Beta-catenin-binding peptides and peptidomimetics and uses thereof

Abstract

The invention relates to β-catenin-binding peptides and peptidomimetics comprising an amino acid sequence ESILDEHXQRVW or EYPESILDEHXQRVWR, wherein X is L, M, I, F, Y, W or C, or a variant of said amino acid sequences, and to uses thereof.

Description

[0001] P137673PC00 Title: Beta-catenin-binding peptides and peptidomimetics and uses thereof Field of the invention The invention relates to the field of β-catenin-binding peptides and peptidomimetics, which serve as inhibitors of the Wingless / Int-1 (Wnt) signalling pathway in cells. Wnt inhibition finds use in treating Wnt-mediated disease conditions, such as aberrant cell proliferation and / or cell differentiation. Background of the invention Small molecule inhibitors of proteins have dominated drug discovery for the last century, but the identification of new addressable therapeutic targets is increasingly challenging. This owes to the fact that small-molecular scaffolds preferably bind to defined pockets or cavities, not present in many potential targets. Protein-based therapeutics, such as antibodies, possess the ability to bind flat target surfaces, as they are often found in protein-protein interactions (PPI). Different from small molecules, however, proteins do not exhibit sufficient cell penetration capabilities to address intracellular targets. This leaves a large number of therapeutically relevant proteins currently unaddressable. Peptidic scaffolds (i.e., class A and B peptidomimetics) (Pelay-Gimeno et al.2015) have the potential to fill that void as they combine binding abilities similar to proteins with a comparably low molecular weight which supports cellular uptake. Without further modification, most class A and B peptidomimetics, however, exhibit insufficient cellular uptake hampering the inhibition of intracellular targets. To increase uptake, positively charged cell-penetrating peptide sequences have been added or grafted onto peptidic scaffolds (Copolovici, et al. 2014; Collado Camps 2018) which comes at the cost of an increased molecular weight and potential toxicity due to the resulting membrane activity (El-Andaloussi et al 2007). A prime example for an intracellular target that lacks defined binding pockets is the oncogene β-catenin (Cui et al.2018; Kessler et al.2021). It is the central hub in the Wnt signalling pathway, engaging in a multitude of interactions with pathway modulators (Hahne and Grossmann 2013). Wnt signalling is central to cell proliferation as well as differentiation and involved in the onset and progression of numerous types of cancer (Nusse and Clevers 2017). β-Catenin plays a crucial role in these processes and, in particular, its interaction with transcription factors of the TCF / LEF family moved into the focus of drug discovery efforts (Liu et al. 2022). So far, peptidomimetic strategies either yielded small- molecular scaffolds with low affinity, or high-affinity binders with relatively large molecular weight which then prompted the addition of cell penetrating peptides or their conversion into β-catenin degraders (PROTACs) to achieve bioactivity (McCoy et al. 2022; Yang et al. 2022; Koelman et al.2022; McLoughlin et al. 2018; Liao et al. 2020; Wang et al.2022). Grossmann et al. 2012, WO 2012 / 040459 and WO 2019 / 051327 describe axin-derived β-catenin targeting peptides the peptides consist of between 13 and 16 amino acids, including stapled Axin derivative peptides. Summary of the invention It is an object of the present invention to provide β-catenin-binding peptides and peptidomimetics, in particular high affinity β-catenin-binding peptides and peptidomimetics. Such β-catenin-binding peptides and peptidomimetics find use as inhibitors of the Wnt signalling pathway, and thus as therapeutics agents. The invention therefore provides a β-catenin-binding peptide or peptidomimetic having a length of 7-12 amino acids and comprising an amino acid sequence ESILDEHXQRVW, wherein X is L, M, I, F, Y, W or C, or a variant of said amino acid sequence, wherein said variant comprises at least amino acids 2-8 of said sequence and optionally having: - up to three substitutions of an amino acid at position 1, 2, 6, 7, 9, 10, 11 and / or 12 by another amino acid, - S at position 2 and E at position 6 each substituted by a non-proteinogenic amino acid which non-proteinogenic amino acids are linked to one another and / or E at position 6 and Q at position 9 each substituted by a non-proteinogenic amino acid which non-proteinogenic amino acids are linked to one another, and - one of the 5 most C-terminal amino acids is substituted by a modified amino acid, preferably X at position 8, Q at position 9, R at position 10, V at position 11 and W at position 12 substituted by a modified amino acid. In preferred embodiments, the modified amino acid at position 8, 9, 10, 11 or 12 comprises an aromatic moiety. Said aromatic moiety preferably is selected from para-bromobenzyl and naphthylmethyl. In preferred embodiments, X is C or L, including modified C or L, such as modified D-cysteine (c). In preferred embodiments, said up to three optional substitutions are selected from: - substitution of E at position 1 by Y, W, F or a corresponding non-proteinogenic amino acid; - substitution of S at position 2 by Y, W, H, F, D or a corresponding non- proteinogenic amino acid; - substitution of E at position 6 by F, W, Y, D or a corresponding non-proteinogenic amino acid; - substitution of H at position 7 by Y or a corresponding non-proteinogenic amino acid; - substitution of Q at position 9 by A, M, Y, W, R, N, L, K, H, F, E, C or a corresponding non-proteinogenic amino acid; - substitution of R at position 10 by Y, W, F or a corresponding non-proteinogenic amino acid - substitution of V at position 11 by Y, W, M, L, I, H, F or a corresponding non- proteinogenic amino acid; and / or - substitution of W at position 12 by M, Y, Q, N, L, I, H, G, F, E, D, C, A or a corresponding non-proteinogenic amino acid such as homocysteine. In further preferred embodiments, said up to three optional substitutions are selected from: - substitution of H at position 7 by Y or a corresponding non-proteinogenic amino acid; - substitution of V at position 11 by Y, W, L, I, F or a corresponding non- proteinogenic amino acid; and / or - substitution of W at position 12 by Y, L, F or a corresponding non-proteinogenic amino acid. In some preferred embodiments, E at position 1 is Y, W, F or a corresponding non-proteinogenic amino acid, preferably Y, W or a corresponding non- proteinogenic amino acid. In some preferred embodiments, S at position 2 is Y, W, H, F, D or a corresponding non-proteinogenic amino acid, preferably Y, W, F or a corresponding non-proteinogenic amino acid. In some preferred embodiments, E at position 6 is F, W, Y, D or a corresponding non-proteinogenic amino acid, preferably Y, W or a corresponding non-proteinogenic amino acid. In some preferred embodiments, H at position 7 is Y or a corresponding non- proteinogenic amino acid, preferably Y, or a corresponding non-proteinogenic amino acid. In some preferred embodiments, Q at position 9 is A, M, Y, W, R, N, L, K, H, F, E, C or a corresponding non-proteinogenic amino acid, preferably Y, W, R, N, F, C or a corresponding non-proteinogenic amino acid. In some preferred embodiments, R at position 10 is Y, W, F or a corresponding non-proteinogenic amino acid. In some preferred embodiments, V at position 11 is Y, W, M, L, I, H, F or a corresponding non-proteinogenic amino acid, preferably Y, W, L, I, F or a corresponding non-proteinogenic amino acid. In some preferred embodiments, W at position 12 is M, Y, Q, N, L, I, H, G, F, E, D, C, A or a corresponding non-proteinogenic amino acid, preferably Y, L, I, G, F, E, C or a corresponding non-proteinogenic amino acid. In preferred embodiments, said peptide or peptidomimetic has a length of 7- 11 amino acids. In preferred embodiments, said peptide has a length of 7-11 amino acids and S at position 2 and E at position 6 are each substituted by a non-proteinogenic amino acid which non-proteinogenic amino acids are linked to one another by a crosslink, and / or E at position 6 and Q at position 9 each substituted by a non- proteinogenic amino acid which non-proteinogenic amino acids are linked to one another by a crosslink, and / or L at position 8 and W at position 12 each substituted by a non-proteinogenic amino acid which non-proteinogenic amino acids are linked to one another by a crosslink, wherein each of said crosslinks is independently selected from the group consisting of a hydrocarbon crosslink, a lactam crosslink, a disulfide crosslink, a thioether crosslink, a triazole crosslink and a carbamate crosslink. In preferred embodiments, each of said crosslinks is a hydrocarbon crosslink. In a further aspect, the invention provides a β-catenin binding peptide or peptidomimetic having a length of 7-20 amino acids and comprising an amino acid sequence EYPESILDEHXQRVWR, wherein X is L, M, I, V, F, Y, W or C, including alpha-amino acids and beta-amino acids and both the D- and L-isomers of said amino acids, or a variant of said amino acid sequence, wherein said variant comprises at least amino acids 5-11 of said sequence and optionally having up to three substitutions of an amino acid at position 1, 2, 3, 4, 5, 9, 10, 12, 13, 14, 15 and / or 16 by another amino acid. In embodiments, one of the 5 most C-terminal amino acids is substituted by a modified amino acid, preferably Q at position 12, R at position 13, V at position 14, W at position 15, or R at position 16. In preferred embodiments, the modified amino acid at position 12, 13, 14, 15 or 16 comprises an aromatic moiety. Said aromatic moiety preferably is selected from para-bromobenzyl and naphthylmethyl. In embodiments, an aromatic moiety may form an aromatic crosslink between two amino acid residues, such as between two cysteine residues, between two homocysteine residues, or between a cysteine residue and a homocysteine residue. In preferred embodiments, said up to three optional substitutions of an amino acid by another amino acid are selected from: - substitution of E at position 1 by Y, W, F, C, I; - substitution of Y at position 2 by N, W, F, D, C; - substitution of P at position 3 by Y, F, A; - substitution of E at position 4 by Y, W, E; - substitution of S at position 5 by Y, W, H, F, D; - substitution of E at position 9 by F, W, Y, D; - substitution of H at position 10 by Y; - substitution of Q at position 12 by A, M, Y, W, R, N, L, K, H, F, E, C; - substitution of R at position 13 by Y, W, F , - substitution of V at position 14 by Y, W, M, L, I, H, F; - substitution of W at position 15 by M, Y, Q, N, L, I, H, G, F, E, D, C, A, or a corresponding non-proteinogenic amino acid such as homocysteine; and / or - substitution of R at position 16 by Y, W, Q, L, F In embodiments, said up to three optional substitutions may include a non- proteinogenic amino acid substituent for cysteine, such as β-cysteine, α-methylated cysteine, cysteic acid and homocysteine, preferably homocysteine, at position 12 and / or 15, preferably at position 15. In further preferred embodiments, said up to three optional substitutions are selected from: - substitution of E at position 1 by Y, W, F; - substitution of Y at position 2 by W, F; - substitution of Q at position 12 by Y, W, F; - substitution of V at position 14 by Y, W, L, I, F; - substitution of W at position 15 by C, or a substituent for cysteine, such as β- cysteine, α-methylated cysteine, cysteic acid and homocysteine, and / or - substitution of R at position 16 by W, F, L. In a further aspect, the invention provides a nucleic acid molecule comprising a nucleic acid sequence encoding a β-catenin-binding peptide according to the invention. In some preferred embodiments, said nucleic acid molecule encodes a β- catenin-binding peptide having a length of 7-12 amino acids and comprising an amino acid sequence ESILDEHXQRVW, wherein X is L, M, I, F, Y, W or C, or a variant of said amino acid sequence, wherein said variant has up to three substitutions of an amino acid at position 1, 2, 6, 7, 9, 10, 11 and / or 12 by another amino acid or a β-catenin-binding peptide according to claim 11 or 12. In some preferred embodiments, said nucleic acid molecule encodes a β- catenin-binding peptide having a length of 7-20 amino acids and comprising an amino acid sequence EYPESILDEHXQRVWR, wherein X is L, M, I, F, Y, W or C, or a variant of said amino acid sequence, wherein said variant comprises at least amino acids 5-11 of said sequence and optionally having up to three substitutions of an amino acid at position 1, 2, 3, 4, 5, 9, 10, 12, 13, 14, 15 and / or 16 by another amino acid. In a further aspect, the invention provides a β-catenin-binding peptide or peptidomimetic according to the invention for use as a medicament. In a further aspect, the invention provides a β-catenin-binding peptide or peptidomimetic according to the invention for use in a method of treating an individual suffering from a tumor or a metastasis thereof. In a further aspect, the invention provides a method for the treatment or prevention of a tumor, metastasis or pre-malignant condition or any other disease that is dependent on an activated Wingless / integrase1 (Wnt) signaling pathway in an individual in need thereof comprising administering to the individual a peptide or peptidomimetic or nucleic acid molecule according to the invention. In some preferred embodiments, the tumor preferably is selected from a carcinoma such as a colorectal carcinoma, esophageal adenocarcinoma, pancreatic ductal adenocarcinoma and breast carcinoma. In a further aspect, the invention provides a β-catenin-binding peptide or peptidomimetic according to the invention for use in a method of preventing a pre- malignant condition in an individual to become cancerous. In some preferred embodiments, said pre-malignant condition preferably selected from colorectal adenoma and Barrett’s esophagus. In a further aspect, the invention provides a use of the peptide or peptidomimetic according to the invention, for inhibiting Wingless / integrase-1 (Wnt)-signalling in isolated tissues or cells. Detailed description The present inventors have successfully designed a family of peptides and peptidomimetics derived from the β-catenin-binding motif of Axin that have high binding affinity. The high binding affinity was achieved by several processes including sequence maturation, (bi) cyclization and further derivatization. The design process was assisted by novel crystal structures elucidating inhibitor interactions with β-catenin. The novel peptides and peptidomimetics are characterized by a superior peptides sequence, a superior crosslink architecture and / or chemical modification that address a hydrophobic pocket on the β-catenin surface. The following substitutions resulted in increased binding affinity: E467 → Y, W, F, or C; N468 → Y, W, or F, C; P469 → Y; S471 → Y, W, or F; E475 → Y, or W; H476 → Y; V477 → Y,W, L, I, F, or C; Q478 → Y, W, R, N, F, or C; V480 → Y, W, L, I, or F; M481 → Y, W, L, I, G, F, E, or C; and R482 → W, L, or F. The following substitution did not affect binding affinity: E467 → I; N468 → D; P469 → F, or A; E470 → Y, or W; S471 → H, or D; E475 → F; V477 → M, or E; Q478 → M, L, K, H, E, or A; R479 → Y, W, or F; V480 → M, or H; M481 → Q, N, H, D, or A; and R482 → Y, S, or Q. As further demonstrated in the Examples herein, the design process of the novel peptides and peptidomimetics was started with a sequence maturation to provide a 12-mer peptide with more than 150-fold increased affinity compared to the corresponding wild-type sequence (a12). Several substitutions in the wild-type sequence were identified that have such increased affinity or even higher affinity (e.g. a12-LW). A crystal structure of the a12-LW / β-catenin complex was obtained confirming the expected binding site and guiding the subsequent crosslink design. Both an i,i+4 and i,i+3 staple, at amino acid residues 5 (N) and 9 (E) of the 16 aa wildtype sequence, respectively, after ring closing metathesis and a combination of the two staples ((i,i+4,i+7)) provided stapled peptides and a stitched peptide having further increased affinity. The introduction of different aromatic side chain substitutions replacing the C-terminal tryptophan (W12), resulted in peptides with high binding efficiency. As used herein, "to comprise" and its conjugations is used in its non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded. In addition, the verb “to consist” may be replaced by “to consist essentially of” meaning that a compound or adjunct compound as defined herein may comprise additional component(s) than the ones specifically identified, said additional component(s) not altering the unique characteristic of the invention. The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. The word “approximately” or “about” when used in association with a numerical value (e.g. approximately 10, about 10) preferably means that the value may be the given value (e.g.10), plus or minus 5% of the value (e.g. 10, plus or minus 5%), preferably plus or minus 1% of the value. The use of the alternative (e.g., "or") should be understood to mean either one, both, or any combination thereof of the alternatives. As used herein, the term “individual” refers to humans and animals, preferably mammals. Preferably, an individual is a mammal, more preferably a human. As used herein, the term “treatment” refers to inhibiting a disease or condition, i.e., halting or reducing its development or at least one clinical symptom of the disease or disorder, and / or to relieving symptoms of the disease or condition. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence. As used herein, the term “prevention” refers to precluding or delaying the onset of a disease or condition and / or the appearance of clinical symptoms of the disease or condition in a subject that does not yet experience clinical symptoms of the disease. The term "therapeutically effective amount," as used herein, refers to an amount of a compound being administered sufficient to relieve one or more of the symptoms of the disease or condition being treated to some extent. This can be a reduction or alleviation of symptoms, reduction or alleviation of causes of the disease or condition or any other desired therapeutic effect. The term “peptide” refers to a compound comprising amino acids joined via peptide bonds. The term “peptidomimetic” as used herein refers to a peptide-like molecule that has the mode-of-action of a peptide upon which it is structurally based. Such peptidomimetics include chemically modified peptides, peptide-like molecules containing non-proteinogenic amino acids, peptide-like molecules that comprise side chain to side chain crosslinks. In particular, a peptidomimetic as used herein refers to a molecule that has one or more of the modifications as defined herein, i.e. non-proteinogenic amino acids, amino acids that are crosslinked to one another and / or modified amino acids. The term “amino acid” includes both alpha-amino acids and beta-amino acids and both the D- and L-isomers of an amino acid. Amino acids in amino acid sequences or variants thereof as defined herein are denoted by single-letter symbols. These single-letter symbols and three-letter symbols are well known to the person skilled in the art and have the following meaning: A (Ala) is alanine, C (Cys) is cysteine, D (Asp) is aspartic acid, E (Glu) is glutamic acid, F (Phe) is phenylalanine, G (Gly) is glycine, H (His) is histidine, I (Ile) is isoleucine, K (Lys) is lysine, L (Leu) is leucine, M (Met) is methionine, N (Asn) is asparagine, P (Pro) is proline, Q (Gln) is glutamine, R (Arg) is arginine, S (Ser) is serine, T (Thr) is threonine, V (Val) is valine, W (Trp) is tryptophan, Y (Tyr) is tyrosine. In preferred embodiments, the single-letter symbol indicates the L-amino acid. In other embodiments, the single-letter symbol indicates the alpha-amino acid. In other embodiments, the single-letter symbol indicates the L-isomer of the alpha-amino acid. The term “homocysteine” (hC) includes reference to D-homocysteine and L- homocysteine. In some embodiments, D-cysteine is indicated as “c”, and D- homocysteine as “hc”. Examples of conservative amino acid substitutions include the following: alanine for serine, valine for isoleucine, aspartate for glutamate, threonine for serine, alanine for glycine, alanine for threonine, serine for asparagine, alanine for valine, serine for glycine, tyrosine for phenylalanine, alanine for proline, lysine for arginine, aspartate for asparagine, leucine for isoleucine, leucine for valine, alanine for glutamate, aspartate for glycine, and vice versa. Preferably, a conservative substitution is an exchange of one amino acid within a group for another amino acid within the same group, whereby the groups are the following: (1) alanine, valine, leucine, isoleucine, methionine, and phenylalanine: (2) histidine, arginine, lysine, glutamine, and asparagine; (3) aspartate and glutamate; (4) serine, threonine, alanine, tyrosine, phenylalanine, tryptophan, and cysteine; and (5) glycine, proline, and alanine. As used herein with respect to the amino acids sequence of a peptide or peptidomimetic, the terms “N- terminal” and “C-terminal” refer to relative positions in the amino acid sequence of the peptide or peptidomimetic toward the N-terminus and the C-terminus, respectively. “N- terminus” and “C-terminus” refer to the extreme amino and carboxyl ends of the peptide or peptidomimetic, respectively. A peptide “staple” refers to a crosslink that joins two amino acid residues in a peptide or peptidomimetic. The term may for instance refer to the joining of two amino acid residues comprising an olefin-containing side chain and thus to hydrocarbon crosslinks. Stapling involves the introduction of olefin-containing, α- methylated amino acids which can be crosslinked via a ring-closing metathesis (RCM), optionally including alpha methylation. Staples are typically defined by the amino acids of which the side chains are crosslinked by the indicated i,i+x, whereby x is an integer, in particular from 2-10. In this annotation, i indicates the first amino acid, i+x indicates the second amino acid which is located x positions from the first amino acid. E.g. i,i+4 indicates that the two amino acids of which the side chains are crosslinked are separated by 3 amino acids and i,i+3 indicates that the two amino acids of which the side chains are crosslinked are separated by 2 amino acids. In some embodiments, a peptide or peptidomimetic of the invention comprises non- proteinogenic amino acids, preferably two or three non- proteinogenic amino acids, that can participate in a crosslink in the peptide. In preferred embodiments, such peptide or peptidomimetic of the invention comprises, preferably two or three, non-proteinogenic amino acids that comprise an olefin- containing side chain and that can participate in a staple. An “olefin” as used herein refers to a moiety consisting of hydrogen and carbon atoms that contain one or more pairs of carbon atoms linked by a double bond. A peptide that comprises more than one staple, e.g. two, or three, etc. staples, is also referred to as stitched peptide. Staple formation can be achieved by an olefin metathesis or ring closing metathesis (RCM), optionally including alpha methylation, e.g. as described in Kim et al. (2011), which is incorporated herein by reference. In some embodiments, a peptide or peptidomimetic of the invention has a length of 7-12 amino acids, meaning that the peptide or peptidomimetic does not comprise more than 12 amino acids. Similarly, a peptide or peptidomimetic of the invention having a length of 11 amino acids does not comprise more than 11 amino acids, a peptide or peptidomimetic of the invention having a length of 7 or 8 amino acids does not comprise more than 8 amino acids, and a peptide or peptidomimetic of the invention having a length of 7 amino acids does not comprise more than 7 amino acids. In some embodiments, a peptide or peptidomimetic of the invention has a length of 7-20 amino acids, meaning that the peptide or peptidomimetic does not comprise more than 20 amino acids. In some embodiments, a peptide or peptidomimetic of the invention has a length of 7-16 or 8-16 amino acids, meaning that the peptide or peptidomimetic does not comprise more than 16 amino acids. However, a peptide or peptidomimetic of the invention may comprise one or more modifications and / or moieties in addition to the indicated number of amino acids. In particular, a peptide or peptidomimetic of the invention may comprise modifications, in particular N-terminal, C-terminal modifications and / or internal modifications, such as staples, chemical modifications of amino acid side chains, C- terminal amidation, N-terminal acylation, fatty acid modifications, esterification and combinations thereof, e.g. as defined herein below in more detail. A peptide or peptidomimetic according to the invention comprising one or more modifications and / or moieties in addition to the indicated number of amino acids is herein also referred to as a peptidomimetic. As used herein, a nucleic acid molecule or nucleic acid sequence of the invention comprises a chain of nucleotides of any length, preferably DNA and / or RNA. In some embodiments a nucleic acid molecule or nucleic acid sequence of the invention comprises other kinds of nucleic acid structures such as for instance a DNA / RNA helix, peptide nucleic acid (PNA), locked nucleic acid (LNA) and / or a ribozyme. Hence, the term “nucleic acid sequence” also encompasses a chain comprising non-proteinogenic nucleotides, modified nucleotides and / or non- nucleotide building blocks which exhibit the same function as natural nucleotides. The term nucleic acid molecule includes recombinant and synthetic nucleic acid molecules. In a preferred embodiment of the present invention the at least one nucleic acid molecule is selected from the group consisting of DNA, mRNA, cDNA, DNA aptameres, and viral and non-viral vectors. A peptide or peptidomimetic of the invention is a β-catenin-binding peptide or peptidomimetic. “β-catenin-binding” as used herein refers to the ability of a peptide or peptidomimetic of the invention to specifically bind to β-catenin. In particular, the peptides and peptidomimetics of the invention bind to the armadillo repeat domain of