Novel notch receptor inhibitors and uses thereof

Abstract

Novel Notch receptor binding peptides and polynucleotides, expression constructs, vectors, cells or cell cultures, and compositions encoding, expressing or comprising said peptides are provided herein. These novel components may be used to inhibit Notch receptor dimerization and / or activation. Associated methods for using the novel components provided herein are also described.

Description

[0001] Novel Notch receptor inhibitors and uses thereof

[0002] Novel Notch receptor binding peptides and polynucleotides, expression constructs, vectors, cells or cell cultures, and compositions encoding, expressing or comprising said peptides are provided herein. These novel components may be used to inhibit Notch receptor dimerization and / or activation. Associated methods for using the novel components are also provided.

[0003] Background

[0004] The Notch pathway is an ancient, ubiquitously expressed cell signalling system, which is essential for embryonic and post-embryonic cell fate control and tissue growth. It is activated via intercellular interactions between receptors and ligands expressed on neighbouring cells. This releases the latent transcription activating potential of the receptor via proteolytic cleavage of the intracellular domain, which translocates to the nucleus and directly stimulates target gene expression as part of a DNA-bound transcription activation complex. Broadly, to date, it has been assumed that this process involves interactions between ligand homomers and receptor homomers.

[0005] The ubiquitous Notch signalling system is one of the seven major cell signalling pathways whose basic features and central functions in animal tissue biology have remained evolutionarily conserved (1,2). It was first identified in Drosophila during the early part of the last century, and so-named because variants caused a characteristic notch in the fruit fly wings (3). Since then, the molecular details of its basic mechanisms, and its pivotal role in tissue development and maintenance, have been comprehensively dissected in a wide range of species covering the span of metazoan evolution from insects to humans (4,5). The core pathway is composed of type 1 transmembrane receptors and type 1 transmembrane ligands. Invertebrates, such as Drosophila, possess a single Notch receptor family member controlled by two ligands, whilst vertebrates encode up to four distinct receptor types (Notch1-4) and five different ligands: Jagged (JAG)1, JAG2, Delta-Like (DLL)1, DLL3, and DLL4 (6,7). The overall architecture of the receptors, from Drosophila to human, has remained relatively unchanged. Mature heteromeric Notch receptors are large (upwards of 300 KDa) and consist of an extracellular ligand binding domain coupled to a membrane-anchoring intracellular portion which encodes the intrinsic Notch receptor transcription activation potential. The extracellular domain (ECD) constitutes the bulk of the mass (in the range of 250 KDa) composed of linked epidermal growth factor (EGF)-like domains: Notchl and Notch2 encode 36 such domains, Notch3 has 34, and Notch4 has 29 (8). Structural studies utilizing specific ECD domains suggest that the EGF-like repeats minimally function as sites of interaction with the structurally similar EGF-like repeats, and other distinct domains, of the Notch ligands, and a number of such sites have been mapped for a subset of receptor-ligand combinations (9-12). The EGF-like domains are connected to a juxtamembrane negative regulatory region (NRR) and the heterodimerisation domain. The NRR is formed of three contiguous LIN-12 / Notch repeats (LNRs), which are understood to function as an essential component of the mechanosensory activity reported to underlie ligand-dependent receptor activation (13). Operationally, in the absence of ligand, this domain adopts an autoinhibitory conformation and upon ligand binding, pulling forces expose a buried ADAM metalloprotease S2 cleavage site which initiates the cascade of proteolytic events, which ultimately lead to activation of Notch receptor target genes (14-17).

[0006] Significantly, these analyses provided important insights into the mechanistic basis of aberrant Notch receptor activation in diseases such as T-acute lymphoblastic leukaemia (T-ALL) (21), which is characterized by activating mutations which cluster in the NRR of Notchl (22-25). Indeed, the central importance of Notch in normal tissue development and homeostasis is also revealed by the broad spectrum of diseases in which normal Notch signalling is corrupted (2,8). In addition to T-ALL, Notch plays an important role in oncogenesis in a wide spectrum of other tumours including lymphoma, prostate cancer and colorectal cancer (26-28). Disease-promoting mutations of the Notch receptor are also found in non-tumour related diseases, for example, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and pulmonary arterial hypertension have been linked to Notch3 mutations (29,30), and bicuspid aortic valve disease, which have been linked to mutations of Notchl (31).

[0007] Consequently, during the last two decades there has been a global effort to identify molecules which can specifically block aberrant Notch signalling, notably gamma secretase inhibitors (GSIs), which were the first Notch receptor inhibitors to be tested clinically (two decades ago) and which remain at the forefront of efforts to devise a treatment of clinical utility (32-37). However, a major drawback of such approaches is overt toxicity which results from the large number of substrates (in excess of ninety), in addition to the majority of Notch receptor paralogues, which are targeted by these enzymes. Moreover, during tissue growth and differentiation, distinct Notch paralogues perform specific functions in an exquisitely regulated, spatially and temporally restricted manner which can be either stimulatory or inhibitory depending on the context. Likewise, depending on the tumour cell or its function in the tumour microenvironment, Notch signalling can be either tumour-promoting or tumour suppressive (38), and for these reasons pan-Notch signalling inhibition can yield unpredictable and unfavourable outcomes.

[0008] The inventor has identified a novel class of peptide inhibitors of Notch receptor activation, including highly specific peptides which can selectively target each Notch paralogue separately, as a potential solution to these currently intractable problems. The inventor has taken a biochemical approach to reexamine Notch receptor transactivation. Whereas downstream transcriptionally active cleaved Notch intracellular domain has been shown to assemble on DNA as a dimeric complex (39-41), in the absence of alternative models, it has, generally, been assumed that the initiation of signalling at the cell surface is executed via essentially monomeric receptor / ligand interactions, which has significantly limited therapeutic design The inventor has surprisingly discovered that receptor dimerization / oligomerization (hereafter referred to as dimerization) is necessary for Notch receptor transactivation which has enabled the identification of novel peptide inhibitors, including highly specific peptide inhibitors, which block both receptor dimerization and the resultant receptor transactivation. These first-in-class inhibitors could unveil a new approach to treating diseases in which normal Notch signalling is disrupted.

[0009] In particular, the inventor has found that: 1) Notch receptors can efficiently self-associate, which is mediated via a short motif found in the negative regulatory region (NRR) of the extracellular domain; 2) Deletion of this motif ablates receptor homodimerization and blocks both ligand binding and receptor transactivation; 3) a novel class of short peptides, including highly specific peptides, targeting the dimerization motif similarly block receptor dimerization and receptor transactivation. Since the Notch pathway is corrupted in a wide range of disorders, the unveiling of a novel mechanism of Notch receptor transactivation, coupled to the discovery of a novel class of Notch signalling inhibitors, opens up the possibility of developing new therapeutic approaches to treating these diseases. The inventor has demonstrated the utility of these first-in-class inhibitors in a proof-of-concept study exemplified below.

[0010] The inventor has identified highly specific peptides, capable of specifically inhibiting Notch 1, Notch2 or Notch3. This remarkable specificity may reduce toxic off target effects associated with current non-specific Notch inhibitors.

[0011] There remains a need for a new approach to treating diseases in which normal Notch signalling is disrupted, with higher specificity and reduced off target effects. One or more aspects or embodiments of the present invention aim to solve at least this problem.

[0012] Brief summary of the disclosure

[0013] The inventor recently identified that Notch receptor dimerization is necessary for Notch receptor transactivation. The invention is based, in part, on the identification of a short amino acid motif in the negative regulatory region (NRR) of the extracellular domain of Notch receptors and peptides which can bind this motif to inhibit Notch receptor dimerization.

[0014] Accordingly, in a first aspect there is provided an isolated peptide having a total length of up to 30 amino acids, wherein the peptide is capable of binding to a Notch receptor and inhibiting Notch receptor dimerization and / or activation.

[0015] In one embodiment, the peptide may be considered a peptide inhibitor. Therefore the first aspect may equally relate to a peptide inhibitor of Notch receptor dimerization and / or activation having a total length of up to 30 amino acids. In one embodiment, the peptide may be considered to be a Notch inhibitor. Therefore the first aspect may equally relate to a Notch inhibitor comprising a peptide having the features of the first aspect.

[0016] In some embodiments, the peptide is capable of binding to the Notch receptor at a binding site. The binding site may be in the extracellular domain of the Notch receptor. The binding site may be in the negative regulatory region (NRR) of the extracellular domain of the Notch receptor. Suitably, the binding site comprises an amino acid motif comprising the sequence YCXDH (SEQ ID NO:23), wherein X is an amino acid selected from A, K, H, and R. Preferably, the binding site comprises an amino acid motif comprising the sequence YCXDH (SEQ ID NO:23) wherein X is selected from A, K and H.

[0017] In some embodiments, the peptide has a total length of 11-25, 11-20, or 11-15 amino acids. Preferably, the peptide has a total length of 11-14 amino acids.

[0018] In some embodiments, the peptide comprises an amino acid motif comprising the sequence YCXDH (SEQ ID NO:23) wherein X is an amino acid selected from A, K, H and R. Preferably, the peptide comprises an amino acid motif comprising the sequence YCXDH (SEQ ID NO:23) wherein X is selected from A and K.

[0019] In some embodiments, the peptide comprises an amino acid motif comprising the sequence X1X2YCX3DHF (SEQ ID NO:1), wherein Xi is selected from E and D, X2is selected from K and Q, and X3is selected from A and K.

[0020] Suitably, the peptide comprises or consists of an amino acid sequence selected from EKYCADHFADGR (SEQ ID NO:2), KYDKYCADHFK (SEQ ID NO:3), PLYDQYCKDHFSDG (SEQ ID NO:4), PVYEKYCADHFADGRCDQ (SEQ ID NO:5), PVYEKYCADHFADGR (SEQ ID NO:6), EKYCADHFADGRCDQ (SEQ ID NO:7), and NPLYDQYCKDHFSDG (SEQ ID NO:8), a sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto, or a functional variant thereof.

[0021] In some embodiments, the Notch receptor is selected from Notch1, Notch2, Notch3 and / or Notch4.

[0022] In some embodiments, the Notch receptor is Notch3. Suitably, in some embodiments, the Notch receptor is Notch3 and the peptide comprises or consists of an amino acid sequence selected from EKYCADHFADGR (SEQ ID NO:2), PVYEKYCADHFADGRCDQ (SEQ ID NO:5), PVYEKYCADHFADGR (SEQ ID NO:6), and EKYCADHFADGRCDQ (SEQ ID NO:7), a sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto, or a functional variant thereof. In some preferred embodiments, the Notch receptor is Notch3 and the peptide comprises or consists of the amino acid sequence EKYCADHFADGR (SEQ ID NO:2), a sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto, or a functional variant thereof.

[0023] In another embodiment, the Notch receptor is Notch3 and the peptide comprises or consists of the amino acid sequence PVYEKYCADHFADGRCDQ (SEQ ID NO:5) a sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto, or a functional variant thereof.

[0024] In another embodiment, the Notch receptor is Notch3 and the peptide comprises or consists of the amino acid sequence PVYEKYCADHFADGR (SEQ ID NO:6) a sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto, or a functional variant thereof.

[0025] In another embodiment, the Notch receptor is Notch3 and the peptide comprises or consists of the amino acid sequence EKYCADHFADGRCDQ (SEQ ID NO:7), a sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto, or a functional variant thereof.

[0026] In some embodiments, the Notch receptor is Notchl. Suitably, in some embodiments, the Notch receptor is Notchl and the peptide comprises or consists of an amino acid sequence selected from PLYDQYCKDHFSDG (SEQ ID NO:4) and NPLYDQYCKDHFSDG (SEQ ID NO:8), a sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto, or a functional variant thereof.

[0027] In some preferred embodiments, the Notch receptor is Notchl and the peptide comprises or consists of the amino acid sequence PLYDQYCKDHFSDG (SEQ ID NO:4), a sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto, or a functional variant thereof.

[0028] In some preferred embodiments, the Notch receptor is Notchl and the peptide comprises or consists of the amino acid sequence NPLYDQYCKDHFSDG (SEQ ID NO:8), a sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto, or a functional variant thereof.

