sequence X6X7X8X9X10X11X12 according to SEQ ID NO: 1, or its pharmacologically acceptable salts, derivatives and / or conjugates, wherein X6 is G or A, X7 is R or A, X8 is R or A, X9 is T or A, X10 is R or A, X11 is L or A, X12 is C or A, with the proviso that one of the amino acids at position X6, X7, X8, X9, X10, X11 or X12 may be alanine, wherein the peptide has a total length in the range of 7 to 30 amino acids, or of a peptide according to any one of claims 2 to 5, its pharmacologically acceptable salts, derivatives and / or conjugates, for the manufacture of a medicament, in particular for the manufacture of a medicament for the therapeutic and / or prophylactic treatment or for the diagnosis of diseases as defined in claim 7. Use according to claim 9, wherein the therapeutic and / or prophylactic treatment takes place in tumoral, urogenital or pulmonary microenvironments with a high CXCR4 / CXCL12 gradient.

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