β-catenin. The term “specifically bind” as used herein refer to the interaction between a peptide or peptidomimetic of the invention and its target. The term means that said peptide or peptidomimetic preferentially binds to said target over binding to other proteins, (poly)peptides, amino acid sequences or parts or domains thereof. Although the peptide or peptidomimetic may non-specifically bind to other proteins, (poly)peptides, amino acid sequences or parts or domains thereof, the binding affinity of said peptide or peptidomimetic for its target is significantly higher than the non-specific binding affinity of said peptide or peptidomimetic for other proteins, (poly)peptides, amino acid sequences or parts or domains thereof. Whether or not a peptide or peptidomimetic binds to β-catenin can be determined using any method know in the art. For instance, binding affinity can be determined. “Binding affinity” refers to the strength of the total sum of the noncovalent interactions between a peptide or peptidomimetic and its binding partner, i.e. β-catenin. The affinity can generally be represented by the equilibrium dissociation constant (KD). An example of a method for determining binding of a peptide or peptidomimetic to β-catenin is detailed in the Examples herein. Such method described in the Examples uses µSPOT peptide arrays in which peptides are synthesized and a microarray binding assay for determining binding affinity. The latter assay involves incubation of the peptides with GST-β-catenin, followed by washing and labelling of the GST-β-catenin with 2.5 mL of an HRP-conjugated anti-GST antibody. Peptide binding was detected chemiluminescently and binding intensities were evaluated using FIJI including the Microarray Profile addon (OptiNav) as described in more detail in the Examples herein. In a first aspect, the invention provides a β-catenin-binding peptide or peptidomimetic having a length of 7-12 amino acids and comprising an amino acid sequence ESILDEHXQRVW, wherein X is L, M, I, F, Y, W or C, or a variant of said amino acid sequence, wherein said variant comprises at least amino acids 2-8 of said sequence and optionally having: - up to three substitutions of an amino acid at position 1, 2, 6, 7, 9, 10, 11 and / or 12 by another amino acid, - S at position 2 and E at position 6 each substituted by a non-proteinogenic amino acid which non- proteinogenic amino acids are crosslinked to one another and / or E at position 6 and Q at position 9 each substituted by a non-proteinogenic amino acid which non-proteinogenic amino acids are crosslinked to one another, and - X at position 8, Q at position 9, R at position 10, V at position 11 and W at position 12 substituted by a modified amino acid. In some preferred embodiments, X is L, I, F, Y, or W. In some preferred embodiments, X is L, I, F, or W. In some preferred embodiments, X is L. In some preferred embodiments, X is I. In some preferred embodiments, X is F. In some preferred embodiments, X is W In some preferred embodiments, X is C, including c. A variant of the amino acid sequence ESILDEHXQRVW, wherein X is L, M, I, F, Y, W or C, preferably L, I, F, Y, or W, more preferably L, comprises at least amino acids 2-8 of said sequence, optionally with one or more substitutions and / or modifications as defined herein. I.e. a variant of said sequence comprises at least the sequence SILDEHX, wherein X is as defined herein, optionally with one or more substitutions and / or modifications as defined herein. This means that the optional substitutions and / or modifications may occur at amino acids 2-8, in particular at positions 2, 6, 7 and 8, as defined herein. In some preferred embodiments, a variant of said sequence comprises at least amino acids 2-9 of said sequence, i.e. the sequence SILDEHXQ, wherein X is as defined herein, optionally with one or more substitutions and / or modifications as defined herein. This means that the optional substitutions and / or modifications may occur at amino acids 2-9, in particular at positions 2, 6, 7, 8 and 9, as defined herein. In other preferred embodiments, a variant of said sequence comprises at least amino acids 2-10 of said sequence, i.e. the sequence SILDEHXQR, wherein X is as defined herein, optionally with one or more substitutions and / or modifications as defined herein. This means that the optional substitutions and / or modifications may occur at amino acids 2-10, in particular at positions 2, 6, 7, 8, 9 and 10, as defined herein. In other preferred embodiments, a variant of said sequence comprises at least amino acids 2-11 of said sequence, i.e. the sequence SILDEHXQRV, wherein X is as defined herein, optionally with one or more substitutions and / or modifications as defined herein. This means that the optional substitutions and / or modifications may occur at amino acids 2-11, in particular at positions 2, 6, 7, 8, 9, 10 and 11, as defined herein. In other preferred embodiments, a variant of said sequence comprises at least amino acids 2-12 of said sequence, i.e. the sequence SILDEHXQRVW, wherein X is as defined herein, optionally with one or more substitutions and / or modifications as defined herein. This means that the optional substitutions and / or modifications may occur at amino acids 2-12, in particular at positions 2, 6, 7, 8, 9, 10, 11 and 12, as defined herein. A variant of the sequence ESILDEHXQRVW, wherein X is L, M, I, F, Y, W or C, preferably L, I, F, Y, or W, more preferably L, further has up to three substitutions of an amino acid by another amino acid. Said up to three substitutions are selected from amino acids at position 1, 2, 6, 7, 9, 10, 11 and / or 12. Preferably a variant has up to two substitutions of an amino acid at position 1, 2, 6, 7, 9, 10, 11 and / or 12 by another amino acid. More preferably, a variant has optionally one substitution of an amino acid at position 1, 2, 6, 7, 9, 10, 11 or 12 by another amino acid. In some embodiments, the variant does not comprise such substitution of an amino acid by another amino acid. In a preferred embodiment, the up to three substitutions, preferably up to two substitutions, more preferably up to one substitution, are selected from the group consisting of: - substitution of E at position 1 by Y, W, F or a corresponding non-proteinogenic amino acid; - substitution of S at position 2 by Y, W, H, F, D or a corresponding non- proteinogenic amino acid; - substitution of E at position 6 by F, W, Y, D or a corresponding non-proteinogenic amino acid; - substitution of H at position 7 by Y or a corresponding non-proteinogenic amino acid; - substitution of Q at position 9 by A, M, Y, W, R, N, L, K, H, F, E, C or a corresponding non-proteinogenic amino acid; - substitution of R at position 10 by Y, W, F or a corresponding non-proteinogenic amino acid; - substitution of V at position 11 by Y, W, M, L, I, H, F or a corresponding non- proteinogenic amino acid; and / or - substitution of W at position 12 by M, Y, Q, N, L, I, H, G, F, E, D, C, A or a corresponding non-proteinogenic amino acid. As demonstrated in the Examples herein, see in particular figure 1, the indicated substitutions result in peptides that have least the binding affinity of the peptide without such substitution. In a preferred embodiment, the up to three substitutions, preferably up to two substitutions, more preferably up to one substitution, are selected from the group consisting of: - substitution of E at position 1 by Y, W, F; - substitution of S at position 2 by Y, W, H, F, D; - substitution of E at position 6 by F, W, Y, D; - substitution of H at position 7 by Y; - substitution of Q at position 9 by A, M, Y, W, R, N, L, K, H, F, E, C; - substitution of R at position 10 by Y, W, F; - substitution of V at position 11 by Y, W, M, L, I, H, F; and / or - substitution of W at position 12 by M, Y, Q, N, L, I, H, G, F, E, D, C, A. In further preferred embodiments, the up to three substitutions, preferably up to two substitutions, more preferably up to one substitution, are selected from the group consisting of: - substitution of H at position 7 by Y or a corresponding non-proteinogenic amino acid; - substitution of V at position 11 by Y, W, L, I, F or a corresponding non- proteinogenic amino acid; and / or - substitution of W at position 12 by Y, L, F or a corresponding non-proteinogenic amino acid. In further preferred embodiments, the up to three substitutions, preferably up to two substitutions, more preferably up to one substitution, are selected from the group consisting of: - substitution of V at position 11 by Y, W, L, I, F or a corresponding non- proteinogenic amino acid; and / or - substitution of W at position 12 by Y, L, F or a corresponding non-proteinogenic amino acid. As demonstrated in the Examples herein, see in particular figure 1, the indicated substitutions result in peptides that have a higher binding affinity than the peptide without such substitution. In further preferred embodiments, the up to three substitutions, preferably up to two substitutions, more preferably up to one substitution, are selected from the group consisting of: - substitution of H at position 7 by Y; - substitution of V at position 11 by Y, W, L, I, F; and / or - substitution of W at position 12 by Y, L, F. In further preferred embodiments, the up to three substitutions, preferably up to two substitutions, more preferably up to one substitution, are selected from the group consisting of: - substitution of V at position 11 by Y, W, L, I, F; and / or - substitution of W at position 12 by Y, L, F. In some preferred embodiments, a variant of the sequence ESILDEHXQRVW, wherein X is L, M, I, F, Y, W or C, preferably L, I, F, Y, C, or W, more preferably C or L, has W at position 12. In some preferred embodiments, the peptide or peptidomimetic comprises L at position 8 and W at position 12. In some preferred embodiments, E at position 1 is Y, W, F or a corresponding non-proteinogenic amino acid, preferably Y, W or a corresponding non- proteinogenic amino acid. In some preferred embodiments, S at position 2 is Y, W, H, F, D or a corresponding non-proteinogenic amino acid, preferably Y, W, F or a corresponding non-proteinogenic amino acid. In some preferred embodiments, E at position 6 is F, W, Y, D or a corresponding non-proteinogenic amino acid, preferably Y, W or a corresponding non-proteinogenic amino acid. In some preferred embodiments, H at position 7 is Y or a corresponding non- proteinogenic amino acid, preferably Y, or a corresponding non-proteinogenic amino acid. In some preferred embodiments, Q at position 9 is A, M, Y, W, R, N, L, K, H, F, E, C or a corresponding non-proteinogenic amino acid, preferably Y, W, R, N, F, C or a corresponding non-proteinogenic amino acid. In some preferred embodiments, R at position 10 is Y, W, F or a corresponding non-proteinogenic amino acid. In some preferred embodiments, V at position 11 is Y, W, M, L, I, H, F or a corresponding non-proteinogenic amino acid, preferably Y, W, L, I, F or a corresponding non-proteinogenic amino acid. In some preferred embodiments, W at position 12 is M, Y, Q, N, L, I, H, G, F, E, D, C, A or a corresponding non-proteinogenic amino acid, preferably Y, L, I, G, F, E, C or a corresponding non-proteinogenic amino acid. In preferred embodiments, a peptide or peptidomimetic according to the invention comprising the sequence ESILDEHXQRVW, wherein X is as defined herein, or a variant of said sequence as defined herein, has a length of 10-12 amino acids. In some preferred embodiments, such peptide or peptidomimetic according to the invention has a length of 7-11 amino acids. In some preferred embodiments, such peptide or peptidomimetic according to the invention has a length 11 or 12 amino acids. In some preferred embodiments, such peptide or peptidomimetic according to the invention has a length 11 amino acids. In some preferred embodiments, such peptide or peptidomimetic according to the invention has a length 12 amino acids. A variant of amino acid sequence ESILDEHXQRVW as defined herein comprised in a peptide or peptidomimetic according to the invention can be part of a larger peptide or peptidomimetic, i.e. of a peptide or peptidomimetic that has been N terminally and / or C-terminally extended by a one or more additional amino acids. For instance, the amino acid sequence can be extended to include an additional C-terminal amino acid, optionally a C-terminal amino acid comprising a modified side chain as described herein below, in particular an amino acid comprising a side chain comprising an aromatic moiety as defined herein. In some preferred embodiments, a peptide or peptidomimetic of the invention comprises no, one or two amino acids in addition to the variant of amino acid sequence ESILDEHXQRVW, wherein X is L, M, I, F, Y, W or C, preferably L, I, F, Y, C, or W, more preferably C or L, in particular if the variant comprises less than 12 amino acids, such as a variant comprising amino acids SILDEHL. More preferably, a peptide or peptidomimetic of the invention comprises no or one N-terminal or C- terminal amino acid in addition to the variant sequence ESILDEHXQRVW, wherein X is L, M, I, F, Y, W or C, preferably L, I, F, Y, C, or W, more preferably C or L, and wherein the variant comprises less than 12 amino acids, such as a variant comprising amino acids SILDEHL, preferably no or one additional C- terminal amino acid. A used herein “non-proteinogenic amino acid” refers to any amino acids other than the proteinogenic amino acids that are naturally encoded in the genome of organisms. Such amino acids are therefore also referred to as non-coded amino acids. Non-proteinogenic amino acids include natural non-proteinogenic amino acids and non-natural amino acids. As used herein, a “corresponding non- proteinogenic amino acid” refers to a non-proteinogenic amino acid that is a derivative of the reference natural amino acid. Examples of corresponding non- proteinogenic amino acids include the corresponding β-amino acid and the corresponding α-methylated amino acid for each of the 20 natural amino acids. β- amino acids have their amino group bonded to the β carbon rather than the α carbon as in the natural amino acids. For instance, α-alanine is substituted by β- alanine, etc. An α-methylated amino acid carries a methyl group at the α carbon of the natural amino acid. For instance, α-methylated alanine is a corresponding α- methylated amino acid of alanine. Preferred corresponding non-proteinogenicamino acids are α-methylated amino acids. Other preferred examples ofcorresponding non-proteinogenic amino acids include other derivatives of the natural amino acid by a non-proteinogenic amino acid that is a derivative of said natural amino acid are the following. A preferred corresponding non-proteinogenic amino acid substituent for alanine is selected from the group consisting of beta- alanine, α-methylated alanine, t-butylalanine, 2-napthylalanine; L-3-(2- naphthyl)alanine and 2-aminoisobutyric acid. A preferred corresponding non- proteinogenic amino acid substituent for arginine is selected from the group consisting of β-arginine, α-methylated arginine, homoarginine, ornithine, N5- carbamoylornithine and 3-amino-propionic acid. A preferred corresponding non- proteinogenic amino acid substituent for asparagine is β-asparagine, α-methylated asparagine, or N-ethylasparagine. A preferred corresponding non-proteinogenic amino acid substituent for aspartic acid is β-aspartic acid, α-methylated aspartic acid or 4-tert-butyl hydrogen 2-azidosuccinate. A preferred corresponding non- proteinogenic amino acid substituent for cysteine is selected from the group consisting of β-cysteine, α-methylated cysteine, cysteic acid and homocysteine. A preferred corresponding non-proteinogenic amino acid substituent for glutamic acid is selected from the group consisting of β-glutamic acid, α-methylated glutamic acid, γ-carboxy-D / L-glutamic acid and 4-fluoro-D / L-glutamic acid. A preferred corresponding non-proteinogenic amino acid substituent for glutamine is selected from the group consisting of β-glutamine, α-methylated glutamine, D-citrulline and thio-L-citrulline. A preferred corresponding non-proteinogenic amino acid substituent for glycine is selected from the group consisting of β-glycine, α- methylated glycine, N-methylglycine, t-butylglycine, N-methylglycine and D- allylglycine. A preferred corresponding non-proteinogenic amino acid substituent for histidine is β-histidine, α-methylated histidine or 3-(3-methyl-4-nitrobenzyl)-L- histidine methyl ester. A preferred corresponding non-proteinogenic amino acid substituent for isoleucine is selected from the group consisting of β-isoleucine, α- methylated isoleucine, isodesmosine, N-methylisoleucine and allo-isoleucine. A preferred corresponding non-proteinogenic amino acid substituent for leucine is selected from the group consisting of β-leucine, α-methylated leucine, norleucine, desmosine and 5,5,5-trifluoro-leucine. A preferred corresponding non-proteinogenic amino acid substituent for lysine is selected from the group consisting of β-lysine, α-methylated lysine, 6-N-methyllysine, 2-aminoheptanoic acid, N-acetyl lysine, hydroxylysine and allo-hydroxylysine. A preferred corresponding non-proteinogenic amino acid substituent for methionine is β-methionine, α-methylated methionine, or methionine sulfoxide. A preferred corresponding non-proteinogenic amino acid substituent for phenylalanine is selected from the group consisting of β- phenylalanine, α-methylated phenylalanine, p-amino-L-phenylalanine, 3- benzothienyl alanine p-bromophenylalanine, p-acyl-L-phenylalanine, 2- fluorophenylalanine, 3- fluorophenylalanine and 4-fluorophenylalanine. A preferred corresponding non-proteinogenic amino acid substituent for proline is selected from the group consisting of β-proline, α-methylated proline, 3- hydroxyproline, 4-hydroxyproline and 1-acetyl-4-hydroxy-L-proline. A preferred corresponding non-proteinogenic amino acid substituent for serine is selected from the group consisting of β-serine, α-methylated serine, homoserine, isoserine and 3- phenylserine. A preferred corresponding non-proteinogenic amino acid substituent for threonine is selected from the group consisting of β-threonine, α-methylated threonine, D-thyroxine and allo-threonine. A preferred corresponding non- proteinogenic amino acid substituent for tryptophan is selected from the group consisting of β-tryptophane, α-methylated tryptophane, 5-hydroxy-tryptophan, 5- methoxy-tryptophan and 5-fluoro-tryptophan. A preferred corresponding non- proteinogenic amino acid substituent for tyrosine is selected from the group consisting of β-tyrosine, α-methylated tyrosine, O-methyl-L-tyrosine, O-4-allyl-L- tyrosine and 3-chloro-tyrosine. A preferred corresponding non-proteinogenic amino acid substituent for valine is selected from the group consisting of β-valine, α- methylated valine, norvaline, N-methylvaline and 3-fluoro-valine. As used herein “corresponding non-proteinogenic amino acid” refers to a non- proteinogenic amino acid corresponding to the original amino acid at the relevant position or corresponding to an amino acid that can be substituted at the relevant position. For instance, in the indication that E at position 1 can be substituted by Y, W or a corresponding non-proteinogenic amino acid, the corresponding non- proteinogenic amino acid is a non-proteinogenic amino acid corresponding to E, Y, or W. In some preferred embodiments, the non-proteinogenic amino acid corresponds to the original amino acid at said position. I.e. in preferred embodiments said up to three, preferably up to two, more preferably one, optional substitutions of an amino acid by another amino acid in a variant of amino acid sequence ESILDEHXQRVW, wherein X is as defined herein, are selected from: - substitution of E at position 1 by Y, W, F or a non-proteinogenic amino acid corresponding to E; - substitution of S at position 2 by Y, W, H, F, D or a non-proteinogenic amino acid corresponding to S; - substitution of E at position 6 by F, W, Y, D or a non-proteinogenic amino acid corresponding to E; - substitution of H at position 7 by Y or a non-proteinogenic amino acid corresponding to H; - substitution of Q at position 9 by A, M, Y, W, R, N, L, K, H, F, E, C or a non- proteinogenic amino acid corresponding to Q; - substitution of R at position 10 by Y, W, F or a non-proteinogenic amino acid corresponding to R; - substitution of V at position 11 by Y, W, M, L, I, H, F or a non-proteinogenic amino acid corresponding to V; and / or - substitution of W at position 12 by M, Y, Q, N, L, I, H, G, F, E, D, C, A or a non- proteinogenic amino acid corresponding to W. In some embodiments a peptide or peptidomimetic of the invention comprises one or more side chain to side chain crosslinks, preferably one or two side chain to side chain crosslinks. In some embodiments, such crosslink is preferably formed between the side chains of the amino acids at positions 2 and 6 of the sequence ESILDEHXQRVW, wherein X is L, M, I, F, Y, W or C, preferably L, I, F, Y, or W, more preferably L, or a variant as defined herein, between the side chains of the amino acids at positions 6 and 9 of said sequence or a variant as defined herein, or both. Hence, in some preferred embodiments, crosslinks are formed between the side chains of the amino acids at positions 2 and 6 of the sequence ESILDEHXQRVW, wherein X is L, M, I, F, Y, W or C, preferably L, I, F, Y, C, or W, more preferably C or L, or a variant as defined herein, and between the side chains of the amino acids at positions 6 and 9 of said sequence or a variant as defined herein. Hence, in some preferred embodiments the amino acids at these positions are each substituted by a proteinogenic- or non-proteinogenic amino acid which non- proteinogenic amino acids contain side chains that allow crosslinking thereof. In some embodiments, S at position 5 and E at position 9 are each substituted by a non-proteinogenic amino acid which non-proteinogenic amino acids are crosslinked to one another and / or E at position 9 and Q at position 12 are each substituted by a non-proteinogenic amino acid which non-proteinogenic amino acids are crosslinked to one another. The one or more crosslinks present in a peptide or peptidomimetic of the invention can be any crosslink that can be introduced between the side chains of two amino acids. In preferred embodiments, such crosslink is selected from the group consisting of a hydrocarbon crosslink, a lactam crosslink, a disulfide crosslink, a thioether crosslink, a triazole crosslink and a carbamate crosslink. If two or more crosslinks between the side chains of two non-proteinogenic amino acids are present in a peptide or peptidomimetic of the invention, each of said crosslinks is independently selected from the group consisting of a hydrocarbon crosslink, a lactam crosslink, a disulfide crosslink, a thioether crosslink, a triazole crosslink and a carbamate crosslink. The term "independently selected" means that if there is more than one crosslink, these crosslinks may be the same or different from each other. In preferred embodiments, if two or more crosslinks are present, the crosslinks are the same type of crosslink, preferably the crosslinks are hydrocarbon crosslinks. In preferred embodiments, the crosslinks result from crosslinking of olefin-containing side chains in both amino acids. The non-proteinogenic amino acids of which the side chains are or can be crosslinked can be any amino acid that allows such crosslinking. In some preferred embodiments said amino acid residues comprise olefin-containing side chains. In further preferred embodiments, said amino acids are α-methylated amino acids comprising an olefin-containing side chain. Such olefin-containing side chains can be crosslinked via a ring-closing metathesis (RCM). In preferred embodiments, a peptide or peptidomimetic of the invention comprises, preferably two or three, non- proteinogenic amino acids that comprise an olefin-containing side chain and that can participate in a staple. In preferred embodiments, such olefin comprises between two and ten carbon atoms, i.e. two to ten carbon atoms in the side chain. More preferably, such olefin comprises between 3 and 6 carbon atoms, more preferably 4 or 5 carbon atoms. In further preferred embodiments, such olefin comprises one carbon-carbon double bond. In some preferred embodiments, the amino acids are selected from the following amino acids: Amino acids 5R, and 5S are amino acids that participate in one crosslink. Amino acid 5B can be used as an amino acid that participates in two crosslinks. In preferred embodiments, the non-proteinogenic amino acids are selected from R5, S5 and / or B5. In preferred embodiments, the crosslinks are i,i+4 and / or i,i+3 crosslinks, in particular staples, and the non-proteinogenic amino acids are selected from R5, S5 and / or B5. The resulting crosslink are then two amino acids S5 and amino acid B5. Examples of crosslinks lactam, carbamate, thioether, triazole and disulfide crosslinks are shown in Figure 14. In some embodiments, in particular in a peptide or peptidomimetic of the invention having a length of 7-20 amino acids and comprising an amino acid sequence EYPESILDEHXQRVWR, wherein X is L, M, I, F, Y, W or C, preferably L, I, F, Y, or W, more preferably L, or a variant of said amino acid sequence as defined herein, crosslinks are preferably formed between the side chains of the amino acids at positions 5 and 9 of the sequence EYPESILDEHXQRVWR, wherein X is L, M, I, F, Y, W or C, preferably L, I, F, Y, or W, more preferably L, or a variant as defined herein, between the side chains of the amino acids at positions 9 and 12 of said sequence or a variant as defined herein, or a combination thereof. The type of crosslink, amino acids side chains that participate in a crosslink and the non- proteinogenic amino acid of which the side chains participate in a crosslink are as defined herein above. As described in the Examples herein, the present inventors have identified a previously unknown hydrophobic binding pocket at the surface of β-catenin. Without being bound to theory, it is hypothesized that the side chain of the modified amino acids fits into hydrophobic binding pockets. Therefore, in some embodiments a peptide or peptidomimetic of the invention comprises a modified amino acid at or close to the C-terminus of the peptide or peptidomimetic. In preferred embodiments, one of the 5 most C-terminal amino acids is substituted by a modified