[0029] In some embodiments, the Notch receptor is Notch2 and the peptide comprises or consists of the amino acid sequence KYDKYCADHFK (SEQ ID NO:3), a sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto, or a functional variant thereof. According to a second aspect, there is provided herein a modified Notch receptor protein comprising a deletion of an amino acid motif in the extracellular domain thereof, wherein the amino acid motif comprises the sequence YCXDH (SEQ ID NO:23), wherein X is an amino acid selected from A, K, H and R. Suitably, the modified Notch receptor is selected from Notchl, Notch2, Notch3 or Notch4.

[0030] According to a third aspect, there is provided herein a polynucleotide encoding a peptide according to the first aspect or the modified Notch receptor of the second aspect of the present invention.

[0031] According to a fourth aspect, there is provided herein an expression construct or vector comprising a polynucleotide according to the third aspect adapted for expression in a host cell. Suitably the vector may itself comprise the expression construct.

[0032] According to a fifth aspect, there is provided herein a cell or cell culture adapted to express a peptide according to the first aspect or modified Notch receptor according to the second aspect and comprising a polynucleotide according to the third aspect, or comprising an expression construct or vector according to the fourth aspect.

[0033] According to a sixth aspect, there is provided herein a composition comprising a peptide according to the first aspect, a modified Notch receptor according to the second aspect, a polynucleotide according to the third aspect, an expression construct or vector according to the fourth aspect, or a cell or cell culture according to the fifth aspect. In preferred embodiments, the composition comprises a peptide according to the first aspect of the present invention.

[0034] In some embodiments, the composition is a pharmaceutical composition comprising the peptide, modified Notch receptor, polynucleotide, expression construct or vector, cell or cell culture as a first therapeutic agent and one or more pharmaceutically acceptable excipients.

[0035] In some embodiments, the composition or pharmaceutical composition further comprises a second therapeutic agent.

[0036] According to a seventh aspect, the peptide or composition according to the first or sixth aspect is for use as a medicament.

[0037] According to an eighth aspect, there is provided herein the peptide according to the first aspect or the composition according to the sixth aspect for use in the treatment of a disease or disorder associated with aberrant Notch signalling.

[0038] Suitably, the disease or disorder is selected from cancer, a monogenic disease, a cardiovascular disease, a neuromuscular disorder, a bone disorder, an inflammatory disease, etc. In some embodiments, the disease or disorder is cancer, optionally selected from leukaemia, T-cell acute lymphoblastic leukaemia, lymphoma, breast cancer, gastrointestinal cancer, colorectal cancer and prostate cancer.

[0039] In some embodiments, the disease or disorder is a monogenic disease, optionally selected from Cerebral Autosomal Dominant Arteriopathy with Subcortical infarcts and Leukoencephalopathy (CADASIL), bicuspid aortic valve disease, Hypoplastic Left Heart Syndrome, Thoracic aortic syndrome, Adams-Oliver syndrome, Hajdu-Cheney disease and Alagille syndrome.

[0040] In some embodiments, the disease or disorder is a cardiovascular disease such as pulmonary arterial hypertension, Chronic Obstructive Pulmonary Disease (COPD), fibrosis, atherosclerosis, heart failure, ischemic heart disease, hypertrophic cardiomyopathy, a congenital heart defect, myocardial infarction or vascular dysfunction. In some preferred embodiments, the disease or disorder is selected from pulmonary arterial hypertension and COPD.

[0041] In some embodiments, the disease or disorder is a neuromuscular disorder, such as muscular dystrophies Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA), myasthenia gravis, Charcot-Marie-Tooth disease, peripheral neuropathy, neurogenic muscle atrophy or congenital myopathies.

[0042] In some embodiments, the disease or disorder is a bone disorder, such as Klippel-Feil syndrome, osteoporosis, osteogenesis imperfecta, Paget’s disease of bone, skeletal dysplasias, avascular necrosis, fracture healing disorders or chondrogenic disorders.

[0043] In some embodiments, the disease or disorder is an inflammatory disease, such as pancreatitis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, asthma, systemic lupus erythematosus, psoriasis, atherosclerosis, sepsis, allergic inflammation, or Graft-Versus-Host disease.

[0044] In some embodiments, the disease or disorder is an autoimmune disease, such as Addison’s disease, Alopecia areata, Ankylosing spondylitis, Antiphospholipid syndrome, Autoimmune hepatitis, Autoimmune pancreatitis, Autoimmune thyroiditis (Hashimoto’s thyroiditis), Behget’s disease, Celiac disease, Crohn’s disease, Dermatomyositis, Discoid lupus erythematosus, Graves’ disease, Guillain-Barré syndrome, Lupus (Systemic lupus erythematosus), Multiple sclerosis, Myasthenia gravis, Psoriasis, Psoriatic arthritis, Rheumatoid arthritis, Scleroderma, Sjogren’s syndrome, Type 1 diabetes, Ulcerative colitis, Vasculitis, or Vitiligo.

[0045] According to a ninth aspect, the peptide or composition according to the first or sixth aspect is for use in inhibiting tumour angiogenesis. In some embodiments, therefore there is provided the peptide or composition according to the first or sixth aspect is for use in the treatment of cancer by inhibiting tumour angiogenesis. In a tenth aspect, there is provided herein the peptide or composition according to the first or sixth aspect for use in manufacturing a medicament.

[0046] In an eleventh aspect, there is provided herein a method for treating or preventing a disease or disorder in a subject in need thereof, the method comprising administering an effective amount of the peptide or composition according to the first or sixth aspect to the subject.

[0047] In a twelfth aspect, there is provided herein a method for inhibiting Notch receptor dimerization and / or activation in a subject, the method comprising administering to the subject a peptide or composition of the first or sixth aspect in an amount effective to inhibit Notch receptor dimerization and / or activation.

[0048] In a thirteenth aspect, there is provided herein a method for inhibiting tumour angiogenesis in a subject, the method comprising administering to the subject a peptide or composition of the first or sixth aspect in an amount effective to inhibit tumour angiogenesis.

[0049] According to a fourteenth aspect, there is provided herein an in vitro or ex vivo method of inhibiting Notch dimerization and / or activation in a cell, comprising contacting said cell with an effective amount of a peptide according to the first aspect or a composition according to the sixth aspect. In some embodiments, the cell is a cancer cell.

[0050] In some embodiments, the cell is a T-cell acute lymphoblastic leukaemia (T-ALL) cell.

[0051] According to a fifteenth aspect, there is provided herein the use of a peptide according to the first aspect, a modified Notch receptor according to the second aspect, a polynucleotide according to the third aspect, an expression construct or vector according to the fourth aspect, a cell or cell culture according to the fifth aspect, or a composition according to the sixth aspect for research. Throughout the description and claims of this specification, the words “comprise” and “contain” and variations of them mean “including but not limited to”, and they are not intended to (and do not) exclude other moieties, additives, components, integers or steps.

[0052] Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

[0053] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith.

[0054] Various aspects of the invention are described in further detail below. Brief Description of the Drawings

[0055] Embodiments of the invention are further described hereinafter with reference to the accompanying drawings, in which:

[0056] Figure 1 shows that a short helical motif in the NRR of Notch3 (N3) is necessary and sufficient for receptor dimerization / oligomerization. (A & B) N3 receptor homo-dimerization / oligomerization in vitro (A) and in tissue-culture cells (B). (A) Upper Left panel: Non-denaturing acrylamide gel electrophoresis of purified HIS epitope-tagged N3 extra cellular domain (ECD). The mass of the Notch3 ECD corresponds in size to a receptor dimer. Lower Left Panel: SEC-MALS analysis of a N3 ECD / DLL1 receptor-ligand complex. The detected mass of the complex indicates that the ligand binds to a receptor dimer, not a receptor monomer. (B) Left Panel: Purified recombinant N3 ECD was incubated with HA-epitope tagged N3-ECD produced by in vitro translation. Complexes were resolved by immunoprecipitation and receptor-receptor interactions were determined by Western blotting using the shown antibodies. Right panel: The indicated combinations of HA and HIS epitope tagged versions of full length N3 were transfected into tissueculture cells. Complexes were resolved by immunoprecipitation and visualized with the shown antibodies. (C) Biochemical mapping of the N3 dimerization motif. The indicated epitope tagged constructs were transfected into tissue-culture cells (a schematic representation of the constructs is shown- right panel). Complexes were resolved by immunoprecipitation and visualized by Western blotting with the highlighted antibodies. (D) Biochemical fine-mapping of the N3 dimerization motif. Left panel: The indicated mutations were engineered in the E-ECD construct (highlighted in C). The conserved sequence of the mutated motif is shown. Epitope tagged versions of these constructs were co-transfected, with full length N3, into tissue-culture cells. Complexes were resolved by immunoprecipitation and visualized by Western blotting with the highlighted antibodies. Right panel: the same as the left panel except mutations were made in full length N3. (E) In silico modelling of an N3 NRR dimer. The helix encompassing the core dimerization motif is highlighted with an *. (F) Representative images of PLA assays (see Methods) performed on 293T cells stably expressing HA epitope-tagged NOTCH3 in the presence or absence of 2 ng / ml recombinant human DLL1. Relative amounts of detectable receptor dimerization per cell is presented graphically (an average of 100 cells were scored in each experiment). Scale bar = 10 pM. (n = 3). (G) Representative images of PLA assays (see Methods) performed on 293T cells stably expressing either HA epitope-tagged NOTCH3 or HA epitope tagged NOTCH3A(Y-D), which lacks the dimerization motif. Experiments were performed in the presence of 2 pg / ml recombinant human DLL1. Relative amounts of detectable receptor dimerization per cell is presented graphically (an average of 100 cells were scored in each experiment). Scale bar = 10 pM. Total NOTCH3 receptor levels were determined by Western blotting using the indicated antibody, and relative receptor cell surface expression was determined by biotin labelling (see Methods). Experiments described in the figure were performed 3 times. The statistical hypothesis tests were performed using Student’s t-test. We defined P<0.001 as a highly significant difference (**), and P<0.005 as a significant difference (*).

[0057] Figure 2 shows that N3 dimerization mediates N3 receptor transactivation. (A) Tissue culture cells stably expressing wild type N3 or N3 lacking the dimerization motif, Notch3A(Y-H), were incubated in the presence or absence of DLL1 for the indicated time course. Receptor cleavage was monitored by Western blotting using the indicated antibody. (B) Luciferase reporter assays were performed as described in Example 1, and depicted schematically (left panel). (C) Tissue culture cells stably expressing the indicated N3 constructs were cultured in the presence or absence of DLL1 for the indicated time-course. Endogenous gene expression levels were determined by Realtime qPCR (see Example 1). Values represent ±S. D. (n = 3). (D) Cell surface ligand-receptor binding assays were performed as described in Example 1, and depicted schematically. Cells stably expressing the indicated HA epitope tagged N3 receptors were incubated with or without the indicated HIS epitope tagged ligand. Complexes were resolved by immunoprecipitation and ligand-receptor binding was determined by Western blotting using the indicated antibodies.

[0058] Figure 3 shows the identification of highly specific N3 inhibitors. (A) Schematic representation of N3 dimerization-blocking peptides. In silica modelling of an N3 NRR dimer (as shown in Fig 1E). Peptide sequences were centred on the helix encompassing the core dimerization motif (highlighted green; see Table 1). (B) HIS epitope N3 immunopurified from tissue culture cells and immobilized on nickel beads was incubated with HA epitope tagged N3 in the presence or absence of the indicated peptides. Receptor-receptor interactions were visualized by Western blotting using the indicated antibodies. (C) Tissue culture cells stably expressing wild type N3 or N3 lacking the dimerization motif, Notch3A(Y-H), were incubated in the presence or absence of DLL1, and the indicated peptides, for the shown time course. Receptor cleavage was monitored by Western blotting using the indicated antibody. (D) Luciferase reporter assays were performed as described in Example 1, in the presence or absence of the indicated peptides. (E) Tissue culture cells stably expressing the N3 receptor were cultured (for 3hrs) in the presence or absence of DLL1 and the indicated peptides. Endogenous gene expression levels were determined by Realtime qPCR (see Example 1). Values represent ±S. D. (n = 3). (F) Cell surface ligand-receptor binding assays were performed as described in Example 1, and depicted schematically. Cells stably expressing the indicated HA epitope tagged N3 receptors were incubated with or without the indicated HIS epitope tagged ligand, in the presence or absence of the indicated peptides. Complexes were resolved by immunoprecipitation and ligand-receptor binding was determined by Western blotting using the indicated antibodies. (G) A Surface Plasmon Resonance (SPR) analysis to determine the binding affinity of the N34 peptide (EKYCADHFADGR, SEQ ID NO:2) and control peptide (EKYGGGHFADGR, SEQ ID NO:169) to pure recombinant N3 ECD. Assays (as described in the Methods) were performed 3 times and a representative example is shown. (H) Non-denaturing acrylamide gel electrophoresis of purified HIS epitope-tagged N3 ECD incubated in the presence or absence of the N34 peptide or a control peptide (as described in G). Molecular weight standards used: thyroglobulin (660 kDa), apoferritin (440 kDa), beta-amylase (200 kDa). (n = 3).