amino acid, with the provision that any amino acids that participate in a staple are not substituted by such modified amino acid. As an example, in a peptide or peptidomimetic having the sequence ESILDEHXQRVW, X at position 8, Q at position 9, R at position 10, V at position 11 or M at position 12 may be substituted by a modified amino acid. As another example in a peptide or peptidomimetic having the sequence S5*ILD B5*#HL S5#, wherein * indicates that the side chains of the indicated amino acids 5S and 5B are crosslinked#indicates that the side chains of the indicated amino acids 5B and 5S are crosslinked, H at position 6, and / or L at position 7 are substituted by a modified amino acid. In some preferred embodiments, the modified amino acid is a modified cysteine residue. In embodiments, a modified cysteine residue is present at position 8 of the sequence ESILDEHXQRVW. In some preferred embodiments, the modified amino acid is a modified D-cysteine residue, such as a modified D-cysteine residue. In preferred embodiments, the modified amino acid is a modified homocysteine residue. The modified amino acid is preferably an amino acid with a side chain comprising an aromatic moiety. As used herein, the term “aromatic moiety” refers to moieties comprising at least one stable unsaturated ring of atoms. The aromatic moiety can comprise one or more aryl groups or a heteroaromatic moiety, preferably comprises one or more substituted or unsubstituted aryl groups, preferably one or two substituted or unsubstituted aryl groups. As used herein the term “aryl” refers to a mono- or polyaromatic moiety of which all the ring atoms are carbon. In preferred embodiments, the aromatic moiety, preferably comprising one or two aryls, consists of 3-20 atoms, more preferably 6 to 18 atoms, more preferably 6- 13 atoms. The optional substituents of the one or more aryl groups are preferably selected from the group consisting of C1-4 alkyl optionally substituted by one or more halogens, NH2, NMeH, NMe2, OH, more preferably ethyl, methyl, isopropyl or trifluoromethyl, more preferably methyl, isopropyl or trifluoromethyl. In further preferred embodiments, an aryl group contains one optional substituent. In further preferred embodiments, the aromatic moiety comprises a benzene derivative. In further preferred embodiments, the aromatic moiety comprises one, two or three phenylene moieties optionally substituted with one substituent as defined herein, a naphthalene or an antracene. Preferred modified amino acids comprising a side chain comprising an aromatic moiety are the following: R can also be absent. Hence, in preferred embodiments, the aromatic moiety is selected is selected from the group consisting of: , wherein R is absent of F, Cl, OH, CF3, NH2, NMe2, NMeH, methyl, ethyl, iso-propyl or butyl. In further preferred embodiments, R is absent, CF3, methyl, ethyl, iso-propyl or butyl, more preferably R is absent, CF3, methyl, ethyl, or iso-propyl.In some preferred embodiments, the aromatic moiety is selected from , wherein R is absent of F,Cl, OH, CF3, NH2, NMe2, NMeH, methyl, ethyl, iso-propyl or butyl, preferably R isabsent, CF3, methyl, ethyl, iso-propyl or butyl, more preferably R is absent, CF3,methyl, ethyl, or iso-propyl. In some preferred embodiments, the aromatic moiety is selected from , wherein R is absent of F, Cl, OH, CF3, NH2,NMe2, NMeH, methyl, ethyl, iso-propyl or butyl, preferably R is absent, CF3,methyl, ethyl, iso-propyl or butyl, more preferably R is absent, CF3, methyl, ethyl,or iso-propyl. In some preferred embodiments, the aromatic moiety is selected from one of the modifications indicated in figure 10: . In some preferred embodiments, the aromatic moiety is selected from , wherein R is absent of F, Cl, OH, CF3, NH2, NMe2, NMeH,methyl, ethyl, iso-propyl or butyl, preferably R is absent, CF3, methyl, ethyl, iso-propyl or butyl, more preferably R is absent, CF3, methyl, ethyl, or iso-propyl, morepreferably absent, methyl or CF3. In some preferred embodiments, the aromatic moiety is selected from benzyl, naphthyl, naphthylmethyl, para-bromobenzyl, meta-methylbenzyl and meta- (trifluoromehtly)benzyl. In a second aspect, the invention provides a β-catenin-binding peptide or peptidomimetic having a length of 7-20 amino acids and comprising an amino acid sequence EYPESILDEHXQRVWR , wherein X is L, M, I, F, Y, W or C, or a variant of said amino acid sequence, wherein said variant comprises at least amino acids 5- 11 of said sequence and optionally having up to three substitutions of an amino acid at position 1, 2, 3, 4, 5, 9, 10, 12, 13, 14, 15 and / or 16 by another amino acid. In some preferred embodiments, X is L, I, F, Y, C, or W. In some preferred embodiments, X is L, I, F, C, or W. In some preferred embodiments, X is L. In some preferred embodiments, X is I. In some preferred embodiments, X is F. In some preferred embodiments, X is W. In some preferred embodiments, X is C. A variant of the amino acid sequence EYPESILDEHXQRVWR, wherein X is L, M, I, F, Y, W or C, preferably L, I, F, Y, C, or W, more preferably C or L, comprises at least amino acids 5-11 of said sequence, optionally with one or more substitutions as defined herein. I.e. a variant of said sequence comprises at least the sequence SILDEHX, optionally with one or more substitutions as defined herein. This means that the optional substitutions as defined herein may occur at amino acids 5-11, in particular at positions 5, 9 and 10 of the sequence EYPESILDEHXQRVWR, wherein X is L, M, I, F, Y, W or C, preferably L, I, F, Y, C, or W, more preferably L. In some preferred embodiments, a variant of said sequence comprises at least amino acids 2-9 of said sequence, i.e. the sequence SILDEHXQ, optionally with one or more substitutions as defined herein. This means that the optional substitutions may occur at amino acids 2-9, in particular at positions 2, 6, 7, 8 and 9, as defined herein. In preferred embodiments, such peptide or peptidomimetic comprises 7-16 amino acids, more preferably 10-16 amino acids, more preferably of 13-16 amino acids, more preferably of 15 or 16 amino acids. A variant of amino acid sequence EYPESILDEHXQRVWR as defined herein comprised in a peptide or peptidomimetic can, however, be part of a larger peptide or peptidomimetic, i.e. of a peptide or peptidomimetic that has been N terminally and / or C-terminally extended by a one or more additional amino acids. For instance, the amino acid sequence can be extended to include an additional C- terminal amino acid comprising a modified side chain as described herein below. In some preferred embodiments, a peptide or peptidomimetic of the invention comprises no, one or two N- or C-terminal amino acids in addition to the variant of amino acid sequence EYPESILDEHXQRVWR as defined herein, in particular if the variant comprises less than 16 amino acids. More preferably, a peptide or peptidomimetic of the invention comprises one amino acid in addition to a variant of the amino acid sequence EYPESILDEHXQRVWR as defined herein, and wherein the variant comprises less than 16 amino acids. preferably no or one additional N- or C-terminal amino acids. In some preferred embodiments, a variant of the amino acid sequence EYPESILDEHXQRVWR, wherein X is L, M, I, F, Y, W or C, preferably L, I, F, Y, C, or W, more preferably C or L, comprises at least amino acids 4-16 of said sequence, i.e. the sequence ESILDEHXQRVWR, optionally with one or more substitutions as defined herein. This means that the optional substitutions may occur at amino acids 4-16, in particular at positions 4, 5, 9, 10, 12, 13, 14, 15 and / or 16, as defined herein. In other preferred embodiments, a variant of the amino acid sequence EYPESILDEHXQRVWR, wherein X is L, M, I, F, Y, W or C, preferably L, I, F, Y, C, or W, more preferably C or L, comprises at least amino acids 3-16 of said sequence, i.e. the sequence PESILDEHXQRVWR, optionally with one or more substitutions as defined herein. This means that the optional substitutions may occur at amino acids 3-16, in particular at positions 3, 4, 5, 9, 10, 12, 13, 14, 15 and / or 16, as defined herein. In other preferred embodiments, a variant of the amino acid sequence EYPESILDEHXQRVWR, wherein X is L, M, I, F, Y, W or C, preferably L, I, F, Y, C, or W, more preferably C or L, comprises at least amino acids 2-16 of said sequence, i.e. the sequence NPESILDEHXQRVWR, optionally with one or more substitutions as defined herein. This means that the optional substitutions and / or modifications may occur at amino acids 2-16, in particular at positions 2, 3, 4, 5, 9, 10, 12, 13, 14, 15 and / or 16, as defined herein. In other preferred embodiments, a variant of the amino acid sequence EYPESILDEHXQRVWR, wherein X is L, M, I, F, Y, W or C, preferably L, I, F, Y, C, or W, more preferably C or L, comprises at least amino acids 2-15 of said sequence, i.e. the sequence NPESILDEHXQRVW, optionally with one or more substitutions as defined herein. This means that the optional substitutions and / or modifications may occur at amino acids 2-15, in particular at positions 2, 3, 4, 5, 9, 10, 12, 13, and / or 14, as defined herein. In other preferred embodiments, a variant of the amino acid sequence EYPESILDEHXQRVWR, wherein X is L, M, I, F, Y, W or C, preferably L, I, F, Y, C, or W, more preferably C or L, comprises the sequence NPESILDEHXQRVW, optionally with one or more substitutions as defined herein. This means that the optional substitutions and / or modifications may occur at amino acids 2-15, in particular at positions 1, 2, 3, 4, 5, 9, 10, 12, 13, 14, 15 and / or 16, as defined herein. A variant of the amino acid sequence EYPESILDEHXQRVWR, wherein X is L, M, I, F, Y, W or C, preferably L, I, F, Y, C, or W, more preferably C or L, further has up to three substitutions of an amino acid by another amino acid. Said up to three substitutions are selected from amino acids at position 1, 2, 3, 4, 5, 9, 10, 12, 13, 14, 15 and / or 16. Preferably a variant has up to two substitutions of an amino acid at position 1, 2, 3, 4, 5, 9, 10, 12, 13, 14, 15 and / or 16 by another amino acid. More preferably, a variant has optionally one substitution of an amino acid at position 1, 2, 3, 4, 5, 9, 10, 12, 13, 14, 15 and / or 16 by another amino acid. In a preferred embodiment, the up to three substitutions, preferably up to two substitutions, more preferably up to one substitution, are selected from the group consisting of: - substitution of E at position 1 by Y, W, F, C, I; - substitution of Y at position 2 by N, W, F, D, C; - substitution of P at position 3 by Y, F, A; - substitution of E at position 4 by Y, W, E; - substitution of S at position 5 by Y, W, H, F, D; - substitution of E at position 9 by F, W, Y, D; - substitution of H at position 10 by Y; - substitution of Q at position 12 by A, M, Y, W, R, N, L, K, H, F, E, C; - substitution of R at position 13 by Y, W, F, - substitution of V at position 14 by Y, W, M, L, I, H, F; - substitution of W at position 15 by M, Y, Q, N, L, I, H, G, F, E, D, C, A, or a corresponding non-proteinogenic amino acid such as homocysteine; and / or - substitution of R at position 16 by Y, W, Q, L, F. As demonstrated in the Examples herein, see in particular figure 1, the indicated substitutions result in peptides that have least the binding affinity of the peptide without such substitution. In further preferred embodiments, the up to three substitutions, preferably up to two substitutions, more preferably up to one substitution, are selected from the group consisting of: - substitution of E at position 1 by Y, W, F; - substitution of Y at position 2 by W, F; - substitution of Q at position 12 by Y, W, F; - substitution of V at position 14 by Y, W, L, I, F; - substitution of W at position 15 by Y, L, C, F, or a corresponding non- proteinogenic amino acid such as homocysteine; and / or - substitution of R at position 16 by W, F, L In further preferred embodiments, the up to three substitutions, preferably up to two substitutions, more preferably up to one substitution, are selected from the group consisting of: - substitution of Y at position 2 by N, F or a corresponding non-proteinogenic; - substitution of H at position 10 by Y or a corresponding non-proteinogenic amino acid; - substitution of Q at position 12 by Y, W, F, or a corresponding non-proteinogenic; - substitution of V at position 14 by Y, W, L, I, F or a corresponding non- proteinogenic; - substitution of W at position 15 by Y, L, C, F, or a corresponding non- proteinogenic amino acid such as homocysteine; and / or; and / or - substitution of R at position 16 by W, F or a corresponding non-proteinogenic amino acid. In further preferred embodiments, the up to three substitutions, preferably up to two substitutions, more preferably up to one substitution, are selected from the group consisting of: - substitution of V at position 14 by Y, W, L, I, F or a corresponding non- proteinogenic amino acid; and / or - substitution of W at position 15 by Y, L, C, F or a corresponding non-proteinogenic amino acid. As demonstrated in the Examples herein, see in particular figure 1, the indicated substitutions result in peptides that have a higher binding affinity than the peptide without such substitution. A peptide or peptidomimetic according to the invention may comprise an N- terminal, C-terminal modification and / or an internal modification, such as C- terminal amidation, N-terminal acylation, fatty acid modifications, esterification and combinations thereof. Provided is therefore a peptide or peptidomimetic according to the invention comprising an N-terminal modification, C-terminal modification and / or an internal modification. Also provided is a compound comprising a peptide or peptidomimetic according to the invention, wherein said peptide or peptidomimetic has an N-terminal modification, a C-terminal modification or an internal modification. In some preferred embodiments, a peptide or peptidomimetic of the invention has a length of 7 or 8 amino acids. In some preferred embodiments, such peptide or peptidomimetic has a length of 8 amino acids. Such peptide or peptidomimetic preferably comprises the sequence SILDEHX or SILDEHXQ, or a variant thereof having one or more of the substitutions and / or modifications as defined herein. Such peptide or peptidomimetic further preferably comprises one or two pairs of amino acids that are crosslinked as defined herein. In particular, S at position 1 of the amino acids sequence SILDEHX or SILDEHXQ or a variant thereof and E at position 5 of said sequence are each substituted by a non-proteinogenic amino acid which non-proteinogenic amino acids are linked to one another by a crosslink and / or E at position 5 of said sequences, and Q at position 8 of said sequence SILDEHXQ are each substituted by a non-proteinogenic amino acid which non- proteinogenic amino acids are linked to one another by a crosslink. Hence, in some preferred embodiments, a peptide or peptidomimetic of the invention has a length of 7 amino acids and comprise the sequence SILDEHX, wherein the amino acids S and E are both substituted by a non-proteinogenic amino acid comprising a side chain, preferably an olefin-containing side chain, which side chains are crosslinked to one another. In some preferred embodiments, a peptide or peptidomimetic of the invention has a length of 8 amino acids and comprise the sequence SILDEHXQ, wherein the amino acids S and E are both substituted by a non-proteinogenic amino acid comprising a side chain, preferably an olefin-containing side chain, which side chains are crosslinked to one another. In some preferred embodiments, a peptide or peptidomimetic of the invention has a length of 8 amino acids and comprise the sequence SILDEHXQ, wherein the amino acids E and Q are both substituted by a non-proteinogenic amino acid comprising a side chain, preferably an olefin-containing side chain, which side chains are crosslinked to one another. In some preferred embodiments, a peptide or peptidomimetic of the invention has a length of 8 amino acids and comprise the sequence SILDEHXQ, wherein the amino acid E is substituted by a non-proteinogenic amino acid comprising two side chains, preferably an olefin-containing side chain, whereby the side chain of the amino acid that has substituted amino acid S and one of the side chains of the amino acid that has substituted amino acid E are crosslinked to one another and the side chain of the amino acid that has substituted amino acid Q and the other of the side chains of the amino acid that has substituted amino acid E are crosslinked to one another. In preferred embodiments such peptide or peptidomimetic comprising one or two crosslinks further comprise a modified amino acid at the one or two most C- terminal amino acid position. In particular, Q in the sequence SILDEHXQ or X in the sequence SILDEHX or SILDEHXQ is substituted by a modified amino acid. Such modified amino acid is preferably an amino acid with a side chain comprising an aromatic moiety as defined herein. In preferred embodiments, a peptide or peptidomimetic of the invention is selected from the group consisting of: - SILDEHLQRVW, - S5*ILD S5*HLQRVW, wherein * indicates that the side chains of the indicated amino acids 5S are crosslinked, - S5*ILD B5*#HL S5#RVW, wherein * indicates that the side chains of theindicated amino acids S5 and B5 are crosslinked; # indicates that the side chains ofthe indicated amino acids B5 and S5 are crosslinked,- S5*ILD S5*HLQRVX(MOD), wherein * indicates that the side chains of theindicated amino acids S5 are crosslinked, and X(MOD) indicates an amino acidresidue with a modified side chain comprising an aromatic moiety as defined herein, - S5*ILD B5*#HL S5#RVX(MOD), wherein * indicates that the side chains of theindicated amino acids S5 and B5 are crosslinked; # indicates that the side chains ofthe indicated amino acids B5 and S5 are crosslinked, and X(MOD) indicates an aminoacid residue with a modified side chain comprising an aromatic moiety as defined herein, - S5*ILD B5*#HL 5S#RVX(MOD), wherein * indicates that the side chains of theindicated amino acids S5 and B5 are crosslinked # indicates that the side chains ofthe indicated amino acids B5 and S5 are crosslinked, and X(MOD) indicates an amino acid residue with a modified side chain comprising an aromatic moiety as defined herein, - SILDEHL, - SILDEHLQ, - S5*ILD S5*HL, wherein * indicates that the side chains of the indicated aminoacids S5 are crosslinked,- S5*ILD S5*HLQ, wherein * indicates that the side chains of the indicated aminoacids S5 are crosslinked,- S5*ILD B5*#HL S5#, wherein * indicates that the side chains of the indicatedamino acids S5 and B5 are crosslinked, # indicates that the side chains of theindicated amino acids B5 and S5 are crosslinked,- S5*ILD S5*HX(MOD), wherein * indicates that the side chains of the indicatedamino acids S5 are crosslinked, and X(MOD) indicates an amino acid residue with amodified side chain comprising an aromatic moiety as defined herein, - S5*ILD S5*HLX(MOD), wherein * indicates that the side chains of the indicatedamino acids S5 are crosslinked, and X(MOD) indicates an amino acid residue with amodified side chain comprising an aromatic moiety as defined herein, - S5*ILD B5*#HX(MOD) S5#, wherein * indicates that the side chains of theindicated amino acids S5 and B5 are crosslinked, # indicates that the side chains ofthe indicated amino acids B5 and S5 are crosslinked, and X(MOD) indicates an aminoacid residue with a modified side chain comprising an aromatic moiety as defined herein, - S5*ILD S5*HX(MOD)Q, wherein * indicates that the side chains of the indicatedamino acids S5 are crosslinked, and X(MOD) indicates an amino acid residue with amodified side chain comprising an aromatic moiety as defined herein, - ENPESILDEHLQRVWR, - ENPE S5*ILD S5*HLQRVWR, wherein * indicates that the side chains of theindicated amino acids S5 are crosslinked, - ENPE S5*ILD B5*#HL S5#RVWR, wherein * indicates that the side chains of theindicated amino acids S5 and B5 are crosslinked, # indicates that the side chains ofthe indicated amino acids B5 and S5 are crosslinked,- ENPESILDEHLQRVW, - ENPE S5*ILD S5*HLQRVW, wherein * indicates that the side chains of theindicated amino acids S5 are crosslinked,- ENPE S5*ILD B5*#HL S5#RVW, wherein * indicates that the side chains of theindicated amino acids S5 and B5 are crosslinked, # indicates that the side chains ofthe indicated amino acids B5 and S5 are crosslinked,- ENPESILDEHLQRVX(MOD), wherein X(MOD) indicates an amino acid residue with a modified side chain comprising an aromatic moiety as defined herein - ENPE S5*ILD S5*HLQRVX(MOD), wherein * indicates that the side chains of theindicated amino acids S5 are crosslinked and X(MOD) indicates an amino acid residuewith a modified side chain comprising an aromatic moiety as defined herein, - ENPE S5*ILD B5*#HL S5#RVX(MOD), wherein * indicates that the side chains ofthe indicated amino acids S5 and B5 are crosslinked, # indicates that the sidechains of the indicated amino acids B5 and S5 are crosslinked and X(MOD) indicatesan amino acid residue with a modified side chain comprising an aromatic moiety as defined herein, - EYPESILDEHLQRVWR, - EYPE S5*ILD S5*HLQRVWR, wherein * indicates that the side chains of theindicated amino acids S5 are crosslinked,- EYPE S5*ILD B5*#HL S5#RVWR, wherein * indicates that the side chains ofthe indicated amino acids S5 and B5 are crosslinked; # indicates that the sidechains of the indicated amino acids B5 and S5 are crosslinked,- EYPESILDEHLQRVW, - EYPE S5*ILD S5*HLQRVW, wherein * indicates that the side chains of theindicated amino acids S5 are crosslinked, - EYPE S5*ILD B5*#HL S5#RVW, wherein * indicates that the side chains of theindicated amino acids S5 and B5 are crosslinked; # indicates that the side chains ofthe indicated amino acids B5 and S5 are crosslinked,- EYPESILDEHLQRVX(MOD), wherein X(MOD) indicates an amino acid residue with a modified side chain comprising an aromatic moiety as defined herein, - EYPE S5*ILD S5*HLQRVX(MOD), wherein * indicates that the side chains of theindicated amino acids S5 are crosslinked, and X(MOD) indicates an amino acidresidue with a modified side chain comprising an aromatic moiety as defined herein, - EYPE S5*ILD B5*#HL S5#RVX(MOD), wherein * indicates that the side chains ofthe indicated amino acids S5 and B5 are crosslinked; # indicates that the sidechains of the indicated amino acids B5 and S5 are crosslinked, and X(MOD) indicatesan amino acid residue with a modified side chain comprising an aromatic moiety as defined herein, - S5* ILD S5*HLQRV, wherein * indicates that the side chains of the indicated amino acids S5 are crosslinked, - E S5*ILD S5* HLQRV, wherein * indicates that the side chains of the indicated amino acids S5 are crosslinked, - E S5*ILD S5* HcQRV, wherein * indicates that the side chains of the indicated amino acids S5 are crosslinked, - E S5*ILD S5* HcQRVC, wherein * indicates that the side chains of the indicated amino acids S5 are crosslinked, - E S5*ILD S5* HcQRV(hC), wherein * indicates that the side chains of the indicated amino acids S5 are crosslinked, - S5* ILD B5*#Hc(mod)S5#RVC(mod), wherein * indicates that the side chains of the indicated amino acids S5 and B5 are crosslinked, # indicates that the side chains of the indicated amino acids B5 and S5 are crosslinked, c(mod) and C(mod) indicate that the side chains of the indicated amino acids are crosslinked via a thioether crosslink, - S5* ILD B5*# HC(mod)S5# RVC(mod), wherein * indicates that the side chains of the indicated amino acids S5 and B5 are crosslinked, # indicates that the side chains of the indicated amino acids B5 and S5 are crosslinked, C(mod) indicates that the side chains of the indicated amino acids are crosslinked via a thioether crosslink, - S5* ILD B5*# HC(mod)S5# RVc(mod), wherein * indicates that the side chains of the indicated amino acids S5 and B5 are crosslinked, # indicates that the side chains of the indicated amino acids B5 and S5 are crosslinked, c(mod) and C(mod) indicate that the side chains of the indicated amino acids are crosslinked via a thioether crosslink, - S5* ILD B5*# Hc(mod)S5# RVc(mod), wherein * indicates that the side chains of the indicated amino acids S5 and B5 are crosslinked, # indicates that the side chains of the indicated amino acids B5 and S5 are crosslinked, c(mod) indicates that the side chains of the indicated amino acids are crosslinked via a thioether crosslink, - S5* ILD B5*# Hc(mod)S5# RVhC(mod), wherein * indicates that the side chains of the indicated amino acids S5 and B5 are crosslinked, # indicates that the side chains of the indicated amino acids B5 and S5 are crosslinked, c(mod) and hC(mod) indicate that the side chains of the indicated amino acids are crosslinked via a thioether crosslink, - S5* ILD B5*# HC(mod)S5# RVhC(mod), wherein * indicates that the side chains of the indicated amino acids S5 and B5 are crosslinked, # indicates that the side chains of the indicated amino acids B5 and S5 are crosslinked, C(mod) indicates that the side chains of the indicated amino acids are crosslinked via a thioether crosslink, - S5* ILD B5*# HC(mod)S5# RVhc(mod), wherein * indicates that the side chains of the indicated amino acids S5 and B5 are crosslinked, # indicates that the side chains of the indicated amino acids B5 and S5 are crosslinked, c(mod) and hc(mod) indicate that the side chains of the indicated amino acids are crosslinked via a thioether crosslink, - S5* ILD B5*# Hc(mod)S5# RVhc(mod), wherein * indicates that the side chains of the indicated amino acids S5 and B5 are crosslinked, # indicates that the side chains of the indicated amino acids B5 and S5 are crosslinked, c(mod) and hc(mod) indicate that the side chains of the indicated amino acids are crosslinked via a thioether crosslink, - S5* ILD B5*# Hhc(mod)S5# RVhC(mod), wherein * indicates that the side chains of the indicated amino acids S5 and B5 are crosslinked, # indicates that the side chains of the indicated amino acids B5 and S5 are crosslinked, hc(mod) and hC(mod) indicate that the side chains of the indicated amino acids are crosslinked via a thioether crosslink, - S5* ILD B5*# HhC(mod)S5# RVhC(mod), wherein * indicates that the side chains of the indicated amino acids S5 and B5 are crosslinked, # indicates that the side chains of the indicated amino acids B5 and S5 are crosslinked, hC(mod) indicates that the side chains of the indicated amino acids are crosslinked via a