[0059] Figure 4 shows the identification of highly specific Notch2 (N2) and Notchl (N1) inhibitors. (A) Luciferase reporter assays were performed as described in the Example 1, in the presence or absence of the indicated peptides. (B) Tissue culture cells stably expressing wild type N2 receptors were incubated in the presence or absence of DLL1, and the indicated peptides, for the shown time course. Receptor cleavage was monitored by Western blotting using the indicated antibody. (C) Cell surface ligand-receptor binding assays were performed as described in Fig 3F (see Example 1). (D) Luciferase reporter assays were performed as described in Example 1. Tissue culture cells stably expressing the indicated Notch receptors were stimulated with the indicated Notch ligands in the presence or absence of the indicated peptides. (E) Tissue culture cells stably expressing the indicated Notch receptors were stimulated (for 3hrs) by the indicated Notch ligands in the presence or absence of and the indicated peptides or DAPT (20 uM). Endogenous gene expression levels were determined by Realtime qPCR (see Methods). Values represent ±S. D. (n = 3).

[0060] Figure 5 shows that the N1 receptor inhibitor (N110) specifically blocks mutant N1 receptor activation and cell proliferation of T-ALL cell lines. (A) Cell viability assays of the indicated T-ALL cell lines (see Example 1), were performed in the presence or absence of the indicated treatments. Values represent ±S. D. of 6 replicates per data point. (B) Cell cycle status of the indicated T-ALL lines was determined as described in Example 1. (C) The indicated T-ALL cell lines were cultured overnight (12 hours) in the presence or absence of the indicated treatments. Endogenous gene expression levels were determined by Realtime qPCR (see Example 1). Values represent ±S. D. (n = 3). (D) Endogenous N1 receptors expressed at the cell surface of MOLT4 cells were labelled with biotin (see Example 1). N1 receptor complexes were immunopurified from cell lysates and visualized by Western blotting with a N1 antibody. (E) Zebrafish embryo tumour cell invasion assay. Zebrafish embryos were injected with the indicated fluorescently labelled T-ALL cell lines in the presence or absence of the N1 peptide inhibitor or control peptide. Cell invasion into non-vascular tissue was quantified after 4 days (see Example 1).

[0061] Figure 6 shows in silico modelling of an N3 NRR dimer in the presence or the absence of the dimerization motif. The helix encompassing the core dimerization motif is highlighted (green). Figure 7 shows that deletion of the N3 dimerization motif does not compromise receptor stability, cell surface expression or subcellular localization. (A) N3 receptor protein stability assay. Tissue culture cells stably expressing either wild type N3 or N3 lacking the dimerization motif (Notch3D(Y- H)) receptor proteins were incubated in the presence or absence of 50 ug / ml cycloheximide (Sigma) for the shown time-course. Protein levels were determined by Western blotting with the indicated antibodies. (B) Cell surface expression of N3 receptors. Tissue culture cells stably expressing either wild type N3 or N3 lacking the dimerization motif (Notch3D(Y-H)) receptor proteins were labelled with biotin (see Methods). N3 receptors were immunopurified from cell lysates and visualized by Western blotting with the indicated antibody. (C) Immunofluorescence staining using the indicated antibodies was performed on tissue culture cells stably expressing either wild type N3 or N3 lacking the dimerization motif (Notch3D(Y-H)) receptors, as previously described.

[0062] Figure 8 shows that the dimerization motif is not necessary for Notch ligand binding. The indicated combinations of HA epitope tagged Notch ligands and HIS epitope tagged full length N3 were expressed in tissue-culture cells. Receptor-ligand complexes were resolved by immunoprecipitation and visualized with the shown antibodies.

[0063] Figure 9 shows cell viability assays of the indicated T-ALL cell lines (see Example 1), were performed in the presence or absence of the indicated treatments. Values represent ±S. D. of 6 replicates per data point.

[0064] Detailed description

[0065] The principles and operation of the present invention may be better understood with reference to the drawings and accompanying descriptions. Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not necessarily limited in its application to the details set forth in the following description or exemplified by the Examples. The invention is capable of other embodiments or of being practiced or carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting.

[0066] General definitions

[0067] As used herein “polynucleotide”, “nucleic acid sequence”, “nucleic acid” and “nucleic acid molecule” are used interchangeably to refer to an oligonucleotide sequence or polynucleotide sequence. The nucleotide sequence may be of genomic, synthetic or recombinant origin, and may be double-stranded or single-stranded (representing the sense or antisense strand). The term "nucleotide sequence" includes genomic DNA, cDNA, synthetic DNA, and RNA(e.g. mRNA) and analogs of the DNA or RNA generated, e.g., by the use of nucleotide analogs. In one example, the nucleotide sequence lacks introns. In other words, it is an intronless nucleic acid sequence. For example, the nucleotide sequence may be a DNA sequence that does not comprise intron sequences. The term “Notch receptor binding peptide” as used herein refers to a peptide that is capable of binding to one or more Notch receptors.

[0068] Amino acid residues are denoted throughout using the accepted alphabetic amino acid code i.e. capital letters in the context of amino acid sequences or peptide denote the relevant genetically encoded amino acid residue in accordance with the accepted alphabetic amino acid code.

[0069] A “non-essential” (or “non-critical”) amino acid residue is a residue that can be altered from the wild-type sequence of (e.g., the sequence identified by SEQ ID NO herein) without abolishing or, more preferably, without substantially altering a biological activity, whereas an “essential” (or “critical”) amino acid residue results in such a change. For example, amino acid residues that are conserved are predicted to be particularly non-amenable to alteration, except that amino acid residues within the hydrophobic core of domains can generally be replaced by other residues having approximately equivalent hydrophobicity without significantly altering activity.

[0070] A “conservative amino acid substitution” is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), non-polar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, a nonessential (or non-critical) amino acid residue in a protein is preferably replaced with another amino acid residue from the same side chain family. Alternatively, in another embodiment, mutations can be introduced randomly, and the resultant mutants can be screened for activity to identify mutants that retain activity.

[0071] Calculations of sequence homology or identity (the terms are used interchangeably herein) between sequences are performed as follows.

[0072] To determine the percent identity of two amino acid sequences, or of two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). In a preferred embodiment, the length of a reference sequence aligned for comparison purposes is at least 30%, preferably at least 40%, more preferably at least 50%, even more preferably at least 60%, and even more preferably at least 70%, 75%, 80%, 82%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of the length of the reference sequence. The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position (as used herein amino acid or nucleic acid “identity” is equivalent to amino acid or nucleic acid “homology”). The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences.

[0073] The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. In a preferred embodiment, the percent identity between two amino acid sequences is determined using the Needleman et al. (1970) J. Mol. Biol.

[0074] 48:444-453) algorithm which has been incorporated into the GAP program in the GCG software package (available at http: / / www.gcg.com), using either a BLOSUM 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. In yet another preferred embodiment, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package (available at http: / / www.gcg.com), using a NWSgapdna. CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. A particularly preferred set of parameters (and the one that should be used if the practitioner is uncertain about what parameters should be applied to determine if a molecule is within a sequence identity or homology limitation of the invention) are a BLOSUM 62 scoring matrix with a gap penalty of 12, a gap extend penalty of 4, and a frameshift gap penalty of 5.

[0075] Alternatively, the percent identity between two amino acid or nucleotide sequences can be determined using the algorithm of Meyers et al. (1989) CABIOS 4:11-17) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4.

[0076] The nucleic acid and protein sequences described herein can be used as a “query sequence” to perform a search against public databases to, for example, identify other family members or related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul, et al. (1990) J. Mol. Biol. 215:403-410). BLAST nucleotide searches can be performed with the NBLAST program, score = 100, wordlength = 12 to obtain nucleotide sequences homologous to nucleic acid molecules of the invention. BLAST protein searches can be performed with the XBLAST program, score = 50, wordlength = 3 to obtain amino acid sequences homologous to protein molecules of the invention. To obtain gapped alignments for comparison purposes, gapped BLAST can be utilized as described in Altschul et al. (1997, Nucl. Acids Res. 25:3389-3402). When using BLAST and gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used. See <http: / / www.ncbi.nlm.nih.gov>.

[0077] The polypeptides and nucleic acid molecules described herein can have amino acid sequences or nucleic acid sequences sufficiently or substantially identical to the sequences identified by SEQ ID NO. The terms “sufficiently identical” or “substantially identical” are used herein to refer to a first amino acid or nucleotide sequence that contains a sufficient or minimum number of identical or equivalent (e.g. with a similar side chain) amino acid residues or nucleotides to a second amino acid or nucleotide sequence such that the first and second amino acid or nucleotide sequences have a common structural domain or common functional activity. In other words, amino acid sequences or nucleic acid sequences having one or several (e.g. two, three, four etc) amino acid or nucleic acid substitutions compared to the corresponding sequences identified by SEQ ID NO may be sufficiently or substantially identical to the sequences identified by SEQ ID NO (provided that they retain the requisite functionality). In such examples, the one or several (e.g. two, three, four etc) amino acid or nucleic acid substitutions may be conservative substitutions. For example, amino acid or nucleotide sequences that contain a common structural domain having at least about 60%, or 65% identity, likely 75% identity, more likely 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity are defined herein as sufficiently or substantially identical. As used herein, the term “ex vivo" refers to “outside” the body. The term “in vitro" can be used to encompass “ex vivo" components, compositions and methods.

[0078] The terms “individual,” “subject,” and “patient” are used interchangeably, and refer to any individual subject with a disease or condition in need of treatment. Suitably, the subject is a human.

[0079] Unless defined otherwise herein, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although any methods and materials similar or equivalent to those described herein find use in the practice of the present invention, the preferred methods and materials are described herein. Accordingly, the terms defined immediately below are more fully described by reference to the Specification as a whole. Also, as used herein, the singular terms "a", "an," and "the" include the plural reference unless the context clearly indicates otherwise. Unless otherwise indicated, nucleic acids are written left to right in 5' to 3' orientation; amino acid sequences are written left to right in amino to carboxy orientation, respectively. It is to be understood that this invention is not limited to the particular methodology, protocols, and reagents described, as these may vary, depending upon the context they are used by those of skill in the art.

[0080] Peptide The present invention provides a peptide having a total length of up to 30 amino acids, wherein the peptide binds to a Notch receptor and inhibits Notch receptor dimerization and / or activation. As described herein, the peptide may inhibit Notch receptor dimerization and / or activation, therefore the peptide can be considered a peptide inhibitor. By inhibit, it is meant that Notch receptor dimerization and / or activation is reduced or prevented, suitably compared to the level of Notch receptor dimerization and / or activation in the absence of a Notch inhibitor. Consequently, downstream Notch signalling may be inhibited i.e. reduced, prevented or blocked. Suitably inhibition of activation may comprise inhibition of Notch signalling, suitably the peptide may inhibit Notch signalling. “Downstream Notch signalling” refers to the signalling pathway or pathways activated by Notch receptors. In some examples, Notch receptor dimerization is reduced. Suitably, the reduction in Notch receptor dimerization leads to a reduction in or loss of downstream Notch signalling. In some examples, Notch receptor dimerization is prevented. Suitably, the prevention of Notch receptor dimerization leads to a reduction in or loss of downstream Notch signalling. In some examples, Notch receptor activation is reduced. Suitably, the reduction in Notch receptor activation leads to a reduction in or loss of downstream Notch signalling. In some examples, Notch receptor activation is prevented. Suitably, the reduction in Notch receptor activation leads to a reduction in or loss of downstream Notch signalling.

[0081] Notch signalling pathways are known in the art and described in Gazave et al., (2009), Siebel and Lendahl (2017), Morgan (1917), Guruharsha et al., (2012), Bray (2016), Henrique and Schweisguth (2019), Zhou et al., (2022), and Meng et al., (2024) (1-8). Suitably the peptide may inhibit (downstream) Notch signalling and therefore may inhibit the expression of downstream target genes. Downstream target genes which are controlled by activated Notch receptors include HEY and HES family members, and cMyc.