thioether crosslink, - S5* ILD B5*# HhC(mod)S5# RVhc(mod), wherein * indicates that the side chains of the indicated amino acids S5 and B5 are crosslinked, # indicates that the side chains of the indicated amino acids B5 and S5 are crosslinked, hC(mod) and hc(mod) indicate that the side chains of the indicated amino acids are crosslinked via a thioether crosslink, - S5* ILD B5*# Hhc(mod)S5# RVhc(mod), wherein * indicates that the side chains of the indicated amino acids S5 and B5 are crosslinked, # indicates that the side chains of the indicated amino acids B5 and S5 are crosslinked, hc(mod) indicates that the side chains of the indicated amino acids are crosslinked via a thioether crosslink, - S5* ILD B5*# Hhc(mod)S5# RVC(mod), wherein * indicates that the side chains of the indicated amino acids S5 and B5 are crosslinked, # indicates that the side chains of the indicated amino acids B5 and S5 are crosslinked, hc(mod) and C(mod) indicate that the side chains of the indicated amino acids are crosslinked via a thioether crosslink, - S5* ILD B5*# HhC(mod)S5# RVC(mod), wherein * indicates that the side chains of the indicated amino acids S5 and B5 are crosslinked, # indicates that the side chains of the indicated amino acids B5 and S5 are crosslinked, and hC(mod) and C(mod) indicate that the side chains of the indicated amino acids are crosslinked via a thioether crosslink, - S5* ILD B5*# HhC(mod)S5# RVc(mod), wherein * indicates that the side chains of the indicated amino acids S5 and B5 are crosslinked, # indicates that the side chains of the indicated amino acids B5 and S5 are crosslinked, hC(mod) and c(mod) indicate that the side chains of the indicated amino acids are crosslinked via a thioether crosslink, - S5* ILD B5*# Hhc(mod)S5# RVc(mod), wherein * indicates that the side chains of the indicated amino acids S5 and B5 are crosslinked, # indicates that the side chains of the indicated amino acids B5 and S5 are crosslinked, hc(mod) and c(mod) indicate that the side chains of the indicated amino acids are crosslinked via a thioether crosslink, - SILD S5* Hc(mod) S5* RVC(mod), wherein * indicates that the side chains of the indicated amino acids S5 and S5 are crosslinked, c(mod) and C(mod) indicate that the side chains of the indicated amino acids are crosslinked via a thioether crosslink, - S5* ILD S5* Hc(mod)QRVC(mod), wherein * indicates that the side chains of the indicated amino acids S5 and S5 are crosslinked, c(mod) and C(mod) indicate that the side chains of the indicated amino acids are crosslinked via a thioether crosslink, - S5* ILD S5* Hc(mod)QRVc(mod), wherein * indicates that the side chains of the indicated amino acids S5 and S5 are crosslinked, c(mod) indicates that the side chains of the indicated amino acids are crosslinked via a thioether crosslink, - S5* ILD S5* HC(mod)QRVC(mod), wherein * indicates that the side chains of the indicated amino acids S5 and S5 are crosslinked, C(mod) indicates that the side chains of the indicated amino acids are crosslinked via a thioether crosslink, - S5* ILD S5* HC(mod)QRVc(mod), wherein * indicates that the side chains of the indicated amino acids S5 and S5 are crosslinked, C(mod) and c(mod) indicates that the side chains of the indicated amino acids are crosslinked via a thioether crosslink, - S5* ILD S5* Hhc(mod)QRVC(mod), wherein * indicates that the side chains of the indicated amino acids S5 and S5 are crosslinked, hc(mod) and C(mod) indicate that the side chains of the indicated amino acids are crosslinked via a thioether crosslink, - S5* ILD S5* Hhc(mod)QRVc(mod), wherein * indicates that the side chains of the indicated amino acids S5 and S5 are crosslinked, hc(mod) and c(mod) indicate that the side chains of the indicated amino acids are crosslinked via a thioether crosslink, - S5* ILD S5* HhC(mod)QRVC(mod), wherein * indicates that the side chains of the indicated amino acids S5 and S5 are crosslinked, hC(mod) and C(mod) indicate that the side chains of the indicated amino acids are crosslinked via a thioether crosslink, - S5* ILD S5* HhC(mod)QRVc(mod), wherein * indicates that the side chains of the indicated amino acids S5 and S5 are crosslinked, hC(mod) and c(mod) indicates that the side chains of the indicated amino acids are crosslinked via a thioether crosslink. - S5* ILD S5* Hc(mod)QRVhC(mod), wherein * indicates that the side chains of the indicated amino acids S5 and S5 are crosslinked, c(mod) and hC(mod) indicate that the side chains of the indicated amino acids are crosslinked via a thioether crosslink, - S5* ILD S5* Hc(mod)QRVhc(mod), wherein * indicates that the side chains of the indicated amino acids S5 and S5 are crosslinked, c(mod) and hc(mod) indicate that the side chains of the indicated amino acids are crosslinked via a thioether crosslink, - S5* ILD S5* HC(mod)QRVhC(mod), wherein * indicates that the side chains of the indicated amino acids S5 and S5 are crosslinked, C(mod) and hC(mod) indicate that the side chains of the indicated amino acids are crosslinked via a thioether crosslink, - S5* ILD S5* HC(mod)QRVhc(mod), wherein * indicates that the side chains of the indicated amino acids S5 and S5 are crosslinked, C(mod) and hc(mod) indicates that the side chains of the indicated amino acids are crosslinked via a thioether crosslink - S5* ILD S5* Hhc(mod)QRVhC(mod), wherein * indicates that the side chains of the indicated amino acids S5 and S5 are crosslinked, hc(mod) and hC(mod) indicate that the side chains of the indicated amino acids are crosslinked via a thioether crosslink, - S5* ILD S5* Hhc(mod)QRVhc(mod), wherein * indicates that the side chains of the indicated amino acids S5 and S5 are crosslinked, hc(mod) indicates that the side chains of the indicated amino acids are crosslinked via a thioether crosslink, - S5* ILD S5* HhC(mod)QRVhC(mod), wherein * indicates that the side chains of the indicated amino acids S5 and S5 are crosslinked, hC(mod) indicates that the side chains of the indicated amino acids are crosslinked via a thioether crosslink, - S5* ILD S5* HhC(mod)QRVhc(mod), wherein * indicates that the side chains of the indicated amino acids S5 and S5 are crosslinked, hC(mod) and hc(mod) indicates that the side chains of the indicated amino acids are crosslinked via a thioether crosslink. Also provided is a nucleic acid molecule comprising a nucleic acid sequence encoding a β-catenin-binding peptide according to the invention. In some preferred embodiments, said nucleic acid sequence encodes a β- catenin-binding peptide having a length of 7-12 amino acids and comprising an amino acid sequence ESILDEHXQRVW, wherein X is L, M, I, F, Y, W or C, preferably L, I, F, Y, C, or W, more preferably C or L, or a variant of said amino acid sequence. Said variant is a variant of the amino acid sequence ESILDEHXQRVW, wherein X is L, M, I, F, Y, W or C, preferably L, I, F, Y, C, or W, more preferably L, A nucleic acid molecule preferably encodes a peptide of the invention comprising only natural amino acids. I.e. said nucleic acid preferably encodes a peptide comprising or consisting of the sequence ESILDEHXQRVW, wherein X is L, M, I, F, Y, W or C, preferably L, I, F, Y, C, or W, more preferably Cor L, or a variant thereof comprising at least amino acids 2-8 of said sequenceESILDEHXQRVW, wherein X is L, M, I, F, Y, W or C, preferably L, I, F, Y, C, or W, more preferably C or L, which variant optionally has up to three substitutions, preferably up to two substitutions, more preferably up to one substitution, of an amino acid at position 1, 2, 6, 7, 9, 10, 11 and / or 12 by another amino acid. Preferred nucleic acid molecules encodes preferred peptides of the invention. In some preferred embodiments, said nucleic acid sequence encodes a -catenin binding peptide or peptidomimetic having a length of 7-20 amino acids and comprising an amino acid sequence EYPESILDEHXQRVWR, wherein X is L, M, I, F, Y, W or C, preferably L, I, F, Y, C, or W, more preferably C or L, or a variant of said amino acid sequence, wherein said variant comprises at least amino acids 5-11 of said sequence and optionally having up to three substitutions of an amino acid at position 1, 2, 3, 4, 5, 9, 10, 12, 13, 14, 15 and / or 16 by another amino acid as defined herein. The invention further provides a pharmaceutical composition, comprising a peptide or peptidomimetic according to the invention or nucleic acid molecule and a pharmaceutically acceptable excipient. Said pharmaceutically acceptable excipient preferably is selected from a carrier or diluent or a combination thereof. Said pharmaceutical composition may further comprise a buffer. Said pharmaceutical composition preferably is for use in a method of treating a patient suffering from a pre-malignant condition, a tumor, metastasis or any other disease that is dependent on an activated Wnt signaling pathway, preferably as defined herein below. Said other disease may be selected from osteoporosis, a chronic lung disease, and a psychiatric disorder. The invention further provides a peptide or peptidomimetic or nucleic acid molecule according to the invention, for use as a medicament. The invention further provides a peptide or peptidomimetic or nucleic acid molecule according to the invention, for use in the prevention or treatment of an individual suffering from a tumor or metastasis, or at risk of suffering from a tumor or pre-malignant condition, or suffering of any other disease that is dependent on an activated Wingless / integrase1 (Wnt) signaling pathway. The invention further provides a use of a peptide or peptidomimetic or nucleic acid molecule according to the invention in the preparation of a medicament for prevention or treatment of an individual suffering from a tumor, metastasis or pre- malignant condition, or at risk of suffering from a tumor, or suffering of any other disease that is dependent on an activated Wingless / integrase1 (Wnt) signaling pathway. The invention further provides a method for the treatment or prevention of a tumor, metastasis or pre-malignant condition or any other disease that is dependent on an activated Wingless / integrase1 (Wnt) signaling pathway in an individual in need thereof comprising administering to the individual a peptide or peptidomimetic or nucleic acid molecule according to the invention. In some embodiments, the individual has, and / or is suffering from a pre- malignant condition, also termed pre-cancerous condition. The term pre-malignant condition refers to a clinically recognizable lesion that is associated with the development of malignant neoplasia. The identification of a pre-malignant condition in an individual helps to identify individuals that have an increased risk cancer development, thereby allowing prophylactic treatment to prevent the development of a malignant neoplasia. Pre-malignant lesions have been identified in especially epithelial organs and include actinic keratosis and Bowen's disease in skin, dysplastic nodule in liver, leukoplakia in the oral cavity, bronchial dysplasia in the bronchus, Barrett's disease in the esophagus (Barrett’s esophagus), adenoma in the colorectal tract, intraepithelial neoplasia in the vulva and cervix, and intraepithelial neoplasia in the anal canal. Progression of these pre-malignant lesions has been reported to involve the Wnt signaling pathway (Takacs et al., 2008. Science 319: 333-336; Clément et al., 2007. Expert Opinion Therapeutic Targets 11: 375-389). Hence, a peptide or peptidomimetic according to the invention that blocks activation of a T-cell factor (TCF) / LEF family member by ^-catenin will aid in blocking or at least reducing progression of these pre-malignant lesions into a malignant neoplasia. Said pre-malignant lesion preferably is selected from colorectal adenoma and Barrett’s esophagus. In some embodiments, the individual has, and / or is suffering, from a tumor. A role of the Wnt pathway is evident in a diverse set of tumors, including carcinomas such as gastrointestinal cancers, including colorectal carcinomas, adenocarcinomas such as esophageal adenocarcinoma and pancreatic ductal adenocarcinoma, and breast carcinoma. Hence, a peptide or peptidomimetic according to the invention that blocks activation of a TCF / LEF family member by ^-catenin will aid in treatment of tumors such as a carcinoma, including a colorectal carcinoma, an adenoma such as esophageal adenocarcinoma and pancreatic ductal adenocarcinoma, and a breast carcinoma. In addition, a role of the Wnt pathway has been suggested in other tumors, including leukemia and melanoma, while a role of the Wnt pathway for the function and maintenance of cancer stem cells is commonly accepted (Zhan et al., 2017. Oncogene 36: 1461–1473). Hence, a peptide or peptidomimetic according to the invention that blocks activation of a TCF / LEF family member by ^-catenin will aid in treatment of further tumors, including leukemia and melanoma. Hence, in preferred embodiments, the tumor is selected from a carcinoma, including a colorectal carcinoma, an adenoma such as esophageal adenocarcinoma and pancreatic ductal adenocarcinoma, a breast carcinoma, leukemia and melanoma. In some embodiments, the individual that is suffering from a tumor is suffering from metastasis of said tumor. In some embodiments, treatment includes treatment of metastasis. After surgery of colorectal cancer, in particular if the colorectal cancer is diagnosed late, which is often the case, there is a high risk of metastasis formation. Hence, in some preferred embodiments a treatment of a tumor in accordance with the invention comprises treatment or prevention of metastasis, including metastasis of colorectal cancer. In some preferred embodiments, said treatment comprises treatment or prevention of metastasis of colorectal cancer following surgery of the colorectal cancer. As is known to a person skilled in the art, the term surgery refers to a physical procedure in which a tumor, or at least part of a tumor, is removed from the body of an individual. Said procedure comprises making incisions in tissue, often skin or tissue aligning internal cavities in an individual. A small tumor can be excised in combination with a margin of healthy tissue surrounding the tumor. The term radiation therapy, also termed radiation oncology, refers to method wherein ionizing radiation is used to kill especially tumor cells. The ionizing radiation is typically X-ray and can be applied either from the outside of the body, or by placing a radioactive source at or near a tumor inside a patient. The mode of action of radiation therapy is by causing DNA damage due to either ionization of DNA directly, or by ionization of water causing the formation of free radicals and indirectly damaging DNA. For the prevention or treatment of an individual suffering from a tumor, metastasis or a pre-malignant lesion, the provision of a peptide or peptidomimetic according to the invention may be combined with one or more further anti-cancer therapies that affect cell growth, cell division and / or cell differentiation. In addition, treatment of an individual with a peptide or peptidomimetic according to the invention may be combined with surgery, radiation therapy, or a combination thereof. Said one or more further anti-cancer therapies may include chemotherapeutic drugs such as an alkylating agent, for example a nitrogen mustard such as bendamustine, chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, and melphalan, a nitrosourea such as carmustine, lomustine, and streptozocin, an alkyl sulfonate such as busulfan, a triazine such as dacarbazine and temozolomide, and an ethylenimine such as altretamine and thiotepa; an antimetabolite such as 5- fluorouracil, hydroxyurea and methotrexate; an alkaloid such as taxane and camptothecan; a mitotic inhibitor such as vinblastine, paclitaxel and etoposide; an antitumor antibiotic such as anthracycline and chromomycin; an topoisomerase inhibitor such as camptothecin. Said one or more further anti-cancer therapies may also include one or more molecules for targeted therapy, immunotherapy and / or hormone therapy. A molecule for targeted therapy is a molecule that specifically blocks growth of cancer cells by interfering with specific targeted molecules which are necessary for carcinogenesis and tumor growth, such as a tyrosine-kinase inhibitor and a phosphoinositide 3-kinase inhibitor, and a molecule that stimulates of the immune system of the individual to inhibit or kill cancer-associated tumor cells. A molecule for immunotherapy is either a molecule that directs the immune system to attack tumor cells directly by targeting antigens displayed on tumor cells, and / or a molecule such as an antibody that targets antigens displayed on tumor cells. Examples of such molecules are immune checkpoint inhibitors such as anti-PD-1, anti-PD-L1 and anti-CTLA-4, CTLA B7-1 and CTLA B7-2 molecules. A molecule for hormone therapy is a molecule that blocks and / or lowers a concentration of one or more specific hormones. This can be performed by either blocking the ability of an individual to produce said specific hormone or said specific hormones, or by interfering with how specific hormones behave in the human body. Some cancers, such as breast, prostate, ovarian and endometrial cancer require hormone stimulation such as steroid stimulation, to grow and / or develop. Hormone therapy specifically prevents the growing and division of hormone dependent / sensitive cancer cells. Examples of such hormone therapeutic molecules are hormone antagonists such as flutamide, goserelin, mitotane and tamoxifen, and aromatase inhibitors such as anastrozole, exemestane and letrozole. Said one or more further anti-cancer therapies may also include cell-based therapy. Examples of such cell-based therapy include immune cell-based therapy, such as natural killer cell, macrophage, neutrophil, eosinophil, or T cell-based therapy. Such immune cell may be chimeric antigen receptor (CAR) expressing immune cells, in particular wherein the CAR is specific for an antigen found on a tumor or metastasis. In some preferred embodiments, a peptide or peptidomimetic of the invention is combined with CAR T cells. In some preferred embodiments, a peptide or peptidomimetic of the invention is combined with CAR T cells that are specific for colorectal cancer and / or colorectal cancer metastasis. The term “combination”, as is used herein, refers to the administration of a peptide or peptidomimetic as defined herein, with one or more further anti-cancer therapies, to an individual in need thereof. Said peptide or peptidomimetic and one or more further anti-cancer drugs may be provided in one pharmaceutical preparation, or as two or more distinct pharmaceutical preparations. When administered as two distinct pharmaceutical preparations, they may be administered on the same day or on different days to a patient in need thereof, and using a similar or dissimilar administration protocol, e.g. daily, twice daily, biweekly, orally and / or by infusion. Said combination is preferably administered repeatedly according to a protocol that depends on the patient to be treated (age, weight, treatment history, etc.), which can be determined by a skilled physician. The invention further provides a peptide or peptidomimetic or nucleic acid molecule according to the invention for use in treating a disease selected from bone-related diseases such as osteoarthritis and osteoporosis, a chronic lung disease, and a psychiatric disorder. The invention further provides a use of a peptide or peptidomimetic or nucleic acid molecule according to the invention in the preparation of a medicament for treating a disease selected from bone-related diseases such as osteoarthritis and osteoporosis, a chronic lung disease, and a psychiatric disorder. Also provided is a method of treating a disease selected from bone-related diseases such as osteoarthritis and osteoporosis, a chronic lung disease, and a psychiatric disorder comprising administering to an individual in need thereof a peptide or peptidomimetic or nucleic acid molecule according to the invention. The Wnt pathway is known to be involved in bone formation. Inhibitors of Wnt signaling have emerged as promising strategies to increase bone mass, lower adiposity and reduce fracture risk (Anastasilakis et al., 2011. Curr Opin Endocrinol Diabetes Obes 18: 383-388). Alterations in the classical Wnt signaling pathway have been linked to chronic lung diseases, including idiopathic pulmonary fibrosis, pulmonary arterial hypertension, asthma and COPD (Baarsma and Königshoff, 2017. Thorax 72: 746– 759). Blocking the interaction of beta-catenin with transcription factors such as TCF may provide an effective treatment of these chronic lung diseases. The regulated expression of the Wnt signaling pathway in the brain is critical for many neurodevelopmental processes, and members of this pathway are candidate genes for several neuropsychiatric disorders, including schizophrenia, and Alzheimer’s disease (Miyaokaet al., 1999. Schizophrenia Res 38: 1-6; Hennig et al., 2017. Mol Neuropsychiatry 3: 53-57; Anderton et al., 2000. Mol Med Today 6: 54 - 59). Inhibition of the interaction between beta-catenin and TCF transcription factors, may be of clinical use for treatment of such psychiatric disorders. A peptide or peptidomimetic or nucleic acid molecule according to the invention may be administered by oral administration, topical administration, and / or parenteral administration, including intramuscular, subcutaneous, intraperitoneal administration. A preferred mode of administration is oral administration and / or parenteral administration such as intramuscular, intravenous and / or subcutaneous administration. The term “administering” as used herein includes all means of introducing the peptide or peptidomimetic or nucleic acid molecule and composition comprising the peptide or peptidomimetic or nucleic acid molecule as described herein to an individual. The compounds and compositions described herein may be administered in unit dosage forms and / or formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles. Said peptide or peptidomimetic or nucleic acid molecule according to the invention preferably is administered parenterally, by injection, infusion, or a combination thereof. A peptide or peptidomimetic according to the invention may be administered at 0.1-1000 milligram, such as 1-100 milligram, including about 50 milligram, or at 0.1-100 milligram per kilogram body weight, such as about 2-50 milligram / kg. The administration of a peptide or peptidomimetic or nucleic acid molecule is preferably performed at regular intervals, such as daily, weekly, twice weekly or 3 times weekly. A peptide or peptidomimetic of the invention may be administered as such or in the form of a nucleic acid molecule comprising a nucleic acid sequence encoding the peptide or peptidomimetic. Hence, in some preferred embodiments, prevention or treatment in accordance with the invention comprises administering a nucleic acid molecule comprising a nucleic acid sequence encoding a peptide or peptidomimetic according to the invention. In some embodiments, said administering is via mRNA delivery. mRNA delivery refers to the process of delivering a mRNA molecule into a cell, typically in order to direct the cell to produce a peptide of the invention encoded by the mRNA. Hence, in some preferred embodiments the nucleic acid molecule is a mRNA molecule. Common mRNA delivery technologies include liposome transfection, electrotransfection, nanoparticle or liposome delivery, and the like. In some embodiments, a nucleic acid molecule according to the invention is a vector, such as an expression vector. The expression vector can be a viral vector or non-viral vector or plasmid. Non-limiting examples of suitable expression vectors include retroviral, adenoviral, adeno-associated, herpes simplex and lentiviral vectors, non-viral vectors and plasmids and engineered vectors. Non-viral expression vectors and plasmids include nude DNA, and nucleic acids packaged into synthetic or engineered compositions such as liposomes, polymers, nanoparticles and molecular conjugates. Methods for the generation of such non- viral expression vectors are well known in the art. The expression vector preferably comprises a strong promoter / enhancer, such as the CMV or SV40 promoter, an optimal translation initiation sequence, such as a ribosomal binding site and start codon, and / or a transcription termination sequence, including a poly(A) signal when the protein is expressed in eukaryotic cells. A person skilled in the art will understand that the expression vector to be used is dependent on the host cell that is used for expression of a peptide according to the invention. An expression vector is preferably suited for expression of a nucleic acid molecule of the invention in eukaryotic host cells, such as mammalian host cells, and / or in CHO cells, NS0 cells, SP2 / 0 cells, PERC.6 cells and / or HEK293 cells. As an alternative, a nucleic acid molecule of the invention may be provided to a subject by gene editing technology, including CRISPR / Cas, zinc-finger nucleases, and transcription activator-like effector nucleases-TALEN, in order to insert the receptor transgenes into specific loci with or without an exogenous promoter. Preferred genomic loci include the AAVS1 locus and the PD-1 locus, as is known to a skilled person. The invention further provides the use of the peptide or peptidomimetic according to the invention for inhibiting Wingless / integrase-1 (Wnt)-signaling in isolated tissues or cells. Said peptide or peptidomimetic may be used, for example, in in vitro studies directed at elucidating the Wnt signal transduction pathways in developmental processes and in adult tissues. Said studies may reveal further antagonists of Wnt signaling pathways that can be used in treatment of an individual in need thereof. Features may be described herein as part of the same or separate aspects or embodiments of the present invention for the purpose of clarity and a concise description. It will be appreciated by the skilled person that the scope of the invention may include embodiments having combinations of all or some of the features described herein as part of the same or separate embodiments. The invention will be explained in more detail in the following, non-limiting examples. Brief description of the drawings Figure 1: a) β-Catenin armadillo repeat domain (surface) in complex with Axin (dark grey, PDB ID 1qz7)

[0038] and TCF4 (light grey, PDB ID 1jpw).

[0039] b) Relative binding affinity map for Axin variants compared to the natural sequence (a16, Axin 467–482, top horizontal). Higher values correspond to stronger binding. c) Selected peptide variants (variations are underlined) with Kd-values derived from a direct fluorescence polarization (FP) assay (n = 3, ± std. error, for binding curves see Figure 2). For list of peptide sequences and characterization see Table 1. Figure 2: FP titration measurement of selected fluorescein-labelled peptides shown in Figure 1C. Constant peptide concentration (c = 10 nM) and full length β-catenin (2.5-fold serial dilution starting at ca. 10 µM, n = 3, ± std. error). Figure 3: Top: Peptide a12-LW (dark grey, cartoon / stick representation) in complex with β-catenin (surface). Bottom: 2mFo-DFc electron density (contoured at 1.0 RMSD) for a12-LW (stick) in complex with β-catenin (surface). Figure 4: a) Overlayed structures of a16 (light grey, PDB ID 1qz7)

[0038] and a12- LW (dark grey) in complex with the β-catenin (surface). Selected residues are shown explicitly and sequence of a12-LW is given (^hot spot residues). b) Chemical structure of crosslinks used for peptide stapling (left) and stitching (right). c) Table of sequences of a11-LW-derived peptides (Table 1) summarizing helicity (Figure 4d), affinity (Figure 4e), and BEI. d) CD spectra of a11-LW and derived peptides (c = 7.5 µM) in buffer (pH 7.5, 5 mM sodium phosphate).[46,47]e) Direct FP assay with FITC-labeled analogues of a11-LW and derived peptides (c = 10 nM) and β-catenin (2.5-fold serial dilution starting at 18.5 µM, n = 3, ± std. error). The obtained affinity values were used to calculate the binding efficiency index (BEI = pKd·MW–1), a measure to assess the status of the maturation process. Figure 5: Overview of results from FP titration measurement of the FITC- labelled peptides originating from the alanine-scan. Constant peptide concentration (c = 10 nM) and full length β-catenin (2.5-fold serial dilution starting at 8.4 µM, n = 1). Figure 6: a) Building blocks used for the synthesis of stapled and / or stitched peptides. b) Schematic representation of the synthetic route towards stapledpeptides. Staple with i,i+4 spacing via two S5 building blocks, and i,i+3 spacing viaa R5 and S5 building block. c) Schematic representation of the synthetic route towards stitched peptides. Stitch with i,i+4 and i,i+3 spacing (i,i+4, i+4+3) via two S5 and one B5 building block. Figure 7: HPLC chromatograms with gradient 5–95% solvent B: ACN + 0.1% TFA (solvent A: H2O + 0.1% TFA) over 10 min or 30 min. MS spectra with found signals (positive mode). a) Acetylated st1 peptide b) Acetylated st2 peptide c) Acetylated st3 peptide. Figure 8: a) Electron density map (2mFo–DFc, contoured at 1 RMSD) around stitched peptide st3 in complex with β-catenin. b) Overlay of a12-LW and st3 bound to β-catenin with crosslinks and selected residues shown explicitly. c) Overview of contacts between st3 (in helix wheel projection) and β-catenin (contact cutoff is d < 4.5 Å).