[0082] Suitably Notch receptor dimerization and the inhibition thereof may be assessed by Western blotting to assess the level of dimerization.

[0083] Suitably Notch receptor dimerization and / or activation and the inhibition thereof may be measured by assessing the level of ligand dependent cleavage of the Notch receptor. When dimerization and / or activation is inhibited, the level of ligand dependent cleavage is expected to be reduced relative to the levels seen in the absence of a Notch inhibitor.

[0084] Suitably Notch receptor dimerization and / or activation and the inhibition thereof may be measured using a reporter assay. For example, Notch receptor dimerization and / or activation and the inhibition thereof may be measured using a luciferase reporter assay. When Notch receptor dimerization and / or activation is inhibited, the reporter activity is expected to be decreased relative to the activity level in the absence of a Notch inhibitor. Suitably Notch receptor dimerization and / or activation and the inhibition thereof may be measured by assessing the activation of endogenous, downstream Notch target genes. Suitably Notch receptor dimerization and / or activation and the inhibition thereof may be measured by assessing the expression of endogenous, downstream Notch target genes. Suitable target genes include HEY, cMyc or HES. The level of activation and / or expression of downstream Notch target genes can be measured using methods well known to the person skilled in the art. Suitably methods include PCR, such as quantitative real-time PCR. The level of activation and / or expression of downstream Notch target genes is expected to be reduced in the presence of a Notch inhibitor, relative to the level of activation and / or expression in the absence of a Notch inhibitor.

[0085] The skilled person is aware of alternative suitable methods for measuring Notch receptor dimerization and / or activation and the inhibition thereof, and could readily apply such methods to identify the level of inhibition achieved by the peptides of the invention.

[0086] Suitably the peptide may inhibit Notch receptor dimerization and / or activation by up to 10%, by up to 20%, by up to 50%, by up to 60 %, by up to 70%, by up to 80%, by up to 90%, or by up to 100% relative to the level of Notch receptor dimerization and / or activation in the absence of a Notch inhibitor.

[0087] The peptide is capable of binding to a Notch receptor and inhibiting Notch receptor dimerization. The peptide is capable of binding to a Notch receptor and inhibiting Notch receptor activation. The peptide is capable of binding to a Notch receptor and inhibiting Notch signalling.

[0088] The peptide may be an isolated peptide. As used herein, an “isolated peptide” refers to a peptide that is not in its natural environment. The peptide may therefore be of synthetic origin (or alternatively, of natural original, but isolated from its natural environment). When the peptides are present e.g. in a pharmaceutical composition (comprising adjuvants etc) they are considered to be in isolated form, as they are not in their natural environment.

[0089] The peptide may be a “natural peptide” i.e. a peptide composed of naturally occurring amino acids. Such peptides are composed of conventional amino acids encoded by the genetic code, linked to each other by a peptide bond. Natural peptides may, for example, be produced by a cell (via protein expression, e.g. using a nucleic acid or vector described herein), or they may be made synthetically (i.e. outside of a cell, using chemical synthesis).

[0090] In some embodiments, the peptide is a synthetic peptide. A synthetic peptide may be made synthetically (i.e. outside of a cell, using chemical synthesis). A synthetic peptide may be a recombinant peptide. A synthetic peptide may comprise a mix of natural amino acids and amino acids other than conventional amino acids encoded by the genetic code (“synthetic amino acids” or “non-natural amino acids”). Alternatively, it may be composed of synthetic amino acids only. Examples of synthetic amino acids are well known in the literature, and include modified amino acids, and amino acid analogues. References to ‘non-natural’ amino acid denote any amino acid that is not naturally occurring and includes synthetic amino acids, modified amino acids, spacers, and non-peptide bonded spacers. These non-natural amino acids may also be referred to as amino acid analogues, and the term ‘amino acid analogue’ may be used interchangeably with the term ‘non-natural amino acid’. Non-natural amino acids may include, for example 6-aminohexanoic acid (X), tetrahydroisoquinoline-3-carboxylic acid (TIC), 1- (amino)cyclohexanecarboxylic acid (Cy), and 3-azetidine-carboxylic acid (Az), 11-aminoundecanoic acid, for example.

[0091] In some embodiments, the peptide is water soluble. A water soluble peptide is capable of dissolving in water, to form a solution containing the peptide. Suitably, a water soluble peptide does not require the use of solvents to allow it to form a solution.

[0092] In some embodiments, the peptide is a therapeutic peptide. Suitably, a therapeutic peptide is capable of preventing or treating a disease or disorder, such as cancer. Suitably, a therapeutic peptide is therapeutically effective i.e. is able to have a therapeutically relevant effect on a disease or disorder such as reducing or ameliorating symptoms of said disease or disorder.

[0093] Peptide Length

[0094] The peptide of the invention has a total length of up to 30 amino acids. The peptide of the invention has a total length of 30 amino acids or a total length of fewer than 30 amino acids. The peptide may have a total length of 5 amino acids, 6 amino acids, 7 amino acids, 8 amino acids, 9 amino acids, 10 amino acids, 11 amino acids, 12 amino acids, 13 amino acids, 14 amino acids, 15 amino acids, 16 amino acids, 17 amino acids, 18 amino acids, 19 amino acids, 20 amino acids, 21 amino acids, 22 amino acids, 23 amino acids, 24 amino acids, 25 amino acids, 26 amino acids, 27 amino acids, 28 amino acids, 29 amino acids or 30 amino acids.

[0095] The peptide may have a total length of 5-30 amino acids, 5-25 amino acids, 5-20 amino acids, 5-15 amino acids, 5-10 amino acids, 10-30 amino acids, 10-25 amino acids, 10-20 amino acids, or 10-15 amino acids. Suitably, the peptide has a total length of between 10-25 amino acids, 10-20 amino acids, or 10-15 amino acids.

[0096] In some embodiments, the peptide has a total length of at least 11 amino acids. Suitably, the peptide has a total length of between 11-30 amino acids, 11-25 amino acids, 11-20 amino acids, or 11-15 amino acids.

[0097] In some examples, the peptide has a total length of up to 20 amino acids. The peptide may have a total length of up to 18 amino acids. The peptide may have a total length of 12-18 amino acids. Suitably, the peptide has a total length of 18 amino acids. Suitably, the peptide has a total length of 11-15 amino acids. Suitably, the peptide has a total length of 11-14 amino acids. The peptide may have a total length of 15 amino acids. The peptide may have a total length of 14 amino acids. The peptide may have a total length of 12 amino acids. The peptide may have a total length of 11 amino acids.

[0098] The peptide of the invention may consist of up to 30 amino acids. The peptide of the invention may consist of 30 amino acids or fewer than 30 amino acids. The peptide may consist of 5 amino acids, 6 amino acids, 7 amino acids, 8 amino acids, 9 amino acids, 10 amino acids, 11 amino acids, 12 amino acids, 13 amino acids, 14 amino acids, 15 amino acids, 16 amino acids, 17 amino acids, 18 amino acids, 19 amino acids, 20 amino acids, 21 amino acids, 22 amino acids, 23 amino acids, 24 amino acids, 25 amino acids, 26 amino acids, 27 amino acids, 28 amino acids, 29 amino acids or 30 amino acids.

[0099] The peptide may consist of 5-30 amino acids, 5-25 amino acids, 5-20 amino acids, 5-15 amino acids, 5-10 amino acids, 10-30 amino acids, 10-25 amino acids, 10-20 amino acids, or 10-15 amino acids. Suitably, the peptide consists of 10-25, 10-20, or 10-15 amino acids.

[0100] In some embodiments, the peptide consists of a minimum of 11 amino acids. Suitably, the peptide consists of 11-30 amino acids, 11-25 amino acids, 11-20 amino acids, or 11-15 amino acids. Suitably, the peptide consists of 11-25, 11-20, or 11-15 amino acids.

[0101] The peptide may consist of up to 20 amino acids. The peptide may consist of up to 18 amino acids. The peptide may consist of 12-18 amino acids The peptide may consist of 18 amino acids. The peptide may consist of 11-15 amino acid. The peptide may consist of 11-14 amino acids. The peptide may consist of 15 amino acids. The peptide may consist of 14 amino acids. The peptide may consist of 12 amino acids. The peptide may consist of 11 amino acids.

[0102] In some examples, the peptide specifically binds to the Notchl receptor and has a total length of up to 30 amino acids. In some examples, the peptide specifically binds to the Notchl receptor and has a total length of 30 amino acids or a total length of fewer than 30 amino acids. In some examples, the peptide specifically binds to the Notchl receptor and has a total length of 5 amino acids, 6 amino acids, 7 amino acids, 8 amino acids, 9 amino acids, 10 amino acids, 11 amino acids, 12 amino acids, 13 amino acids, 14 amino acids, 15 amino acids, 16 amino acids, 17 amino acids, 18 amino acids, 19 amino acids, 20 amino acids, 21 amino acids, 22 amino acids, 23 amino acids, 24 amino acids, 25 amino acids, 26 amino acids, 27 amino acids, 28 amino acids, 29 amino acids or 30 amino acids.

[0103] In some examples, the peptide specifically binds to the Notchl receptor and has a total length of 5-30 amino acids, 5-25 amino acids, 5-20 amino acids, 5-15 amino acids, 5-10 amino acids, 10-30 amino acids, 10-25 amino acids, 10-20 amino acids, or 10-15 amino acids. Suitably, the peptide specifically binds to the Notchl receptor and has a total length of between 10-25 amino acids, 10-20 amino acids, or 10-15 amino acids. In some examples the peptide specifically binds to the Notchl receptor and has a total length of at least 11 amino acids. Suitably, the peptide specifically binds to the Notchl receptor and has a total length of between 11-30 amino acids, 11-25 amino acids, 11-20 amino acids, or 11-15 amino acids.

[0104] In some examples, the peptide specifically binds to the Notchl receptor and has a total length of up to 20 amino acids. The peptide may specifically bind to the Notchl and have a total length of up to 18 amino acids. The peptide may specifically bind to the Notchl receptor and have a total length of 12-18 amino acids. Suitably, the peptide specifically binds to the Notchl receptor and has a total length of 18 amino acids. Suitably, the peptide specifically binds to the Notchl receptor and has a total length of 11-15 amino acids. Suitably, the peptide specifically binds to the Notchl receptor and has a total length of 11-14 amino acids. The peptide may specifically bind to the Notchl receptor and have a total length of 15 amino acids. The peptide may specifically bind to the Notchl receptor and have a total length of 14 amino acids. The peptide may specifically bind to the Notchl receptor and have a total length of 12 amino acids. The peptide may specifically bind to the Notchl receptor and have a total length of 11 amino acids. In some preferred examples, the peptide specifically binds to the Notchl receptor and has a total length of 14 or 15 amino acids, preferably 14 amino acids.

[0105] In some examples, the peptide specifically binds to the Notchl receptor and consists of up to 30 amino acids. In some examples, the peptide specifically binds to the Notchl receptor and consists of 30 amino acids or fewer than 30 amino acids. In some examples, the peptide specifically binds to the Notchl receptor and consists of 5 amino acids, 6 amino acids, 7 amino acids, 8 amino acids, 9 amino acids, 10 amino acids, 11 amino acids, 12 amino acids, 13 amino acids, 14 amino acids, 15 amino acids, 16 amino acids, 17 amino acids, 18 amino acids, 19 amino acids, 20 amino acids, 21 amino acids, 22 amino acids, 23 amino acids, 24 amino acids, 25 amino acids, 26 amino acids, 27 amino acids, 28 amino acids, 29 amino acids or 30 amino acids.

[0106] In some examples, the peptide specifically binds to the Notchl receptor and consists of 5-30 amino acids, 5-25 amino acids, 5-20 amino acids, 5-15 amino acids, 5-10 amino acids, 10-30 amino acids, 10-25 amino acids, 10-20 amino acids, or 10-15 amino acids. Suitably, specifically binds to the Notchl receptor and consists of 10-25, 10-20, or 10-15 amino acids.

[0107] In some examples, the peptide specifically binds to the Notchl receptor and consists of at least 11 amino acids. Suitably, peptide specifically binds to the Notchl receptor and consists of 11-30 amino acids, 11-25 amino acids, 11-20 amino acids, or 11-15 amino acids. Suitably, specifically binds to the Notchl receptor and consists of 11-25, 11-20, or 11-15 amino acids.