[0063] Figure 9: a) Chemical structure of st3. b) Close-up of the crosslink structure (stitch) and the corresponding 2mFo-DFc electron density (contoured at 1.0 RMSD). Positions of the trans (i,i+4 crosslink, between atom 5 and 6) and cis (i,i+3 crosslink, between atom 14 and 15) double bond are indicated. Figure 10 a) Scheme for cysteine modification in a12-LC with a library ofaromatic bromide derivatives. b) Chemical structure of a12-LC. c) Table showingthe library of bromide derivatives used for cysteine derivatization, with their assigned ID and peptide name, binding affinity to β-catenin full length and relative binding affinity compared to parental peptide a12-LW. For binding curves see Figure 11. Figure 11: FP titration measurement of the FITC-labelled peptides shown in Figure 10. Constant peptide concentration (c = 10 nM) and full length β-catenin (2.5-fold serial dilution starting at c = 12 µM, n = 1). Figure 12: a) Chemical structure of stC-scaffold peptides. b) Selected modifications for pocket exploration in stC scaffold. c) Overview of binding affinity (Figure 12d), BEI and activity data (Figure 12e). d) Direct FP assay with fluorescein-labeled analogues of stC, stC-b, stC-mb and stC-fb (c = 10 nM) and β- catenin (2.5-fold serial dilution starting at 6.6 µM, n = 3, ± std. error). e) Effect on reporter activity for stC, stC-b, stC-mb and stC-fb (2-fold serial dilution starting at 40 µM, incubation t = 24 h, n = 3, ± std. error). Figure 13: FP competition assay with stC-b, a12-LW and a11-LW. These were subjected to a 3-fold serial dilution starting at 1.6 µM. Fluorescein-labeled TCF-4 was used as tracer (c = 10 nM) for binding to full length β-catenin (c = 125 nM). Measurements were performed in triplicate. Figure 14: Examples of lactam, carbamate, thioether, triazole and disulfide crosslinks that may be present in a peptidomimetic of the invention. The examples show i,i+4 crosslinks. Figure 15: Characterization of st-E11(-) and its analogs. a) Chemical structure of the compound st-E11(-). b) Summary of peptide sequences and FP- derived binding affinities (Kd) of st-E11(-) and related compounds. c) Fluorescence polarization (mFP) binding curves showing the interaction of described peptides with β-catenin. Constant peptide concentration (c = 10 nM) and full length β-catenin (2.5-fold serial dilution starting at c = 5 µM, n = 3). d) Summary of structural modifications to st-E11(-), including their binding affinities (Kd) and relative affinity improvements compared to the reference compound. Figure 16: Structural and functional analysis of compound 48 and its analogs. a) Chemical structure of the compounds 48-1 / 2. b) Chemical structures of six building blocks (A–F) used to crosslink to compounds 48-1 / 2. c) Table summarizing the sequences and FP-derived binding affinities (Kd) of reference peptides Ax1, 48- 1, and 48-2. d) Table showing the effects of modifications A–F on the binding affinities of 48-1 and 48-2. e) Fluorescence polarization (mFP) binding curves for β- catenin with various analogs of compounds 48-1 / 2. Constant peptide concentration (c = 10 nM) and full length β-catenin (2.5-fold serial dilution starting at c = 6 µM, n = 1). References Drawings

[0016] P. G. Dougherty, A. Sahni, D. Pei, Chem. Rev. 2019, 119, 10241–10287.

[0038] Y. Xing, W. K. Clements, D. Kimelman, W. Xu, Genes Dev. 2003, 17, 2753–2764.

[0039] F. Poy, M. Lepourcelet, R. A. Shivdasani, M. J. Eck, Nat. Struct. Biol. 2001, 8, 1053–1057.

[0040] J. J. Love, X. Li, D. A. Case, K. Giese, R. Grosschedl, P. E. Wright, Nature 1995, 376, 791–795.

[0046] L. Whitmore, B. A. Wallace, Biopolymers 2008, 89, 392–400.

[0047] N. Sreerama, R. W. Woody, Anal. Biochem. 2000, 287, 252–260.

[0063] R. Ferreira De Freitas, M. Schapira, MedChemComm 2017, 8, 1970– 1981. Examples Materials and methods 1. Peptide synthesis and characterization Peptides were synthesized on solid-phase using the Fmoc protecting group strategy (SPPS) in analogy to protocols described earlier.[1]Reagents were used without further purification and purchased from Iris Biotech GMBH, Sigma Aldrich and Carl Roth. All reaction steps were performed in a syringe reactor at room temperature on an orbital shaker. For all scales (10–100 μmol) rink amide MBHA resin (Merck, Art. No. 8.55003) was swollen in DMF (dimethylformamide) for 30 min. For amino acid (aa) coupling, a solution of 4 eq. N-α-Fmoc (fluorenylmethyloxycarbonyl) protected amino acid, 4 eq. COMU ((1-cyano-2- ethoxy-2-oxoethyliden-aminooxy)dimethylamino-morpholino-carbenium hexafluoro-phosphate) and 4 eq. oxyma (ethyl cyano(hydroxyimino) acetate) in DMF was prepared (0.3 mL per 50 mg resin). 8 eq. DIPEA (N,N- diisopropylethylamine) were added to the coupling solution. Subsequently, resin and coupling solution were mixed in a syringe reactor on an orbital shaker. After 30 min, the reaction solution was discarded, and the amino acid coupling repeated. After washing the resin with DMF (3×), DCM (dichloromethane) (3×) and DMF (3×), Fmoc removal was performed by adding a solution of piperidine in DMF (2:8, v / v). After 5 min, the solution was discarded and the Fmoc removal repeated. The resin was washed with DMF (3×), DCM (3×) and DMF (3×) again. Subsequent amino acids were coupled by repeating cycles of amino acid coupling and Fmoc removal. Peptide synthesis was supported by automated SPPS, using the peptide synthesis robot Syro I (MultiSynTech), with a double coupling protocol of 4 eq. PyBOP (1st 40 min coupling, benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate) and 4 eq HATU (2nd40 min coupling, hexafluorophosphate azabenzotriazole tetramethyl uronium) as coupling reagents and DMF as solvent. Additionally, the coupling reaction with 4 eq. Fmoc-protected amino acid was supplemented with 4 eq. Oxyma and 8 eq. DIPEA. Before Fmoc removal was conducted with (25% (v / v) piperidine in DMF), a capping step using Ac2O (acetic anhydride) and DIPEA in NMP (1:1:8, v / v / v) was performed. Between reaction steps, the resin was washed with DMF. Chemical cross-linking of nonnatural amino acids was performed using 0.2 equivalents of Grubbs catalyst 1stgeneration in dichloroethane (DCE) (6 mM) agitating gently under continuous bubbling of nitrogen (N2) for 2 h, afterwards the solution is drained. Subsequent cycles of olefin metathesis were performed adding a freshly prepared solution, to a total of 6 cycles. N-terminally acetylated peptides were synthesized by adding a solution of Ac2O, DIPEA and DMF (1:1:8, v / v / v) to the resin-bound peptide. The reaction solution was discarded after 10 min and the acetylation repeated. Subsequently, the resin was washed DMF (3×) and DCM (3×). N-terminally fluorescently labeled peptides were prepared by first coupling Fmoc-PEG2-OH (8-(9-fluorenylmethyloxycarbonyl-amino)-3,6-dioxaoctanoic acid) as described above. After Fmoc removal (see above), a solution of 6 eq. FITC (fluorescein isothiocyanate) and 12 eq. DIPEA in DMF (0.3 mL per 50 mg resin) was added to the resin. After 16 h, the solution was discarded, and the resin was washed with DMF (3×) and DCM (3×). Peptide cleavage and removal of side chain protecting groups was performed simultaneously, by adding a solution of TFA (trifluoroacetic acid), water, ODT (1,8- octanedithiol) and TIPS (triisopropylsilane) (94:2.5:2.5:1, v / v / v / v) to the resin. After 1 h, the cleavage solution was collected, and the resin was suspended once more for 1 h in fresh cleavage solution. The cleavage solutions were combined and TFA evaporated. The crude peptides were obtained by precipitation in diethyl ether followed by centrifugation (10 min, 4000 rcf). After removal of the supernatant, the crude peptide was dissolved in ACN (acetonitrile) and water (1:1, v / v). Peptide purification was carried out via reverse-phase HPLC (high- performance liquid chromatography) on an Agilent semi preparative system 1100 (Column: Macherey-Nagel Nucleodur C18, 10 × 125 mm, 110 Å, 5 μm) using adjusted gradients of solvent A (H2O + 0.1% TFA) and solvent B (ACN + 0.1% TFA) over 20–60 min with a flow rate of 6 mL min–1. Peptides were analyzed by analytical reverse-phase HPLC coupled to ESI-MS (Agilent 1260 + quadrupole 6120, Column: Agilent Zorbax C18, 4.6 × 150 mm, 5 μm) with solvent A (H2O + 0.1% TFA) and solvent B (ACN + 0.1% TFA) or solvent C (H2O + 0.1 FA (formic acid) + 0.01% TFA) and D (ACN + 0.1% FA + 0.01% TFA) via a 30 min gradient from 5% to 65% or from 10% to 75% solvent B / D. FITC- labeled peptides were quantified via absorption measurements (λ = 495 nm, ε495 = 77000 M-1cm-1) in 100 mM sodium phosphate buffer (pH 8.5). Non-labeled peptides were quantified gravimetrically or via HPLC peptide standards. Synthesized peptides are listed in Table 1. 2. µSPOT microarrays preparation µSPOT peptide arrays[2](CelluSpots, Intavis AG) were synthesized on in- house produced, acid-labile, amino-functionalized cellulose membrane discs containing Fmoc-β-Ala-OH (9-fluorenyl-methyloxycarbonyl-β-alanine) linkers (average loading ca. 130 nmol / disc, 4 mm diameter). Synthesis was initiated by Fmoc deprotection using 20% piperidine in DMF, followed by washing with DMF and EtOH (ethanol). Peptide chain elongation was achieved using a coupling solution consisting of preactivated amino acids (0.5 M) with oxyma (1 M) and DIC (N,N′-diisopropylcarbodiimide, 1 M) in DMF (1:1:1, v / v / v). Couplings were carried out for 3 × 30 min, followed by capping (4% Ac2O in DMF) and washes with DMF and EtOH. Synthesis was finalized by deprotection with 20% piperidine in DMF (2 × 4 µL / disc for 10 min each), followed by washing with DMF and EtOH. Dried discs were transferred to 96 deep-well blocks and treated, while shaking, with sidechain deprotection solution, consisting of 90% TFA, 2% DCM, 5% H2O, and 3% TIPS (150 µL / well) for 1.5 h at room temperature. Subsequently, the deprotection solution was removed, and the discs were solubilized overnight at room temperature, while shaking, using a solvation mixture containing 88.5% TFA, 4% TFMSA (trifluoromethanesulfonic acid), 5% H2O, and 2.5% TIPS (250 µL / well). The resulting peptide-cellulose conjugates (PCCs) were precipitated with ice-cold diethyl ether (0.7 mL / well) and spin down at 2000 × g for 10 min at 4 °C, followed by two additional washes of the formed pellet with ice-cold diethyl ether. The resulting pellets were dissolved in DMSO (250 µL / well) to give final stocks. PCC solutions were mixed 2:1 with saline-sodium citrate (SSC) buffer (150 mM NaCl, 15 mM trisodium citrate pH 7.0) and transferred to a 384-well plate. For the transfer of the PCC solutions to white-coated CelluSpot blank slides (76×26 mm, Intavis AG), a SlideSpotter (Intavis AG) was used. After the completion of the printing procedure, slides were left to dry overnight. 3. Microarray binding assay µSPOT slides were blocked by incubation with 2.5 mL 5% (w / v) powdered milk (Carl Roth, T245.2, MP) in PBS (pH 7.6) for 60 min at 50 rpm and room temperature. Subsequently, slides were incubated with GST-β-catenin at 500 nM in 5% MP in 1 × PBS for 15 min before slides were washed with 3 × 2.5 mL 1 × PBS for 1 min. To label the protein for detection, the slides were incubated with 2.5 mL of a 1:5000 diluted, HRP-conjugated anti-GST antibody (Sigma Aldrich, RPN1236) in 5% MP in 1 × PBS for 15 min, after which the slides were washed with 3 × 2.5 mL 1 × PBS for 1 min. Peptide binding was detected chemiluminescently (Lowest Sensitivity, 60s exposure time) after application of 200 µL of SuperSignal West Femto Maximum Sensitive Substrate (Thermo Scientific) per slide using a c400 imaging system (Azure). Binding intensities were evaluated using FIJI including the Microarray Profile addon (OptiNav). After background subtraction of the mean greyscale value of the microarray surface surrounding the spots, raw greyscale intensities for each position were obtained for the left and right side of the internal duplicate on each microarray slide. Thereafter, the raw spot intensities were averaged for each individual slide, after which the mean intensities were averaged over n = 3 slides used for the experiment. In case of the full positional scan, raw spot intensities were averaged over n = 3 slides after which relative spot intensities for each peptide sequence were obtained by comparison to the mean of all 16 wildtype sequences. 4 Protein expression and purification 4.1 Full-length β-catenin Expression and purification of full length β-catenin (aa 1–781) was based on an earlier published protocol.[3]Briefly, Escherichia coli (E. coli) BL21(DE3) cells were transformed with a pET-28a(+) vector carrying the coding sequence for β- catenin and a C-terminal 3C protease recognition site followed by a His6-tag. A pre-culture of transformants was incubated overnight at 37 °C in TB-medium supplemented with 50 μg mL–1Kanamycin. Subsequently, 2 L of expression culture (TB-medium + 50 μg mL–1Kanamycin) were inoculated with the pre-culture to an optical density at 600 nm (OD600) of 0.1. Cells were incubated at 37 °C and induced with 0.5 mM IPTG (isopropyl-β-D-thiogalactoside) at an OD600 of 1.0. Subsequently, the expression culture was incubated at 20 °C for 16 h under agitation at 150 rpm. Subsequently, the cells were harvested (4 °C, 20 min, 4000 rpm, JA8.100 rotor Beckman Coulter) and resuspended in lysis buffer 1 (50 mM TRIS pH 8.0, 300 mM NaCl, 10 mM imidazole, 5% glycerol, 2 mM β- mercaptoethanol, 100 μM phenylmethylsulfonyl fluoride) with ca. 5 mg of DNAse and 5 mg of lysozyme. Cells were lysed using a LM10 microfluidizer at 15000 psi and cell debris were separated by centrifugation (4 °C, 40 min, 21000 rpm, JA25.50 rotor Beckman Coulter). The supernatant was loaded on an affinity chromatography column (His-Trap FF crude, 5 mL, GE Healthcare) with a flow rate of 1 mL min–1. A total amount of 10 CV (column volumes) wash buffer 1 (50 mM TRIS pH 8, 500 mM NaCl, 25 mM imidazole, 5% glycerol, 1 mM β- mercaptoethanol) with a flow rate of 1 mL min–1was applied. β-Catenin was then eluted using 5 CV of elution buffer 1 (50 mM TRIS pH 8.0, 200 mM NaCl, 250 mM imidazole, 5% glycerol 1 mM β-mercaptoethanol). Then, β-catenin was injected into a size exclusion chromatography (SEC, HiLoad 16 / 600 Superdex 200 pg, GE Healthcare) system using SEC buffer 1 (20 mM TRIS pH 8.0, 150 mM NaCl, 5% glycerol 5 mM β-mercaptoethanol) and a flow rate of 1 mL min–1. Protein containing fractions were pooled, β-catenin was concentrated (MWCO = 30 kDa) to 2 mg mL–1, snap frozen in liquid nitrogen and stored at –80 °C (yield: ca. 1 mg L–1expression culture). 4.2 β-catenin (aa 134–665) and β-catenin (aa 145–665) E. coli BL21(DE3) cells were transformed with a pGEX-6P-1 vector carrying the coding sequence for β-catenin (aa 134–665 or aa 145–665) including the coding sequence for a N-terminal GST-tag followed by a 3C protease cleavage site. A pre- culture of transformants was incubated at 37 °C overnight in TB-medium supplemented with 100 µg mL–1Ampicillin. Subsequently, 2 L of expression culture (TB-medium + 100 µg mL–1Ampicillin) was inoculated to an OD600 of 0.1. Cells were incubated at 37 °C and induced with 0.5 mM IPTG upon reaching an OD600 of 1.0. Cells were subsequently incubated at 20 °C for 16 h under agitation at 150 rpm. Subsequently, cells were harvested by centrifugation (4 °C, 20 min, 4000 rpm, JA8.100 rotor Beckman Coulter) and resuspended in lysis buffer 2 (50 mM TRIS pH 8.5, 500 mM NaCl, 5% glycerol, 2 mM DTT, 100 µM phenylmethylsulphonyl fluoride) with ca.5 mg of DNAse and 5 mg of lysozyme. Cells were lysed using a LM10 microfluidizer at an operational pressure of 18000 psi and cell debris were separated by centrifugation (4 °C, 40 min, 21000 rpm, JA25.50 rotor Beckman Coulter). The supernatant was loaded on an affinity chromatography column with a flow rate of 1 mL min–1(GSTPrep FF 16 / 10 Column, 20 mL, GE Healthcare). Subsequently, the column was washed with 3 CV wash buffer 2 (50 mM TRIS pH 8.5, 300 mM NaCl, 5% glycerol, 2 mM DTT) at a flow rate of 2 mL min–1. β-Catenin was then eluted using 3 CV of elution buffer (50 mM TRIS pH 8.5, 300 mM NaCl, 5% glycerol, 2 mM DTT, 10 mM GSH). The eluted fraction is diluted 1 / 10 in buffer A (50 mM TRIS pH 8.5, 2.5 % Glycerol, 2 mM DTT) and loaded onto an anion exchange chromatography column with a flow rate of 4 mL min–1(HiTrap Q HP column, 5 mL, Cytiva). Following loading, the column underwent washing with 3 CV wash containing 3% buffer B (50 mM TRIS pH 8.5, 2.5 % Glycerol, 2 mM DTT, 1M NaCl) at a flow rate of 2 mL min–1. The fusion protein was eluted with a linear gradient from 3–60% Buffer B, over 20 CV. For the proteolytic cleavage of the GST- tag, the anion exchange elution was diluted in buffer A (50 mM TRIS pH 8.5, 2.5 % Glycerol, 2 mM DTT) to reach a final NaCl concentration of 150 mM. Subsequently, 2 µg of GST-3C protease per mg of fusion protein was added, and the cleavage reaction was allowed to proceed overnight at 4 °C with gentle agitation. Following cleavage, the GST-tag was removed by passing the cleavage solution through the affinity column again, and the supernatant was retained. The supernatant was then concentrated to a volume of 5 mL and injected into a SEC) column (HiLoad 16 / 600 Superdex 75 pg, GE Healthcare) using SEC buffer (20 mM TRIS pH 8.5, 150 mM NaCl, 0.5% Glycerol, 2 mM DTT) with a flow rate of 1 mL min–1. Protein- containing fractions were pooled, β-catenin (aa 134–665) was concentrated (MWCO = 30 kDa) to 1.8 mg mL–1(aa 134–665) and 1.5 mg / mL–1(aa 145–665), snap frozen in liquid nitrogen and stored at –80 °C (yield: ca. 2 mg L–1expression culture for both constructs). 5 Fluorescence polarization (FP) assay for β-catenin-binding For direct FP, full length β-catenin (aa 1–781) was serially diluted in FP buffer (20 mM TRIS pH 8.0, 150 mM NaCl, 5% glycerol, 5 mM β-mercaptoethanol, 0.01% Tween-20) in a 384-well plate (Corning, Ref. 4515). Fluorescently labelled peptides (100 μM DMSO stock solutions) were diluted in FP buffer to 40 nM and subsequently added to the dilution series of β-catenin (aa 1–781) to a final concentration of 10 nM peptide and β-catenin (2.5-fold serial dilution starting at ca. 10 μM). After incubation for 1 h on ice, FP values were measured at room temperature (Tecan Spark 20M, λEx = 470 nm, λEm = 525 nm). All measurements were conducted in triplicates. For data analysis FP-values were fitted using a non- linear regression in Graphpad’s Prism 5.0. For the FP competition of the β-catenin / TCF-4 complex, peptides were dissolved in DMSO (10 mM) and diluted in FP buffer (20 mM TRIS pH 8.0, 150 mM NaCl, 2 mM TCEP, 0.01% Tween-20). Peptide competitors were titrated in a 384-well plate (Corning, Ref. 4515) using FP buffer. In a separate vessel, a solution of 0.5 μM β-catenin (aa 1 – 781) and 40 nM FITC-labelled TCF-4 peptide (Seq.: FITC-PEG2-DELISFKDEGEQE βA βA ERDLADVKSSLVN, βA = β-Alanine, as prev. published in Wendt, M., et al. Angew. Chem. IE 60.25 (2021): 13937-13944) was prepared in FP buffer and incubated on ice for 15 min. Subsequently, the protein-peptide complex was added to the titration series of peptide competitor with a final concentration of 10 nM TCF-4 peptide, 125 nM β-catenin (aa 1–781) and 2.3 ∙ 10–3μM to 1.6 μM peptide competitor. After an incubation time of 1 h at room temperature, the fluorescence polarization (FP) values were measured at room temperature (Tecan Spark 20M, λEx = 470 nm, λEm = 525 nm). Measurements were conducted in triplicates. Data points were fitted using a non-linear regression fit in Prism 5.0 (Graphpad). 6 Circular dichroism Acetylated peptides were diluted in MilliQ (pH 6.5) (+ max. 1.5 % Ethylene glycol) to a final concentration of 7.5 µM. Measurements were performed using a J- 1500 CD spectrometer (Jasco, Easton, MD, United States) and a quartz cuvette (10 mm pathlength, Hellma, Müllheim, Germany) at 20 °C. Spectra were recorded in 3 continuous scans at a scanning speed of 100 nm min−1(1 mdeg sensitivity, 0.5 nm resolution, 1.0 nm bandwidth and 2 s integration time). The spectrum of a buffer blank was subtracted from each measurement and the obtained ellipticity (mdeg) was transformed to mean residue ellipticity (MRE / deg cm2dmol−1). Helicity values were calculated using the DichroWeb software tool developed by Professor B.A. Wallace (Spectra range: 190–240 nm, Analysis programme: Contin-LL (Provencher & Glockner Method), Reference Set: 7. Closest matching solution was selected and disordered and ordered helicity values added.[4,5]7 Crystallization of β-catenin (aa 134–665) / a12-LW complex 7.1 Crystal growth β-Catenin (aa 134–665) was thawed on ice and spin-filtered at 10000 rcf through a 500 µL, 0.2 µm centrifugal filter. The protein concentration was determined on a nanodrop and a 2-molar access of a12-LW in SEC buffer (20 mM Tris pH 8.5, 150 mM NaCl, 0.5% (v / v) glycerol, 2 mM DTT) was added (stock: c = 2.5 mM). The protein / peptide complex was incubated for two hours before it was concentrated to 6.6 g L–1and crystallized in an MRC Maxi 48 well plate (SWISSCI), at room temperature. The sitting drop vapor diffusion experiment was set up using a mosquito (STP Labtech) with a drop ratio of 1 µL protein / peptide complex solution and 1 µL precipitant solution (100 mM NaKPO4 pH 6.0, 2M NaCl). Crystal formation was observed after 72 h. Prior to measurement, crystals were cryoprotected (100 mM NaKPO4 pH 6.0, 2 M NaCl, 15% (v / v) glycerol) before flash cooling in liquid nitrogen. 7.2 Structure determination Crystals were measured at the I04 beamline at the Diamond Light Source (DLS) at 100 K. Four datasets, from two different crystals, grown in the same crystallization condition (100 mM NaKPO4 pH 6.0, 2 M NaCl) were integrated with DIALS.[6]Then scaled and merged with STARANISO[7]to 2.0 Å. The protein- peptide complex was solved by molecular replacement using MrBUMP.[8]Iterative rounds of model building, and refinement were performed on the CCP4 cloud,[9]using COOT