[0108] The peptide may specifically bind to the Notchl receptor and consist of up to 20 amino acids. The peptide may specifically bind to the Notchl receptor and consist of up to 18 amino acids. The peptide may specifically bind to the Notchl receptor and consist of 12-18 amino acids. The peptide may specifically bind to the Notchl receptor and consist of 18 amino acids. The peptide may specifically bind to the Notchl receptor and consist of 11-15 amino acids. The peptide may specifically bind to the Notchl receptor and consist of 11-14 amino acids. In some preferred examples, the peptide specifically binds to the Notchl receptor and consists of 15 amino acids. In some preferred examples, the peptide specifically binds to the Notchl receptor and consists of 14 amino acids. The peptide may specifically bind to the Notchl receptor and consist of 12 amino acids. The peptide may specifically bind to the Notchl receptor and consist of 11 amino acids. In some examples, the peptide specifically binds to the Notch2 receptor and has a total length of up to 30 amino acids. In some examples, the peptide specifically binds to the Notch2 receptor and has a total length of 30 amino acids or a total length of fewer than 30 amino acids. In some examples, the peptide specifically binds to the Notch2 receptor and has a total length of 5 amino acids, 6 amino acids, 7 amino acids, 8 amino acids, 9 amino acids, 10 amino acids, 11 amino acids, 12 amino acids, 13 amino acids, 14 amino acids, 15 amino acids, 16 amino acids, 17 amino acids, 18 amino acids, 19 amino acids, 20 amino acids, 21 amino acids, 22 amino acids, 23 amino acids, 24 amino acids, 25 amino acids, 26 amino acids, 27 amino acids, 28 amino acids, 29 amino acids or 30 amino acids.

[0109] In some examples, the peptide specifically binds to the Notch2 receptor and has a total length of 5-30 amino acids, 5-25 amino acids, 5-20 amino acids, 5-15 amino acids, 5-10 amino acids, 10-30 amino acids, 10-25 amino acids, 10-20 amino acids, or 10-15 amino acids. Suitably, the peptide specifically binds to the Notch2 receptor and has a total length of between 10-25 amino acids, 10-20 amino acids, or 10-15 amino acids.

[0110] In some examples the peptide specifically binds to the Notch2 receptor and has a total length of at least 11 amino acids. Suitably, the peptide specifically binds to the Notch2 receptor and has a total length of between 11-30 amino acids, 11-25 amino acids, 11-20 amino acids, or 11-15 amino acids.

[0111] In some examples, the peptide specifically binds to the Notch2 receptor and has a total length of up to 20 amino acids. The peptide may specifically bind to the Notch2 and have a total length of up to 18 amino acids. The peptide may specifically bind to the Notch2 receptor and have a total length of 12-18 amino acids. Suitably, the peptide specifically binds to the Notch2 receptor and has a total length of 18 amino acids. Suitably, the peptide specifically binds to the Notch2 receptor and has a total length of 11-15 amino acids. Suitably, the peptide specifically binds to the Notch2 receptor and has a total length of 11-14 amino acids. The peptide may specifically bind to the Notch2 receptor and have a total length of 15 amino acids. The peptide may specifically bind to the Notch2 receptor and have a total length of 14 amino acids. The peptide may specifically bind to the Notch2 receptor and have a total length of 12 amino acids. In some preferred examples, the peptide specifically binds to the Notch2 receptor and has a total length of 11 amino acids. In some examples, the peptide specifically binds to the Notch2 receptor and consists of up to 30 amino acids. In some examples, the peptide specifically binds to the Notch2 receptor and consists of 30 amino acids or fewer than 30 amino acids. In some examples, the peptide specifically binds to the Notch2 receptor and consists of 5 amino acids, 6 amino acids, 7 amino acids, 8 amino acids, 9 amino acids, 10 amino acids, 11 amino acids, 12 amino acids, 13 amino acids, 14 amino acids, 15 amino acids, 16 amino acids, 17 amino acids, 18 amino acids, 19 amino acids, 20 amino acids, 21 amino acids, 22 amino acids, 23 amino acids, 24 amino acids, 25 amino acids, 26 amino acids, 27 amino acids, 28 amino acids, 29 amino acids or 30 amino acids.

[0112] In some examples, the peptide specifically binds to the Notch2 receptor and consists of 5-30 amino acids, 5-25 amino acids, 5-20 amino acids, 5-15 amino acids, 5-10 amino acids, 10-30 amino acids, 10-25 amino acids, 10-20 amino acids, or 10-15 amino acids. Suitably, specifically binds to the Notch2 receptor and consists of 10-25, 10-20, or 10-15 amino acids.

[0113] In some examples, the peptide specifically binds to the Notch2 receptor and consists of at least 11 amino acids. Suitably, peptide specifically binds to the Notch2 receptor and consists of 11-30 amino acids, 11-25 amino acids, 11-20 amino acids, or 11-15 amino acids. Suitably, specifically binds to the Notch2 receptor and consists of 11-25, 11-20, or 11-15 amino acids.

[0114] The peptide may specifically bind to the Notch2 receptor and consist of up to 20 amino acids. The peptide may specifically bind to the Notch2 receptor and consist of up to 18 amino acids. The peptide may specifically bind to the Notch2 receptor and consist of 12-18 amino acids. The peptide may specifically bind to the Notch2 receptor and consist of 18 amino acids. The peptide may specifically bind to the Notch2 receptor and consist of 11-15 amino acid. The peptide may specifically bind to the Notch2 receptor and consist of 11-14 amino acids. The peptide may specifically bind to the Notch2 receptor and consist of 15 amino acids. The peptide may specifically bind to the Notch2 receptor and consist of 14 amino acids. The peptide may specifically bind to the Notch2 receptor and consist of 12 amino acids. In some preferred examples, the peptide specifically binds to the Notch2 receptor and consists of 11 amino acids. In some examples, the peptide specifically binds to the Notch3 receptor and has a total length of up to 30 amino acids. In some examples, the peptide specifically binds to the Notch3 receptor and has a total length of 30 amino acids or a total length of fewer than 30 amino acids. In some examples, the peptide specifically binds to the Notch3 receptor and has a total length of 5 amino acids, 6 amino acids, 7 amino acids, 8 amino acids, 9 amino acids, 10 amino acids, 11 amino acids, 12 amino acids, 13 amino acids, 14 amino acids, 15 amino acids, 16 amino acids, 17 amino acids, 18 amino acids, 19 amino acids, 20 amino acids, 21 amino acids, 22 amino acids, 23 amino acids, 24 amino acids, 25 amino acids, 26 amino acids, 27 amino acids, 28 amino acids, 29 amino acids or 30 amino acids.

[0115] In some examples, the peptide specifically binds to the Notch3 receptor and has a total length of 5-30 amino acids, 5-25 amino acids, 5-20 amino acids, 5-15 amino acids, 5-10 amino acids, 10-30 amino acids, 10-25 amino acids, 10-20 amino acids, or 10-15 amino acids. Suitably, the peptide specifically binds to the Notch3 receptor and has a total length of between 10-25 amino acids, 10-20 amino acids, or 10-15 amino acids.

[0116] In some examples the peptide specifically binds to the Notch3 receptor and has a total length of at least 11 amino acids. Suitably, the peptide specifically binds to the Notch3 receptor and has a total length of between 11-30 amino acids, 11-25 amino acids, 11-20 amino acids, or 11-15 amino acids.

[0117] In some examples, the peptide specifically binds to the Notch3 receptor and has a total length of up to 20 amino acids. The peptide may specifically bind to the Notch3 and have a total length of up to 18 amino acids. The peptide may specifically bind to the Notch3 receptor and have a total length of 12-18 amino acids. In some preferred examples, the peptide specifically binds to the Notch3 receptor and has a total length of 18 amino acids. Suitably, the peptide specifically binds to the Notch3 receptor and has a total length of 11-15 amino acids. Suitably, the peptide specifically binds to the Notch3 receptor and has a total length of 11-14 amino acids. In some preferred examples, the peptide specifically binds to the Notch3 receptor and has a total length of 15 amino acids. Suitably, the peptide specifically binds to the Notch3 receptor and has a total length of 14 amino acids. In some preferred examples, the peptide specifically binds to the Notch3 receptor and has a total length of 12 amino acids. The peptide may specifically bind to the Notch3 receptor and have a total length of 11 amino acids.

[0118] In some examples, the peptide specifically binds to the Notch3 receptor and consists of up to 30 amino acids. In some examples, the peptide specifically binds to the Notch3 receptor and consists of 30 amino acids or fewer than 30 amino acids. In some examples, the peptide specifically binds to the Notch3 receptor and consists of 5 amino acids, 6 amino acids, 7 amino acids, 8 amino acids, 9 amino acids, 10 amino acids, 11 amino acids, 12 amino acids, 13 amino acids, 14 amino acids, 15 amino acids, 16 amino acids, 17 amino acids, 18 amino acids, 19 amino acids, 20 amino acids, 21 amino acids, 22 amino acids, 23 amino acids, 24 amino acids, 25 amino acids, 26 amino acids, 27 amino acids, 28 amino acids, 29 amino acids or 30 amino acids.

[0119] In some examples, the peptide specifically binds to the Notch3 receptor and consists of 5-30 amino acids, 5-25 amino acids, 5-20 amino acids, 5-15 amino acids, 5-10 amino acids, 10-30 amino acids, 10-25 amino acids, 10-20 amino acids, or 10-15 amino acids. Suitably, specifically binds to the Notch3 receptor and consists of 10-25, 10-20, or 10-15 amino acids. In some examples, the peptide specifically binds to the Notch3 receptor and consists of at least 11 amino acids. Suitably, peptide specifically binds to the Notch3 receptor and consists of 11-30 amino acids, 11-25 amino acids, 11-20 amino acids, or 11-15 amino acids. Suitably, specifically binds to the Notch3 receptor and consists of 11-25, 11-20, or 11-15 amino acids.

[0120] The peptide may specifically bind to the Notch3 receptor and consist of up to 20 amino acids. The peptide may specifically bind to the Notch3 receptor and consist of up to 18 amino acids. The peptide may specifically bind to the Notch3 receptor and consist of 12-18 amino acids. In some preferred examples, the peptide specifically binds to the Notch3 receptor and consists of 18 amino acids. The peptide may specifically bind to the Notch3 receptor and consist of 11-15 amino acid. The peptide may specifically bind to the Notch3 receptor and consist of 11-14 amino acids. In some preferred examples, the peptide specifically binds to the Notch3 receptor and consists of 15 amino acids. The peptide may specifically bind to the Notch3 receptor and consist of 14 amino acids. In some preferred examples, the peptide specifically binds to the Notch3 receptor and consists of 12 amino acids. Suitably, the peptide specifically binds to the Notch3 receptor and consists of 11 amino acids.

[0121] As defined in aspects herein, the peptide has a total length of up to 30 amino acids. The peptide may further comprise additional groups or moieties at the N terminal and / or C terminal end. For example the peptide may comprise a chemical group at the N terminal and / or C terminal end. Suitably the peptide may comprise an Acetyl or an Amide group at the C terminal end.