[0010] and Refmac.[11,12]The model was optimized before submission with PDB-REDO.

[0013] Collection and refinement statistics are listed in Table 2. 8 Crystallization of β-catenin (aa 145–665) / st3 complex 8.1 Crystal growth β-Catenin (aa 145–665) was thawed on ice and spin filtered at 10000 rcf through a 500 µl, 0.2 µm centrifugal filter. After thawing, β-catenin (aa 145–665) concentration was 0.4 mg mL–1. Protein was crystallized in an MRC Maxi 48 well plate (SWISSCI) at 4°C. The sitting drop vapor diffusion experiment was set up using a mosquito (STP Labtech), at room temperature, with a drop ratio of 1 µL protein and 1 µL precipitant solution (100 mM Tris pH 8.75, 2% (v / v) PEG6000). Crystal formation was observed after 48 h. For soaking, st3 was dissolved in 50% (v / v) ethylene glycol at 1.5 mM, a 40-molar access of st3 was added to the β-catenin (aa 145–665) protein crystals and incubated for five days. Crystals were cryoprotected (100 mM Tris pH 8.75, 2% (v / v) PEG6000, 30% (w / v) glucose) before flash cooling in liquid nitrogen. 8.2 Structure determination Crystals were measured at the I03 beamline at the Diamond Light Source (DLS) at 100 K. One dataset was integrated with DIALS,[6]and scaled and merged with STARANISO[7]to 2.13 Å. The soaked protein peptide complex was solved by molecular replacement using MrBUMP.[8]Iterative rounds of model building, and refinement were performed on the CCP4 cloud,[9]using COOT

[0010] and Refmac.[11,12]Geometrical restraints for the noncanonical amino acids (PDB ID S9X and MK8) were generated with the Grade2 webserver

[0014] and the covalent linkages in the hydrocarbon stitch were generated using AceDRG

[0015] The model was polished before submission with PDB-REDO.

[0013] Collection- and refinement statistics are listed in Table 2. References Materials and Methods [1] M. Wendt, et al., Angew. Chem. Int. Ed.2021, 60, 13937–13944. [2] A. Dikmans, U. Beutling, E. Schmeisser, S. Thiele, R. Frank, QSAR Comb. Sci. 2006, 25, 1069–1080. [3] L. Dietrich, B. Rathmer, K. Ewan, T. Bange, S. Heinrichs, T. C. Dale, D. Schade, T. N. Grossmann, Cell Chem. Biol.2017, 24, 958-968.e5. [4] L. Whitmore, B. A. Wallace, Biopolymers 2008, 89, 392–400. [5] N. Sreerama, R. W. Woody, Anal. Biochem. 2000, 287, 252–260. [6] G. Winter, et al., Acta Crystallogr. Sect. Struct. Biol. 2018, 74, 85–97. [7] I. J. Tickle, C. Flensburg, P. Keller, W. Paciorek, A. Sharff, C. Vonrhein, G. Bricogne, 2016 STARANISO (http: / / staraniso.globalphasing.org / cgi- bin / staraniso.cgi). Cambridge, UK, Global Phasing Ltd. [8] R. M. Keegan, S. J. McNicholas, J. M. H. Thomas, A. J. Simpkin, F. Simkovic, V. Uski, C. C. Ballard, M. D. Winn, K. S. Wilson, D. J. Rigden, Acta Crystallogr. Sect. Struct. Biol.2018, 74, 167–182. [9] E. Krissinel, et al., Acta Crystallogr. Sect. Struct. Biol. 2022, 78, 1079– 1089.

[0010] P. Emsley, B. Lohkamp, W. G. Scott, K. Cowtan, Acta Crystallogr. D Biol. Crystallogr. 2010, 66, 486–501.

[0011] K. Yamashita, M. Wojdyr, F. Long, R. A. Nicholls, G. N. Murshudov, Acta Crystallogr. Sect. Struct. Biol.2023, 79, 368–373.

[0012] G. N. Murshudov, P. Skubák, A. A. Lebedev, N. S. Pannu, R. A. Steiner, R. A. Nicholls, M. D. Winn, F. Long, A. A. Vagin, Acta Crystallogr. D Biol. Crystallogr. 2011, 67, 355–367.

[0013] R. P. Joosten, F. Long, G. N. Murshudov, A. Perrakis, IUCrJ 2014, 1, 213–220.

[0014] O. S. Smart, T. O. Womack, A. Sharff, C. Flensburg, P. Keller, W. Paciorek, C. Vonrhein, G. Bricogne, 2011.

[0015] F. Long, R. A. Nicholls, P. Emsley, S. Gražulis, A. Merkys, A. Vaitkus, G. N. Murshudov, Acta Crystallogr. Sect. Struct. Biol. 2017, 73, 112–122.

[0016] Y. Xing, W. K. Clements, D. Kimelman, W. Xu, Genes Dev. 2003, 17, 2753–2764. Results β-Catenin is composed of a central armadillo repeat domain (grey, Figure 1a) that is flanked by flexible termini.[34,35]The armadillo repeat domain is involved in several PPIs, mainly comprising intrinsically disordered regions within its binding partners that only adopt a defined structure upon interaction with β-catenin. Transcription factors of the TCF / LEF family (Figure 1a) interact with binding site 2 and 3 of the armadillo repeat domain.[25,36]Inhibition of this interaction attenuates formation of the transcriptional activator complex and results in Wnt pathway inhibition.

[0037] Searching for a suitable starting sequence, we revisited the 16-mer β-catenin-binding motif of Axin (a16, 467–482, Figure 1a) which binds to site 2 and competes with transcription factor binding.

[0038] In its bound form, the central part of a16 adopts an α-helix which is flanked by short extended stretches. Initially, we pursued sequence maturation of a16 and, therefore, probed the full single amino acid variation space using a µSPOT peptide array (Figure 1b,).[41,42]For that purpose, peptides were synthesized on acid-labile, amino- functionalized cellulose membrane discs, which were then dissolved, precipitated and reconstituted. Peptide solutions were printed on white-coated CelluSpot slides, blocked and subsequently incubated with the GST-tagged armadillo repeat domain of β-catenin (134-665). Binding was monitored using an HRP-conjugated anti-GST antibody followed by chemiluminescent readout. Analysis of the affinity data revealed amino acid positions with variations that resulted in increased binding affinity (Figure 1b). Over the entire panel, variations V477L and M481F showed the highest binding signals. To assess the binding affinities of these sequences, the corresponding peptides a16-L (V477L) and a16-F (M481F) were synthesized and fluorescently labelled using fluorescein isothiocyanate (FITC) and a polyethylene glycol spacer (PEG2). Dissociation constants (Kd) were determined in a direct fluorescence polarization (FP) assay

[0043] with full length β-catenin. Relative to parent sequence a16, both peptides indeed showed increased affinity (7- and 14-fold, respectively, Figure 1c). We also tested the corresponding two tryptophane variations due to their increased signal intensities in the array (Figure 1b). Again, both resulting peptides showed increased binding (Figure 2) with the M481W variation providing highest-affinity peptide a16-W (25-fold increased affinity, Figure 1c). Aiming to reduce the size of the peptide, we truncated the termini of a16 providing peptide a12 (470–481) involving only the central α-helical segment (Figure 1b). Peptide a12 showed very low affinity for β-catenin (dissociation constant, Kd > 10 µM), which increased substantially when including the two highest-affinity variations (V467L and M480W) to provide peptide a12-LW (Figure 1c, Kd = 60 nM). Truncation of the N-terminal glutamate E470 providing peptide a11-LW resulted in considerably reduced binding affinity (Kd = 1.4 µM). We also tested the following peptides a16_2V, a16_1W, a16_2Y, a16_2W, a16_11W, a16_14W, a16_15F, a16_15W, a16_11L / 15W and a16_2Y / 11L / 15W (Figure 1c). Variation N268Y, V477L / M481W and a combination thereof in addition showed high binding affinity (Figure 1c). Table 1. Characterization of selected peptides with names, sequences as well as calculated and found m / z values. For chemical structures of cysteine modifications see Figure 10. peptide sequence N-term.purity m / z m / z found / % calc. a16 E N P E S I L D E H V Q R V M R FlTC- >90 1241.9 1243.2 PEG2 [M+2H]+2a16-L E N P E S I L D E H L Q R V M R FlTC- >90 1249.9 1250.5 PEG2 [M+2H]+2a16-F E N P E S I L D E H V Q R V F R FlTC- >90 1250.8 1251.6 PEG2 [M+2H]+2a16-W E N P E S I L D E H V Q R V W R FlTC->90 1270.4 1271.1 PEG2 [M+2H]+2a12 E S I L D E H V Q R V M FlTC- >90 995.0 995.5 [M+2H]+2PEG2 a12-LW E S I L D E H L Q R V W Ac >90 782.9 783.5 [M+2H]+2FlTC- >90 1029.0 1029.6 PEG2 [M+2H]+2a11-LW S I L D E H L Q R V W Ac >90 718.3 718.8 [M+2H]+2FlTC- >90 964.6 964.8 [M+2H]+2PEG2 st1 S5 I L D S5 H L Q R V W Ac >90 735.4 736.1 [M+2H]+2FlTC- >90 981.6 982.6 [M+2H]+2PEG2 st2 S I L D R5 H L S5 R V W Ac >90 714.9 715.3 [M+2H]+2FlTC- 81 961.1 961.3 [M+2H]+2PEG2 st3 S5 I L D B5 H L S5 R V W Ac >90 753.9 754.7 [M+2H]+2FlTC- >90 1000.2 1001.1 PEG2 [M+2H]+2a12-LC E S I L D E H L Q R V C FlTC- >90 987.6 988.0 [M+2H]+2PEG2 a12-LC- E S I L D E H L Q R V C(b) FlTC- >90 1032.7 1034.2 b PEG2 [M+2H]+2a12-LC- E S I L D E H L Q R V C(na) FlTC- >90 1057.7 1058.6 na PEG2 [M+2H]+2a12-LC- E S I L D E H L Q R V C(bi) FlTC- >90 1070.7 1071.2 bi PEG2 [M+2H]+2a12-LC- E S I L D E H L Q R V C(ob) FlTC- >90 1039.7 1040.1 ob PEG2 [M+2H]+2a12-LC- E S I L D E H L Q R V C(mb) FlTC- >90 1039.7 1040.2 mb PEG2 [M+2H]+2a12-LC- E S I L D E H L Q R V C(fb) FlTC- >90 1066.7 1067.2 fb PEG2 [M+2H]+2a12-LC- E S I L D E H L Q R V C(pb) FlTC- >90 1039.7 1040.1 pb PEG2 [M+2H]+2a12-LC- E S I L D E H L Q R V C(pf) FlTC- >90 1066.7 1067.6 pf PEG2 [M+2H]+2a12-LC- E S I L D E H L Q R V C(pi) FlTC- 83 1053.7 1054.3 pi PEG2 [M+2H]+2stC S5 I L D B5 H L S5 R V C Ac >90 712.4 713.1 [M+2H]+2FlTC- 75 958.7 959.4 [M+2H]+2PEG2 stC-b S5 I L D B5 H L S5 R V C(b) Ac >90 757.5 757.8 [M+2H]+2FlTC- 79 1003.7 1004.2 PEG2 [M+2H]+2stC-mb S5 I L D B5 H L S5 R V C(mb) Ac 80 764.5 764.8 [M+2H]+2FlTC- 80 1010.7 1011.2 PEG2 [M+2H]+2stC-fb S5 I L D B5 H L S5 R V C(fb) Ac >90 791.5 791.8 [M+2H]+2FlTC- 75 1037.7 1038.2 PEG2 [M+2H]+2Before pursuing further derivatization, we aimed for the structural characterization of the complex between β-catenin and high-affinity peptide a12- LW. Initial screening campaigns of the armadillo repeat domain (134–665) with a12-LW provided crystals that could be further optimized to allow the collection of X-ray diffraction data. Including reflections up to 2.0 Å resolution, the structure was solved in space group P212121 (Table 2) using molecular replacement (MrBUMP,

[0044] PDB ID 2z6g

[0045] ). The obtained crystal structure reveals one armadillo repeat domain per asymmetric unit (Figure 3). Except for one loop (549– 559), the protein residues are well-resolved in the electron density and overlay closely with earlier reported β-catenin armadillo repeat domain structures (e.g., in complex with a16, Cα-RMSD = 0.75 Å). At site 2 of β-catenin, we observed an additional 2mFo–DFc positive difference electron density which clearly defined all residues of a12-LW (Figure 3). When superimposing the β-catenin-bound structures of a12-LW and a16,

[0038] we observe a close overlay of analogous residues in both α-helical peptides (Figure 4a, Cα-RMSD = 0.28 Å). The two introduced variations, V8L and M12W, appear to address previously unexplored cavities on β- catenin. Tryptophane W12 (Figure 4a) in a12-LW explores an area that had not been occupied by the original methionine M481 in Axin peptide a16 (light grey, Figure 4a).