[0122] For example, the peptide may be conjugated directly, or via a linker, to a further therapeutic moiety, a polymer, a polypeptide, a ligand and / or any other moiety e.g. a detectable moiety. Such peptides are referred to herein as “peptide conjugates”. The additional groups or moieties may be joined to the peptide via a linker, such as a PEG containing linker. Suitable linkers are known in the art. In one embodiment, a linker comprises a short amino acid sequence, such as: 5’-GGGGG-3’ (5-G linker) (SEQ ID NO:170), G, C, GGC, B, GS, GSG, or GSGS (SEQ ID NO:171). Suitable linkers include, for example, a C-terminal cysteine residue that permits formation of a disulphide, thioether or thiol-maleimide linkage, a C-terminal aldehyde to form an oxime, a click reaction or formation of a morpholino linkage with a basic amino acid on the peptide or a carboxylic acid moiety on the peptide covalently conjugated to an amino group to form a carboxamide linkage. Peptide Sequence

[0123] In some examples, the peptide comprises an amino acid motif comprising the sequence YCXDH (SEQ ID NO:23) wherein X is an amino acid selected from A, K, H and R. In some examples, the peptide comprises an amino acid motif comprising the sequence YCXDH (SEQ ID NO:23) wherein X is an amino acid selected from A, K, and H. In some examples, the peptide comprises an amino acid motif comprising the sequence YCXDH (SEQ ID NO:23) wherein X is an amino acid selected from A, K, and R. In some examples, the peptide comprises an amino acid motif comprising the sequence YCXDH (SEQ ID NO:23) wherein X is an amino acid selected from K, H and R. Preferably, the peptide comprises an amino acid motif comprising the sequence YCXDH (SEQ ID NO:23) wherein X is selected from A and K. In some examples, the peptide comprises an amino acid motif comprising the sequence YCXDH (SEQ ID NO:23), wherein X is selected from A and H. In some embodiments, the peptide comprises an amino acid motif comprising the sequence YCXDH (SEQ ID NO:23), wherein X is selected from A and R. In some examples, the peptide comprises an amino acid motif comprising the sequence YCXDH (SEQ ID NO:23), wherein X is selected from K and H. In some examples, the peptide comprises an amino acid motif comprising the sequence YCXDH (SEQ ID NO:23), wherein X is selected from K and R. In some examples, the peptide comprises an amino acid motif comprising the sequence YCXDH (SEQ ID NO:23), wherein X is selected from H and R. In some examples, the peptide comprises an amino acid motif comprising or consisting of the sequence YCADH (SEQ ID NO: 9). In some examples, the peptide comprises an amino acid motif comprising or consisting of the sequence YCKDH (SEQ ID NO:10). In some examples, the peptide comprises an amino acid motif comprising the sequence YCHDH (SEQ ID NO: 14). In some examples, the peptide comprises an amino acid motif comprising the sequence YCRDH (SEQ ID NO:15).

[0124] In some examples, the peptide comprises an amino acid motif comprising the sequence YCXDHF (SEQ ID NO:24), wherein X is an amino acid selected from H, A, and K. The peptide may comprise an amino acid motif comprising the sequence YCXDHF (SEQ ID NO:24), wherein X is an amino acid selected from H and A. The peptide may comprise an amino acid motif comprising the sequence YCXDHF (SEQ ID NO:24), wherein X is an amino acid selected from H, and K. The peptide may comprise an amino acid motif comprising the sequence YCXDHF (SEQ ID NO:24), wherein X is an amino acid selected from A and K. The peptide may comprise and amino acid motif comprising the sequence YCHDHF (SEQ ID NQ:70). The peptide may comprise and amino acid motif comprising the sequence YCADHF (SEQ ID NO:71). The peptide may comprise and amino acid motif comprising the sequence comprising the sequence YCKDHF (SEQ ID NO:72). In some examples, the peptide comprises an amino acid motif comprising the sequence X1YCX2DH (SEQ ID NO:80), wherein X1 is an amino acid selected from Q and K, and X2 is selected from H, A, and K. The peptide may comprise an amino acid motif comprising the sequence X1YCX2DH (SEQ ID NO:80), wherein X1 is an amino acid selected from Q and K, and X2 is selected from H and A. The peptide may comprise an amino acid motif comprising the sequence X1YCX2DH (SEQ ID NO:80), wherein X1 is an amino acid selected from Q and K, and X2 is selected from H and K. The peptide may comprise an amino acid motif comprising the sequence X1YCX2DH (SEQ ID NO:80), wherein X1 is an amino acid selected from Q and K, and X2 is selected from A and K. The peptide may comprise an amino acid motif comprising the sequence QYCHDH (SEQ ID NO: 81), The peptide may comprise an amino acid motif comprising the sequence QYCKDH (SEQ ID NO:82). The peptide may comprise an amino acid motif comprising the sequence QYCADH (SEQ ID NO:83). The peptide may comprise an amino acid motif comprising the sequence KYCADH (SEQ ID NO:84). The peptide may comprise an amino acid motif comprising the sequence KYCHDH (SEQ ID NO:85). The peptide may comprise an amino acid motif comprising the sequence KYCKDH (SEQ ID NO:86).

[0125] In some examples, the peptide comprises an amino acid motif comprising the sequence X1YCX2DHF (SEQ ID NO:25), wherein Xi is an amino acid selected from Q and K, and X2is selected from H, A, and K. The peptide may comprise an amino acid motif comprising the sequence X1YCX2DHF (SEQ ID NO:25), wherein Xi is an amino acid selected from Q and K, and X2is selected from H and A. The peptide may comprise an amino acid motif comprising the sequence X1YCX2DHF (SEQ ID NO:25), wherein Xi is an amino acid selected from Q and K, and X2is selected from H and K. The peptide may comprise an amino acid motif comprising the sequence X1YCX2DHF (SEQ ID NO:25), wherein Xi is an amino acid selected from Q and K, and X2is selected from A and K. The peptide may comprise an amino acid motif comprising the sequence QYCHDHF (SEQ ID NO:73). The peptide may comprise an amino acid motif comprising the sequence QYCKDHF (SEQ ID NO:74). The peptide may comprise an amino acid motif comprising the sequence QYCADHF (SEQ ID NO: 77). The peptide may comprise an amino acid motif comprising the sequence KYCADHF (SEQ ID NO:75). The peptide may comprise an amino acid motif comprising the sequence KYCHDHF (SEQ ID NO: 78). The peptide may comprise an amino acid motif comprising the sequence KYCKDHF (SEQ ID NO: 79).

[0126] In some examples, the peptide comprises an amino acid motif comprising the sequence X1X2YCX3DHF (SEQ ID NO:1), wherein Xi is selected from E and D, X2is selected from K and Q, and X3is selected A, K and H. In some examples, the peptide comprises an amino acid motif comprising the sequence X1X2YCX3DHF (SEQ ID NO:1), wherein Xi is selected from E and D, X2is selected from K and Q, and X3is selected from A and K. In some examples, the peptide comprises an amino acid motif comprising the sequence X1X2YCX3DHF (SEQ ID NO:1), wherein Xi is selected from E and D, X2is selected from K and Q, and X3is selected from A and H. In some examples, the peptide comprises an amino acid motif comprising the sequence X1X2YCX3DHF (SEQ ID NO:1), wherein Xi is selected from E and D, X2is selected from K and Q, and X3 is selected from K and H. Suitably, the peptide comprises an amino acid motif comprising the sequence DQYCKDHF (SEQ ID NO:11). Suitably, the peptide comprises an amino acid motif comprising the sequence DKYCADHF (SEQ ID NO:12). Suitably, the peptide comprises an amino acid motif comprising the sequence EKYCADHF (SEQ ID NO: 13). Suitably, the peptide comprises an amino acid motif comprising the sequence DQYCHDHF (SEQ ID NO: 16).

[0127] In some examples, the peptide comprises an amino acid motif comprising the sequence X1X2YCX3DH (SEQ ID NO:17), wherein Xi is selected from E and D, X2is selected from K and Q, and X3is selected A, K, H and R. In some examples, the peptide comprises an amino acid motif comprising the sequence X1X2YCX3DH (SEQ ID NO: 17), wherein Xi is selected from E and D, X2is selected from K and Q, and X3is selected A, K, and H. In some examples, the peptide comprises an amino acid motif comprising the sequence XIX2YCX3DH (SEQ ID NO:17), wherein Xi is selected from E and D, X2is selected from K and Q, and X3is selected A, K, and R. In some examples, the peptide comprises an amino acid motif comprising the sequence XIX2YCX3DH (SEQ ID NO:17), wherein Xi is selected from E and D, X2is selected from K and Q, and X3is selected K, H, and R. In some examples, the peptide comprises an amino acid motif comprising the sequence XIX2YCX3DH (SEQ ID NO: 17), wherein Xi is selected from E and D, X2is selected from K and Q, and X3is selected A and K. In some examples, the peptide comprises an amino acid motif comprising the sequence X1X2YCX3DH (SEQ ID NO:17), wherein X1 is selected from E and D, X2 is selected from K and Q, and X3 is selected A and H. In some examples, the peptide comprises an amino acid motif comprising the sequence XIX2YCX3DH (SEQ ID NO: 17), wherein Xi is selected from E and D, X2is selected from K and Q, and X3is selected A and R. In some examples, the peptide comprises an amino acid motif comprising the sequence XIX2YCX3DH (SEQ ID NO:17), wherein Xi is selected from E and D, X2is selected from K and Q, and X3is selected K and H. In some examples, the peptide comprises an amino acid motif comprising the sequence XIX2YCX3DH (SEQ ID NO: 17), wherein Xi is selected from E and D, X2is selected from K and Q, and X3is selected K and R. In some examples, the peptide comprises an amino acid motif comprising the sequence XIX2YCX3DH (SEQ ID NO: 17), wherein Xi is selected from E and D, X2is selected from K and Q, and X3is selected H and R.

[0128] In one embodiment, the peptide comprises an amino acid motif comprising the sequence DQYCKDH (SEQ ID NO:18). In one embodiment, the peptide comprises an amino acid motif comprising the sequence DKYCADH (SEQ ID NO:19). In one embodiment, the peptide comprises an amino acid motif comprising the sequence EKYCADH (SEQ ID NO:20). In one embodiment, the peptide comprises an amino acid motif comprising the sequence DQYCHDH (SEQ ID NO: 21). In one embodiment, the peptide comprises an amino acid motif comprising the sequence DQYCRDH (SEQ ID NO:22). In one embodiment, the peptide comprises an amino acid motif comprising the sequence EKYCKDH (SEQ ID NO:87). In one embodiment, the peptide comprises an amino acid motif comprising the sequence EKYCHDH (SEQ ID NO:88). In one embodiment, the peptide comprises an amino acid motif comprising the sequence EKYCRDH (SEQ ID NO:89). In one embodiment, the peptide comprises an amino acid motif comprising the sequence EQYCADH (SEQ ID NO:90). In one embodiment, the peptide comprises an amino acid motif comprising the sequence EQYCKDH (SEQ ID NO:91). In one embodiment, the peptide comprises an amino acid motif comprising the sequence EQYCHDH (SEQ ID NO:92). In one embodiment, the peptide comprises an amino acid motif comprising the sequence EQYCRDH (SEQ ID NO:93). In one embodiment, the peptide comprises an amino acid motif comprising the sequence DKYCKDH (SEQ ID NO:94). In one embodiment, the peptide comprises an amino acid motif comprising the sequence DKYCHDH (SEQ ID NO:95). In one embodiment, the peptide comprises an amino acid motif comprising the sequence DKYCRDH (SEQ ID NO:96). In one embodiment, the peptide comprises an amino acid motif comprising the sequence DQYCADH (SEQ ID NO:97). The peptide may comprise an amino acid motif comprising the sequence YX1X2YCX3DH (SEQ ID NO:27) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, and X3is selected from H, A, K and R. The peptide may comprise an amino acid motif comprising the sequence YX1X2YCX3DH (SEQ ID NO:27) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, and X3is selected from H, Aand K. The peptide may comprise an amino acid motif comprising the sequence YX1X2YCX3DH (SEQ ID NO:27) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, and X3is selected from H, A and R. The peptide may comprise an amino acid motif comprising the sequence YX1X2YCX3DH (SEQ ID NO:27) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, and X3 is selected from H, K and R. The peptide may comprise an amino acid motif comprising the sequence YX1X2YCX3DH (SEQ ID NO:27) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, and X3is selected from A, K and R. The peptide may comprise an amino acid motif comprising the sequence YX1X2YCX3DH (SEQ ID NO:27) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, and X3is selected from H and A. The peptide may comprise an amino acid motif comprising the sequence YX1X2YCX3DH (SEQ ID NO:27) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, and X3is selected from H and K. The peptide may comprise an amino acid motif comprising the sequence YX1X2YCX3DH (SEQ ID NO:27) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, and X3 is selected from H and R. The peptide may comprise an amino acid motif comprising the sequence YX1X2YCX3DH (SEQ ID NO:27) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, and X3is selected from A and K, The peptide may comprise an amino acid motif comprising the sequence YX1X2YCX3DH (SEQ ID NO:27) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, and X3 is selected from Aand R. The peptide may comprise an amino acid motif comprising the sequence YX1X2YCX3DH (SEQ ID NO:27) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, and X3is selected from K and R. Suitably, the peptide comprises an amino acid motif comprising the sequence YDQYCHDH (SEQ ID NO:99). Suitably, the peptide comprises an amino acid motif comprising the sequence YDQYCADH (SEQ ID NO:100). Suitably, the peptide comprises an amino acid motif comprising the sequence YDQYCKDH (SEQ ID NO:101 / SEQ ID NO:76). Suitably, the peptide comprises an amino acid motif comprising the sequence YDQYCRDH (SEQ ID NO: 102). Suitably, the peptide comprises an amino acid motif comprising the sequence YDKYCHDH (SEQ ID NO:103), Suitably, the peptide comprises an amino acid motif comprising the sequence YDKYCADH (SEQ ID NO:104). Suitably, the peptide comprises an amino acid motif comprising the sequence YDKYCKDH (SEQ ID NO: 105). Suitably, the peptide comprises an amino acid motif comprising the sequence YDKYCRDH (SEQ ID NO:106). Suitably, the peptide comprises an amino acid motif comprising the sequence YEQYCHDH (SEQ ID NO: 107). Suitably, the peptide comprises an amino acid motif comprising the sequence YEQYCADH (SEQ ID NO: 108). Suitably, the peptide comprises an amino acid motif comprising the sequence YEQYCKDH (SEQ ID NO:109). Suitably, the peptide comprises an amino acid motif comprising the sequence YEQYCRDH (SEQ ID NO: 110). Suitably, the peptide comprises an amino acid motif comprising the sequence YEQYCHDH (SEQ ID NO:111). Suitably, the peptide comprises an amino acid motif comprising the sequence YEQYCADH (SEQ ID NO:112). Suitably, the peptide comprises an amino acid motif comprising the sequence YEQYCKDH (SEQ ID NO:113). Suitably, the peptide comprises an amino acid motif comprising the sequence YEQYCRDH (SEQ ID NO:114).

[0129] The peptide may comprise an amino acid motif comprising the sequence YX1X2YCX3DHF (SEQ ID NO:98) wherein Xi is an amino acid selected from D and E, X2 is selected from Q and K, and X3is selected from H, A, K and R. The peptide may comprise an amino acid motif comprising the sequence YX1X2YCX3DHF (SEQ ID NO:98) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, and X3is selected from H, A and K. The peptide may comprise an amino acid motif comprising the sequence YX1X2YCX3DHF (SEQ ID NO:98) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, and X3is selected from H, Aand R. The peptide may comprise an amino acid motif comprising the sequence YX1X2YCX3DHF (SEQ ID NO:98) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, and X3is selected from H, K and R. The peptide may comprise an amino acid motif comprising the sequence YX1X2YCX3DHF (SEQ ID NO:98) wherein Xi is an amino acid selected from D and E, X2 is selected from Q and K, and X3 is selected from A, K and R. The peptide may comprise an amino acid motif comprising the sequence YX1X2YCX3DHF (SEQ ID NO:98) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, and X3is selected from H and A. The peptide may comprise an amino acid motif comprising the sequence YX1X2YCX3DHF (SEQ ID NO:98) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, and X3is selected from H and K. The peptide may comprise an amino acid motif comprising the sequence YX1X2YCX3DHF (SEQ ID NO:98) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, and X3is selected from H and R. The peptide may comprise an amino acid motif comprising the sequence YX1X2YCX3DHF (SEQ ID NO:98) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, and X3 is selected from A and K, The peptide may comprise an amino acid motif comprising the sequence YX1X2YCX3DHF (SEQ ID NO:98) wherein X1 is an amino acid selected from D and E, X2 is selected from Q and K, and X3 is selected from A and R. The peptide may comprise an amino acid motif comprising the sequence YX1X2YCX3DHF (SEQ ID NO:98) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, and X3is selected from K and R. Suitably, the peptide comprises an amino acid motif comprising the sequence YDQYCHDHF (SEQ ID NO: 115). Suitably, the peptide comprises an amino acid motif comprising the sequence YDQYCADHF (SEQ ID NO: 116). Suitably, the peptide comprises an amino acid motif comprising the sequence YDQYCKDHF (SEQ ID NO: 117). Suitably, the peptide comprises an amino acid motif comprising the sequence YDQYCRDHF (SEQ ID NO: 118). Suitably, the peptide comprises an amino acid motif comprising the sequence YDKYCHDHF (SEQ ID NO:119), Suitably, the peptide comprises an amino acid motif comprising the sequence YDKYCADHF (SEQ ID NO: 120). Suitably, the peptide comprises an amino acid motif comprising the sequence YDKYCKDHF (SEQ ID NO:121). Suitably, the peptide comprises an amino acid motif comprising the sequence YDKYCRDHF (SEQ ID NO:122). Suitably, the peptide comprises an amino acid motif comprising the sequence YEQYCHDHF (SEQ ID NO:123). Suitably, the peptide comprises an amino acid motif comprising the sequence YEQYCADHF (SEQ ID NO: 124). Suitably, the peptide comprises an amino acid motif comprising the sequence YEQYCKDHF (SEQ ID NO:125). Suitably, the peptide comprises an amino acid motif comprising the sequence YEQYCRDHF (SEQ ID NO:126). Suitably, the peptide comprises an amino acid motif comprising the sequence YEQYCHDHF (SEQ ID NO: 127). Suitably, the peptide comprises an amino acid motif comprising the sequence YEQYCADHF (SEQ ID NO:128). Suitably, the peptide comprises an amino acid motif comprising the sequence YEQYCKDHF (SEQ ID NO:129). Suitably, the peptide comprises an amino acid motif comprising the sequence YEQYCRDHF (SEQ ID NO: 130).

[0130] The peptide may comprise an amino acid motif comprising the sequence X1X2YCX3DHX4 (SEQ ID NO:28) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, and X3is selected from H, A, K and R, and X4is selected from F and Y. The peptide may comprise an amino acid motif comprising the sequence XIX2YCX3DHX4(SEQ ID NO:28) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, X3is selected from H, A and K, and X4is selected from F and Y. The peptide may comprise an amino acid motif comprising the sequence XIX2YCX3DHX4(SEQ ID NO:28) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, X3 is selected from H, A and R, and X4is selected from F and Y. The peptide may comprise an amino acid motif comprising the sequence XIX2YCX3DHX4(SEQ ID NO:28) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, X3 is selected from H, K and R, and X4 is selected from F and Y. The peptide may comprise an amino acid motif comprising the sequence XIX2YCX3DHX4(SEQ ID NO:28) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, X3is selected from A, K and R, and X4is selected from F and Y. The peptide may comprise an amino acid motif comprising the sequence XIX2YCX3DHX4(SEQ ID NO:28) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, X3is selected from H and A, and X4is selected from F and Y. The peptide may comprise an amino acid motif comprising the sequence XIX2YCX3DHX4(SEQ ID NO:28) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, X3is selected from H and K, and X4is selected from F and Y. The peptide may comprise an amino acid motif comprising the sequence X1X2YCX3DHX4(SEQ ID NO:28) wherein X1is an amino acid selected from D and E, X2is selected from Q and K, X3is selected from H and R, and X4is selected from F and Y. The peptide may comprise an amino acid motif comprising the sequence XIX2YCX3DHX4(SEQ ID NO:28) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, X3is selected from A and K, and X4is selected from F and Y. The peptide may comprise an amino acid motif comprising the sequence XIX2YCX3DHX4(SEQ ID NO:28) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, X3is selected from A and R, and X4is selected from F and Y. The peptide may comprise an amino acid motif comprising the sequence X1X2YCX3DHX4(SEQ ID NO:28) wherein X1is an amino acid selected from D and E, X2is selected from Q and K, X3is selected from K and R, and X4is selected from F and Y. Suitably, the peptide comprises an amino acid motif comprising the sequence DQYCHDHF (SEQ ID NO: 16) Suitably, the peptide comprises an amino acid motif comprising the sequence DQYCADHF (SEQ ID NO: 131). Suitably, the peptide comprises an amino acid motif comprising the sequence DQYCKDHF (SEQ ID NO:11) Suitably, the peptide comprises an amino acid motif comprising the sequence DQYCRDHF (SEQ ID NO:132). Suitably, the peptide comprises an amino acid motif comprising the sequence DQYCHDHY (SEQ ID NO: 133). Suitably, the peptide comprises an amino acid motif comprising the sequence DQYCADHY (SEQ ID NO: 134) Suitably, the peptide comprises an amino acid motif comprising the sequence DQYCKDHY (SEQ ID NO: 135). Suitably, the peptide comprises an amino acid motif comprising the sequence DQYCRDHY (SEQ ID NO:32) Suitably, the peptide comprises an amino acid motif comprising the sequence DKYCHDHF (SEQ ID NO:136). Suitably, the peptide comprises an amino acid motif comprising the sequence. Suitably, the peptide comprises an amino acid motif comprising the sequence DKYCADHF (SEQ ID NO:12). Suitably, the peptide comprises an amino acid motif comprising the sequence DKYCKDHF (SEQ ID NO: 137). Suitably, the peptide comprises an amino acid motif comprising the sequence DKYCRDHF (SEQ ID NO:138). Suitably, the peptide comprises an amino acid motif comprising the sequence DKYCHDHY (SEQ ID NO: 139). Suitably, the peptide comprises an amino acid motif comprising the sequence DKYCADHY (SEQ ID NO: 140). Suitably, the peptide comprises an amino acid motif comprising the sequence DKYCKDHY (SEQ ID NO:141). Suitably, the peptide comprises an amino acid motif comprising the sequence DKYCRDHY (SEQ ID NO:142). Suitably, the peptide comprises an amino acid motif comprising the sequence. Suitably, the peptide comprises an amino acid motif comprising the sequence EQYCHDHF (SEQ ID NO:143). Suitably, the peptide comprises an amino acid motif comprising the sequence EQYCADHF (SEQ ID NO: 144). Suitably, the peptide comprises an amino acid motif comprising the sequence EQYCKDHF (SEQ ID NO:145). Suitably, the peptide comprises an amino acid motif comprising the sequence EQYCRDHF (SEQ ID NO:146). Suitably, the peptide comprises an amino acid motif comprising the sequence EQYCHDHY (SEQ ID NO: 147). Suitably, the peptide comprises an amino acid motif comprising the sequence EQYCADHY (SEQ ID NO:148). Suitably, the peptide comprises an amino acid motif comprising the sequence EQYCKDHY (SEQ ID NO:149). Suitably, the peptide comprises an amino acid motif comprising the sequence EQYCRDHY (SEQ ID NO:150). Suitably, the peptide comprises an amino acid motif comprising the sequence EKYCHDHF (SEQ ID NO: 151). Suitably, the peptide comprises an amino acid motif comprising the sequence EKYCADHF (SEQ ID NO:13). Suitably, the peptide comprises an amino acid motif comprising the sequence EKYCKDHF (SEQ ID NO: 152). Suitably, the peptide comprises an amino acid motif comprising the sequence EKYCRDHF (SEQ ID NO: 153). Suitably, the peptide comprises an amino acid motif comprising the sequence EKYCHDHY (SEQ ID NO:154). Suitably, the peptide comprises an amino acid motif comprising the sequence EKYCADHY (SEQ ID NO:155). Suitably, the peptide comprises an amino acid motif comprising the sequence EKYCKDHY (SEQ ID NO: 156). Suitably, the peptide comprises an amino acid motif comprising the sequence EKYCRDHY (SEQ ID NO:157).

[0131] Suitably, the peptide comprises or consists of an amino acid sequence selected from SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO 63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, and SEQ ID NO:69, or a sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or 99% identical thereto, or a functional variant thereof.

[0132] Suitably, the peptide comprises or consists of an amino acid sequence selected from EKYCADHFADGR (SEQ ID NO:2), KYDKYCADHFK (SEQ ID NO:3), PLYDQYCKDHFSDG (SEQ ID NO:4), PVYEKYCADHFADGRCDQ (SEQ ID NO:5), PVYEKYCADHFADGR (SEQ ID NO:6), EKYCADHFADGRCDQ (SEQ ID NO:7), and NPLYDQYCKDHFSDG (SEQ ID NO:8), or a sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or 99% identical thereto, or a functional variant thereof. In some preferred examples, the peptide comprises or consists of an amino acid sequence selected from EKYCADHFADGR (SEQ ID NO:2), KYDKYCADHFK (SEQ ID NO:3) and PLYDQYCKDHFSDG (SEQ ID NO:4), a sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto, or a functional variant thereof. Functional variants are peptides comprising or consisting of a variant of the specified amino acid sequences shown herein which retain the ability to bind to a Notch receptor and inhibit Notch receptor dimerization and / or activation. Such functional variants are therefore encompassed herein. The skilled person could identify such variants, for instance using the methods for assessing Notch receptor dimerization and / or activity set out in the Examples below. For instance, Notch receptor dimerization and the inhibition thereof may be assessed by Western blotting. In some examples Notch receptor dimerization and / or activation and the inhibition thereof may be measured by assessing the level of ligand dependent cleavage of the Notch receptor, using a reporter assay such as a luciferase reporter assay, or by measuring the level of activation and / or expression of downstream Notch target genes. Alternative methods for assessing Notch receptor activity are known in the art. Further methods for identifying functional and non-functional variants are well known to a person of ordinary skill in the art.