[0002] Table 2. Crystallographic table of the crystal structure of β-catenin (aa 134–665) in complex with peptide a12-LW and β-catenin (aa 145–665) in complex with st3. β-catenin (aa 134–665) / β-catenin (aa 145–665) / peptide a12-LW peptide st3 Data collection DLS (Beamline I04) DLS (Beamline I03) Wavelength / Å 0.9537 0.9212 Resolution limits / Å 70.99 – 2.00 (2.21 – 2.00) 93.96–2.13 (2.31–2.13) Space group (#) P212121 (19) P212121 (19) Cell dimensions a, b, c / Å 49.53, 91.25, 112.98 64.57, 106.62, 187.92 ⍺, β, γ / ^ 90.00, 90.00, 90.00 90.00, 90.00, 90.00No. of total reflections 963996 (28586) 697985 (36305) No. of unique reflections 18536 (926) 51113 (2551) Multiplicity 52.0 (30.9) 13.7 (14.2) Completeness spherical / 52.5 (10.5) 71.4 (16.6) % Completeness ellipsoidal / 93.5 (61.8) 94.7 (64.9) 11.1 (1.2) 11.9 (1.3) 1 (0.958) 0.999 (0.816) Rpim 0.03 (0.124) 0.036 (0.319) Refinement No. of total reflections 18530 (82) 50924 (321) No. of reflections Rfree 935 (2) 2495 (21) Rwork / Rfree 0.184 / 0.232 0.201 / 0.239 No. atoms (non-hydrogen) 4125 8174 Protein 3886 7663 Peptide 111 108 Ligand / Ion 3 119 Water 125 328 Protein residues 519 1019 R.m.s. deviations Bond lengths / Å 0.007 0.007 Bond angles / ^ 0.98 1.19Ramachandran Favored regions / % 99.61 98.59 Allowed regions / % 0.39 1.41 Outliers / % 0 0.00 Rotamer outliers / % 0.46 0.85 Clash score 1.72 2.69 Average B-factor / Å242.47 48.80 Protein 42.34 48.64 Peptide 53 69.52 Ligand / Ion 39.88 81.80 Water 37.39 37.70 Subsequently, a12-LW was subjected to an alanine-scan, in which each amino acid was individually replaced by alanine and binding to β-catenin assessed in a direct FP assay. In line with the crystal structure, most alanine variations resulted in a considerable decrease in affinity (>50-fold) and can therefore be considered hot spots (* in Figure 4).[48,49]The alanine-substitution of the N-terminal glutamate E1 reduced binding moderately (~10-fold), and the variation of S2, E6 and Q9 did not affect binding. With these findings in mind, we approached the design of hydrocarbon stapled peptides[50–53]to stabilize the α-helical confirmation of the peptide and potentially increase cellular uptake using 11-mer peptide a11-LW as starting point. Peptide stapling involves the introduction of olefin-bearing, α- methylated amino acids which are then crosslinked via a ring-closing metathesis (RCM, Figure 6).[50–53]Utilizing positions 2, 6 and 9, we designed two stapled peptides (left, Figure 4b): st1 with a relative spacing of i,i+4 via two S5-building blocks (positions 2 and 6), and st2 with i,i+3 spacing

[0054] via a R5 and S5 building block (positions 6 and 9, respectively, Figure 4b, Figure 6). In addition, we considered the combination of both staple architectures to provide a so-called stitched peptide.[55,56]In stitched peptides, a central bis-olefin- bearing amino acid (B5) is employed to provide an overall bicyclic peptide scaffold after RCM with the two flanking olefin side chains (right, Figure 4b). Notably, stitched peptides combining i,i+4 and i,i+3 crosslinks (i,i+4,i+7) have not been reported so far. Given the opposite orientation of the olefin side chain at position 6 in st1 (S) and st2 (R), we, however, considered this architecture feasible. The corresponding stitched peptide st3 then comprises non-proteinogenic amino acids at position 2, 6 and 9 (Figure 4c). The three class A peptidomimetics st1, st2 and st3 were assembled using solid-phase peptide synthesis which was followed by RCM with Grubbs catalyst, 1stgeneration.

[0050] Subsequently, the N-terminus was either acetylated or fluorescently labeled (FITC-PEG2) depending on the subsequent assays. In all cases, we obtained the desired fully cyclized products (Figure 7). This includes stitched peptide st3 indicating that indeed both crosslinks were formed and the i,i+4,i+7 stitch is synthetically feasible. However, at this point, it was not clear which epimer of the S5 building block was formed. Initially, the acetylated peptides were characterized using circular dichroism (CD) spectroscopy, to assess their secondary structures in the unbound state (Figure 4d). While parent peptide a11-LW exhibits a predominantly random coil character (7% α-helicity), all three peptidomimetics show increased helicity with stitched peptide st3 revealing the highest α-helical content (30% α-helicity, Figure 4c).[46,47]In addition, binding affinities for full-length β-catenin were determined using a direct FP assay (Figure 4e). Relative to parent peptide a11-LW (Kd = 1.4 µM), both stapled peptides showed increased affinity with st1 (Kd = 27 nM) experiencing 50-fold and st2 (Kd = 360 nM) 4-fold increased affinity for β-catenin. Stitched peptide st3 (Kd = 23 nM) combining both crosslinks, shows with 60-fold the highest affinity increase (Figure 4c). Interestingly, affinities correlate with helicity (st3 > st1 > st2 > a11-LW), suggesting that indeed the pre-organization of the bound conformation in solution and thereby the reduction of entropic penalty upon binding is responsible for increased affinities. To assess the status of the maturation process, the binding efficiency index (BEI = pKd·MW–1)[57,58]for these molecules was determined (Figure 4c). For BEI calculations, we use the Kd-values obtained with labeled peptides in FP assays and the molecular weights (MW) of acetylated peptides, as these will be assessed in subsequent cell-based assays. For reference, parent peptide a16 has a BEI of 2.7 while cell-penetrating KRAS inhibitor LUNA18 has a BEI of 7.3.

[0018] After sequence maturation, truncation and cyclization, the two highest-affinity peptidomimetics st1 and st3 show a considerably increased BEI of 5.1. To investigate the implications of peptide stitching in more detail, we pursued the crystallization of st3 bound to the armadillo repeat domain of β- catenin (145–665). We screened for suitable crystallization conditions and optimized initial hits to obtain X-ray diffraction from four of the resulting crystals. Reflections up to 2.13 Å resolution were included for integration (DIALS),

[0061] merged and scaled (STARANISO).

[0062] Molecular replacement (MrBUMP,

[0044] PDB ID 2z6g

[0045] ) provided a solution in space group P212121 with two protomers per asymmetric unit (Table 2). The armadillo repeat domains are well-resolved (except for loop 549–559) and align with the a12-LW-bound β-catenin (Cα-RMSD = 1.2 Å). The observed 2mFo–DFc difference electron density clearly defines stitched peptide st3 bound to the expected site 2 of one β-catenin protomer. It also confirms the anticipated crosslink connectivity (Figure 9) in which the S5 building block at position 2 is connected with the B5 arm equivalent to the crosslink in st1, and S5 at position 9 is connected to the B5 arm corresponding to st2. Consequently, B5 in st3 has an absolute R configuration (Figure 9). The structure of stitched peptide st3 overlays closely with linear precursor a12-LW both with respect to backbone as well as side chain atoms (Cα-RMSD = 0.27 Å, Figure 8b). In the β-catenin-bound state, st3 adopts a fully α-helical conformation facilitating numerous contacts with target protein residues (Figure 8c). The non-proteinogenic amino acids cyclized during RCM at positions 2, 6, and 9 are the only residues not engaged in direct interactions with β-catenin. The remaining st3 residues form contacts with the four armadillo repeat helices which define binding site 2 (Figure 8c). These interactions involve hydrogen bonds (e.g., R10[st3] / N261+H223[β-catenin] and W12[st3] / T339[β-catenin]), salt bridges (e.g., D5[st3] / K292[β-catenin]) as well as hydrophobic contacts (e.g., I3[st3] / F253[β- catenin], L4[st3] / Y254[β-catenin]). Interestingly, we observe an edge-to-face π-π interaction between W12[st3] / W338 / [β-catenin], which is also present for a12-LW and may explain the observed affinity gain upon M12W substitution (Figure 1b). We aimed for a derivatization of this residue thereby further exploring the corresponding hydrophobic groove on β-catenin (Figure 3, bottom part). In this respect, we considered the testing of different aromatic side chains. To facilitate the installation of a diverse set of substituents at a late stage of the synthesis, we decided to introduce a cysteine instead of the tryptophan (W12C), which can then be reacted with a diverse set of aromatic electrophiles. Initially, linear peptide a12- LW served as scaffold for the derivatization to reduce synthetic efforts. After synthesis and purification, the fluorescently labelled cysteine analog (a12-LC) was functionalized using a small library of commercially available bromo-benzene building blocks yielding nine modified peptides (Figure 10). The binding affinity to β-catenin was determined by direct FP, yielding benzyl (b), meta-methylbenzyl (mb) and meta-(trifluoromehtly)benzyl (fb) as the three highest affinity modifications (3.3–5.5-fold increased Kd relative to a12-LW, Figure 10 and Figure 11). We then tested these three modifications (b, mb and fb), in the context of the stiched peptide applying the corresponding W12C variant of st3 (stC, Figure 12a). The reaction of stC with the bromo-benzyl derivatives yielded peptidomimetics stC-b, stC-mb and stC-fb (Figure 12b). In direct FP binding assays with fluorescently labelled peptidomimetics, we observed increased β-catenin affinities for all three modified versions (2–3-fold increased relative to st3, Figure 12c and 12d). Peptidomimetic stC shows a relatively high affinity (2-fold reduced relative to st3). This is in line with the initially performed signle amio acid screen in which the M-to-C variation increased affinity (Figure 1b). Notably, highest affinity peptdomimetic stC-b (Kd = 7.5 nM) also exhibits the highest binding efficiency (BEI = 5.4). In addition, we verified competition of stC-b with the binding of a labelled TCF4-fragment to β-catenin (Figure 13). The cellular activity was tested in a TOPFLASH reporter gene assay which was stably integrated into HEK293T cells. In brief, this reporter systems uses a TCF / β-catenin promotor that controls the expression of firefly luciferase. As reference, a Wnt-independent promotor controlling renilla luciferase is used. The Wnt pathway was activated with Wnt-3a and cells were incubated with the peptides (t = 24 h). Under these conditions, parent peptide stC-b showed highest activity (Figure 12c and 12e). To further explore the hydrophobic pocket identified in the crystal structure, we synthesized variants with modified D-cysteine (c) instead of L8 (ES5ILDS5HcQRV, st-E11 series, Figure 15). Starting from peptide st+E / -W (ES5ILDS5HLQRV, Kd = 101 nM), introduction of various aromatic modifications at the D-cysteine (c) residue yielded peptides with significantly improved binding affinity. Notably, the naphthyl modification (st-E11(na)) achieved a Kd of 11 nM, representing a 9.2-fold improvement, while the para-bromobenzyl modification (st-E11(pb)) showed even higher affinity with a Kd of 7 nM (14.4-fold improvement, Figure 15 c, d). We next explored aromatic crosslinks between two cysteine residues. Peptides 48-1 (ESILDEHcQRVC) and 48-2 (ESILDEHcQRV(hC)) containing D / L-(homo-) cysteines at positions 8 and 12 were reacted with various dibromide compounds (A- F, Figure 16b) to form aromatic thioether crosslinks. The resulting crosslinked peptides showed improved binding affinities compared to the unmodified parent peptides (48-1 / 2). 48-2(C) and 48-2(E) achieved Kd values of 785 nM and 347 nM, respectively (Figure 16d,e). The use of homo-cysteine (hC) at position 12 (48-2 series) generally provided improved binding compared to regular cysteine. References Results

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Claims

1. Claims 1. A β-catenin-binding peptide or peptidomimetic having a length of 7-12 amino acids and comprising an amino acid sequence ESILDEHXQRVW, wherein X is L, M, I, F, Y, W or C, or a variant of said amino acid sequence, wherein said variant comprises at least amino acids 2-8 of said sequence and optionally having: - up to three substitutions of an amino acid at position 1, 2, 6, 7, 9, 10, 11 and / or 12 by another amino acid, - S at position 2 and E at position 6 each substituted by a non-proteinogenic amino acid which non-proteinogenic amino acids are linked to one another and / or E at position 6 and Q at position 9 each substituted by a non-proteinogenic amino acid which non-proteinogenic amino acids are linked to one another, and - one of the 5 most C-terminal amino acids is substituted by a modified amino acid, preferably X at position 8, Q at position 9, R at position 10, V at position 11 and W at position 12 substituted by a modified amino acid.

2. The β-catenin-binding peptide or peptidomimetic according to claim 1, wherein X is C or L.

3. The β-catenin-binding peptide or peptidomimetic according to claim 1 or 2, wherein said up to three optional substitutions of an amino acid by another amino acid are selected from: - substitution of E at position 1 by Y, W, F or a corresponding non-proteinogenic amino acid; - substitution of S at position 2 by Y, W, H, F, D or a corresponding non- proteinogenic amino acid; - substitution of E at position 6 by F, W, Y, D or a corresponding non-proteinogenic amino acid; - substitution of H at position 7 by Y or a corresponding non-proteinogenic amino acid; - substitution of Q at position 9 by A, M, Y, W, R, N, L, K, H, F, E, C or a corresponding non-proteinogenic amino acid; - substitution of R at position 10 by Y, W, F or a corresponding non-proteinogenic amino acid; - substitution of V at position 11 by Y, W, M, L, I, H, F or a corresponding non- proteinogenic amino acid; and / or - substitution of W at position 12 by M, Y, Q, N, L, I, H, G, F, E, D, C, A or a corresponding non-proteinogenic amino acid.

4. The β-catenin-binding peptide or peptidomimetic according to any one of the preceding claims, wherein said up to three optional substitutions are selected from: - substitution of H at position 7 by Y or a corresponding non-proteinogenic amino acid; - substitution of V at position 11 by Y, W, L, I, F or a corresponding non- proteinogenic amino acid; and / or - substitution of W at position 12 by Y, L, F or a corresponding non-proteinogenic amino acid.

5. The β-catenin-binding peptide or peptidomimetic according to any one of the preceding claims, wherein said peptide or peptidomimetic has a length of 7-11 amino acids.

6. The β-catenin-binding peptide or peptidomimetic according to any one of the preceding claims, wherein said peptide or peptidomimetic has a length of 7-11 amino acids and wherein S at position 2 and E at position 6 are each substituted by a non-proteinogenic amino acid which non-proteinogenic amino acids are linked to one another by a crosslink and / or E at position 6 and Q at position 9 each substituted by a non-proteinogenic amino acid which non-proteinogenic amino acids are linked to one another by a crosslink and / or L at position 8 and W at position 12 each substituted by a non-proteinogenic amino acid which non- proteinogenic amino acids are linked to one another by a crosslink, wherein each of said crosslinks is independently selected from the group consisting of a hydrocarbon crosslink, a lactam crosslink, a disulfide crosslink, a thioether crosslink, a triazole crosslink and a carbamate crosslink.

7. The β-catenin-binding peptide or peptidomimetic according to claim 6, wherein each of said crosslinks is a hydrocarbon crosslink.

8. The β-catenin-binding peptide or peptidomimetic according to any one of the preceding claims, wherein said modified amino acid comprises an aromatic side chain.

9. The β-catenin-binding peptide or peptidomimetic according to any one of the preceding claims, wherein said modified amino acid is the C-terminal amino acid.

10. The β-catenin-binding peptide or peptidomimetic according to any one of the preceding claims, wherein the peptide is selected from the group consisting of: - SILDEHLQRVW, - S5*ILD S5*HLQRVW, wherein * indicates that the side chains of the indicatedamino acids S5 are crosslinked,- S5*ILD B5*#HL S5#RVW, wherein * indicates that the side chains of theindicated amino acids S5 and B5 are crosslinked, # indicates that the side chains ofthe indicated amino acids B5 and S5 are crosslinked,- S5*ILD S5*HLQRVC(mod), wherein * indicates that the side chains of the indicated amino acids 5S are crosslinked, - S5*ILD B5*#HL S5#RVC(mod), wherein * indicates that the side chains of theindicated amino acids S5 and B5 are crosslinked, # indicates that the side chains ofthe indicated amino acids B5 and S5 are crosslinked.- S5* ILD S5*HLQRV, wherein * indicates that the side chains of the indicated amino acids S5 are crosslinked, - E S5*ILD S5* HLQRV, wherein * indicates that the side chains of the indicated amino acids S5 are crosslinked, - E S5*ILD S5* HcQRV, wherein * indicates that the side chains of the indicated amino acids S5 are crosslinked,- E S5*ILD S5* HcQRVC, wherein * indicates that the side chains of the indicated amino acids S5 are crosslinked, - E S5*ILD S5* HcQRV(hC), wherein * indicates that the side chains of the indicated amino acids S5 are crosslinked, - S5* ILD B5*# Hc(mod)S5# RVC(mod), wherein * indicates that the side chains of the indicated amino acids S5 and B5 are crosslinked, # indicates that the side chains of the indicated amino acids B5 and S5 are crosslinked, c(mod) and C(mod) indicate that the side chains of the indicated amino acids are crosslinked via a thioether crosslink, - SILD S5* Hc(mod) S5* RVC(mod), wherein * indicates that the side chains of the indicated amino acids S5 are crosslinked, c(mod) and C(mod) indicate that the side chains of the indicated amino acids are crosslinked via a thioether crosslink, - S5* ILD S5* HLQRVC(mod), wherein * indicates that the side chains of the indicated amino acids S5 and S5 are crosslinked, c(mod) and C(mod) indicate that the side chains of the indicated amino acids are crosslinked via a thioether crosslink.

11. A β-catenin binding peptide having a length of 7-20 amino acids and comprising an amino acid sequence EYPESILDEHXQRVWR, wherein X is L, M, I, F, Y, W or C, or a variant of said amino acid sequence, wherein said variant comprises at least amino acids 5-11 of said sequence and optionally having up to three substitutions of an amino acid at position 1, 2, 3, 4, 5, 9, 10, 12, 13, 14, 15 and / or 16 by another amino acid.

12. The β-catenin-binding peptide according to claim 11, wherein said up to three optional substitutions of an amino acid by another amino acid are selected from: - substitution of E at position 1 by Y, W, F, C, I; - substitution of Y at position 2 by N, W, F, D, C; - substitution of P at position 3 by Y, F, A; - substitution of E at position 4 by Y, W, E; - substitution of S at position 5 by Y, W, H, F, D; - substitution of E at position 9 by F, W, Y, D;- substitution of H at position 10 by Y; - substitution of Q at position 12 by A, M, Y, W, R, N, L, K, H, F, E, C; - substitution of R at position 13 by Y, W, F , - substitution of V at position 14 by Y, W, M, L, I, H, F; - substitution of W at position 15 by M, Y, Q, N, L, I, H, G, F, E, D, C, A, or a corresponding non-proteinogenic amino acid such as homocysteine; and / or - substitution of R at position 16 by Y, W, Q, L, F; preferably wherein said up to three optional substitutions are selected from: - substitution of E at position 1 by Y, W, F; - substitution of Y at position 2 by W, F; - substitution of Q at position 12 by Y, W, F; - substitution of V at position 14 by Y, W, L, I, F; , substitution of W at position 15 by Y, L, C, F, or a corresponding non- proteinogenic amino acid such as homocysteine; and / or - substitution of R at position 16 by W, F, L.

13. A nucleic acid molecule comprising a nucleic acid sequence encoding a β- catenin-binding peptide according to any one of claim 1-12, preferably a β-catenin- binding peptide having a length of 7-12 amino acids and comprising an amino acid sequence ESILDEHXQRVW, wherein X is L, M, I, F, Y, W or C, or a variant of said amino acid sequence, wherein said variant has up to three substitutions of an amino acid at position 1, 2, 6, 7, 9, 10, 11 and / or 12 by another amino acid or a β- catenin-binding peptide according to claim 11 or 12.

14. A β-catenin-binding peptide or peptidomimetic according to any one of claims 1–12 for use as a medicament, preferably for use in a method of treating an individual suffering from a tumor or a metastasis thereof, wherein the tumor preferably is selected from a carcinoma such as a colorectal carcinoma, esophageal adenocarcinoma, pancreatic ductal adenocarcinoma and breast carcinoma, or for use in a method of preventing a pre-malignant condition in an individual to become cancerous, said pre-malignant condition preferably selected from colorectal adenoma and Barrett’s esophagus.

15. A peptide or peptidomimetic for use according to claim 14, wherein said peptide, peptidomimetic or a nucleic acid sequence encoding said peptide, such as mRNA, is coupled to or encapsulated into a carrier or delivery vehicle, preferably selected from the group consisting of a nanoparticle, microparticle, nanocapsule, nanocomplex, polyplex, carbon nanotube, quantum dots, microcapsule, liposome, microsphere, hydrogel, polymer, micelle, dendrimer, lipid or lipid complex, cyclodextrins, dextran, or protein such as serum albumin, an antibody or an antibody fragment.

16. Use of the peptide or peptidomimetic according to any one of claims 1–12, for inhibiting Wingless / integrase-1 (Wnt)-signaling in isolated tissues or cells.

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