[0133] Appropriate functional variants may have at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the reference sequence (e.g. any one of SEQ ID NOs: 2-8). In some examples, functional variants may have at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the reference sequence. In some examples, functional variants may have at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to any one of SEQ ID NOs: 2-8. Suitably, percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. any one of SEQ ID NOs: 2-8). In other words, appropriate functional variants may vary from the sequence shown in the reference sequence by one or several (e.g. two etc) amino acids while retaining the ability to bind to a Notch receptor and inhibit Notch receptor dimerization and / or activation.

[0134] Functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of the reference sequence. The term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one, two or more amino acids of the reference sequence, or substitution, deletion or insertion of non-critical amino acids in non-critical regions of the peptide. Functional variants may have up to 5 amino acid substitutions, deletions or insertions relative to the reference sequence. Suitably, the amino acids which are substituted or deleted are non-essential amino acids.

[0135] In some examples the peptide comprises or consists of the amino acid sequence of SEQ ID NO:4, SEQ ID NO:8, any one of SEQ ID NOs:40-62, a sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or 99% identical thereto, or a functional variant thereof. In some examples the peptide comprises or consists of the amino acid sequence of SEQ ID NO:4, SEQ ID NO:8, any one of SEQ ID NOs:40-62, a sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or 99% identical thereto, or a functional variant thereof and is capable of specifically binding to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0136] In some examples, the peptide comprises the amino acid sequence of PLYDQYCKDHFSDG (SEQ ID NO:4). In some examples, the peptide consists of the amino acid sequence of PLYDQYCKDHFSDG (SEQ ID NO:4). The peptide consisting of SEQ ID NO:4 may be referred to as “Notchl inhibitor N110” or “N110”.

[0137] In some preferred examples, the peptide comprises or consists of the amino acid sequence of PLYDQYCKDHFSDG (SEQ ID NO:4) and specifically binds to a Notchl receptorto inhibit Notchl receptor dimerization and / or activation.

[0138] The peptide may be a functional variant comprising or consisting of an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:4. The peptide may be a functional variant comprising or consisting of a sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:4. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:4. The peptide may be a functional variant comprising a maximum of 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:4. The peptide may be a functional variant comprising a maximum of 4 amino acid substitutions, deletions or insertions relative to SEQ ID NO:4. The peptide may be a functional variant comprising a maximum of 3 amino acid substitutions, deletions or insertions relative to SEQ ID NO:4. The peptide may be a functional variant comprising a maximum of 2 amino acid substitutions, deletions or insertions relative to SEQ ID NO:4. The peptide may be a functional variant comprising a maximum of 1 amino acid substitution, deletion or insertion relative to SEQ ID NO:4. In such instances, the peptide is capable of binding to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation. In some examples, the peptide comprises the amino acid sequence of NPLYDQYCKDHFSDG (SEQ ID NO:8). In some examples, the peptide consists of the amino acid sequence of NPLYDQYCKDHFSDG (SEQ ID NO:8).

[0139] In some preferred examples, the peptide comprises or consists of the amino acid sequence of NPLYDQYCKDHFSDG (SEQ ID NO:8) and specifically binds to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0140] The peptide may be a functional variant comprising an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:8. The peptide may be a functional variant comprising a sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:8. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:8. The peptide may be a functional variant comprising a maximum of 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:8. The peptide may be a functional variant comprising a maximum of 4 amino acid substitutions, deletions or insertions relative to SEQ ID NO:8. The peptide may be a functional variant comprising a maximum of 3 amino acid substitutions, deletions or insertions relative to SEQ ID NO:8. The peptide may be a functional variant comprising a maximum of 2 amino acid substitutions, deletions or insertions relative to SEQ ID NO:8. The peptide may be a functional variant comprising a maximum of 1 amino acid substitution, deletion or insertion relative to SEQ ID NO:8. In such instances, the peptide is capable of binding to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0141] In some examples, the peptide comprises the amino acid sequence of SEQ ID NQ:40. In some examples, the peptide consists of the amino acid sequence of SEQ ID NO:40.

[0142] In some preferred examples, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:40 and specifically binds to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0143] The peptide may be a functional variant comprising an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:40. The peptide may be a functional variant comprising a sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:40. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:40. The peptide may be a functional variant comprising a maximum of 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:40. The peptide may be a functional variant comprising a maximum of 4 amino acid substitutions, deletions or insertions relative to SEQ ID NO:40. The peptide may be a functional variant comprising a maximum of 3 amino acid substitutions, deletions or insertions relative to SEQ ID NO:40. The peptide may be a functional variant comprising a maximum of 2 amino acid substitutions, deletions or insertions relative to SEQ ID NO:40. The peptide may be a functional variant comprising a maximum of 1 amino acid substitution, deletion or insertion relative to SEQ ID NO:40. In such instances, the peptide is capable of binding to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0144] In some examples, the peptide comprises the amino acid sequence of SEQ ID NO:41. In some examples, the peptide consists of the amino acid sequence of SEQ ID NO:41. In some preferred examples, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:41 and specifically binds to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0145] The peptide may be a functional variant comprising an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:41. The peptide may be a functional variant comprising a sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:41. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:41. The peptide may be a functional variant comprising a maximum of 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:41. The peptide may be a functional variant comprising a maximum of 4 amino acid substitutions, deletions or insertions relative to SEQ ID NO:41. The peptide may be a functional variant comprising a maximum of 3 amino acid substitutions, deletions or insertions relative to SEQ ID NO:41. The peptide may be a functional variant comprising a maximum of 2 amino acid substitutions, deletions or insertions relative to SEQ ID NO:41. The peptide may be a functional variant comprising a maximum of 1 amino acid substitution, deletion or insertion relative to SEQ ID NO:41. In such instances, the peptide is capable of binding to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0146] In some examples, the peptide comprises the amino acid sequence of SEQ ID NO:42. In some examples, the peptide consists of the amino acid sequence of SEQ ID NO:42.

[0147] In some preferred examples, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:42 and specifically binds to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0148] The peptide may be a functional variant comprising an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:42. The peptide may be a functional variant comprising a sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:42. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:42. The peptide may be a functional variant comprising a maximum of 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:42. The peptide may be a functional variant comprising a maximum of 4 amino acid substitutions, deletions or insertions relative to SEQ ID NO:42. The peptide may be a functional variant comprising a maximum of 3 amino acid substitutions, deletions or insertions relative to SEQ ID NO:42. The peptide may be a functional variant comprising a maximum of 2 amino acid substitutions, deletions or insertions relative to SEQ ID NO:42. The peptide may be a functional variant comprising a maximum of 1 amino acid substitution, deletion or insertion relative to SEQ ID NO:42. In such instances, the peptide is capable of binding to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0149] In some examples, the peptide comprises the amino acid sequence of SEQ ID NO:43. In some examples, the peptide consists of the amino acid sequence of SEQ ID NO:43.

[0150] In some preferred examples, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:43 and specifically binds to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0151] The peptide may be a functional variant comprising an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:43. The peptide may be a functional variant comprising a sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:43. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:43. The peptide may be a functional variant comprising a maximum of 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:43. The peptide may be a functional variant comprising a maximum of 4 amino acid substitutions, deletions or insertions relative to SEQ ID NO:43. The peptide may be a functional variant comprising a maximum of 3 amino acid substitutions, deletions or insertions relative to SEQ ID NO:43. The peptide may be a functional variant comprising a maximum of 2 amino acid substitutions, deletions or insertions relative to SEQ ID NO:43. The peptide may be a functional variant comprising a maximum of 1 amino acid substitution, deletion or insertion relative to SEQ ID NO:43. In such instances, the peptide is capable of binding to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0152] In some examples, the peptide comprises the amino acid sequence of SEQ ID NO:44. In some examples, the peptide consists of the amino acid sequence of SEQ ID NO:44.

[0153] In some preferred examples, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:44 and specifically binds to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0154] The peptide may be a functional variant comprising an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:44. The peptide may be a functional variant comprising a sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:44. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:44. The peptide may be a functional variant comprising a maximum of 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:44. The peptide may be a functional variant comprising a maximum of 4 amino acid substitutions, deletions or insertions relative to SEQ ID NO:44. The peptide may be a functional variant comprising a maximum of 3 amino acid substitutions, deletions or insertions relative to SEQ ID NO:44. The peptide may be a functional variant comprising a maximum of 2 amino acid substitutions, deletions or insertions relative to SEQ ID NO:44. The peptide may be a functional variant comprising a maximum of 1 amino acid substitution, deletion or insertion relative to SEQ ID NO:44. In such instances, the peptide is capable of binding to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0155] In some examples, the peptide comprises the amino acid sequence of SEQ ID NO:45. In some examples, the peptide consists of the amino acid sequence of SEQ ID NO:45.

[0156] In some preferred examples, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:45 and specifically binds to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0157] The peptide may be a functional variant comprising an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:45. The peptide may be a functional variant comprising a sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:45. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:45. The peptide may be a functional variant comprising a maximum of 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:45. The peptide may be a functional variant comprising a maximum of 4 amino acid substitutions, deletions or insertions relative to SEQ ID NO:45. The peptide may be a functional variant comprising a maximum of 3 amino acid substitutions, deletions or insertions relative to SEQ ID NO:45. The peptide may be a functional variant comprising a maximum of 2 amino acid substitutions, deletions or insertions relative to SEQ ID NO:45. The peptide may be a functional variant comprising a maximum of 1 amino acid substitution, deletion or insertion relative to SEQ ID NO:45. In such instances, the peptide is capable of binding to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0158] In some examples, the peptide comprises the amino acid sequence of SEQ ID NO:46. In some examples, the peptide consists of the amino acid sequence of SEQ ID NO:46.

[0159] In some preferred examples, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:46 and specifically binds to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0160] The peptide may be a functional variant comprising an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:46. The peptide may be a functional variant comprising a sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:46. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:46. The peptide may be a functional variant comprising a maximum of 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:46. The peptide may be a functional variant comprising a maximum of 4 amino acid substitutions, deletions or insertions relative to SEQ ID NO:46. The peptide may be a functional variant comprising a maximum of 3 amino acid substitutions, deletions or insertions relative to SEQ ID NO:46. The peptide may be a functional variant comprising a maximum of 2 amino acid substitutions, deletions or insertions relative to SEQ ID NO:46. The peptide may be a functional variant comprising a maximum of 1 amino acid substitution, deletion or insertion relative to SEQ ID NO:46. In such instances, the peptide is capable of binding to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0161] In some examples, the peptide comprises the amino acid sequence of SEQ ID NO:47. In some examples, the peptide consists of the amino acid sequence of SEQ ID NO:47.

[0162] In some preferred examples, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:47 and specifically binds to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0163] The peptide may be a functional variant comprising an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:47. The peptide may be a functional variant comprising a sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:47. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:47. The peptide may be a functional variant comprising a maximum of 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:47. The peptide may be a functional variant comprising a maximum of 4 amino acid substitutions, deletions or insertions relative to SEQ ID NO:47. The peptide may be a functional variant comprising a maximum of 3 amino acid substitutions, deletions or insertions relative to SEQ ID NO:47. The peptide may be a functional variant comprising a maximum of 2 amino acid substitutions, deletions or insertions relative to SEQ ID NO:47. The peptide may be a functional variant comprising a maximum of 1 amino acid substitution, deletion or insertion relative to SEQ ID NO:47. In such instances, the peptide is capable of binding to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0164] In some examples, the peptide comprises the amino acid sequence of SEQ ID NO:48. In some examples, the peptide consists of the amino acid sequence of SEQ ID NO:48. In some preferred examples, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:48 and specifically binds to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0165] The peptide may be a functional variant comprising an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:48. The peptide may be a functional variant comprising a sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:48. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:48. The peptide may be a functional variant comprising a maximum of 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:48. The peptide may be a functional variant comprising a maximum of 4 amino acid substitutions, deletions or insertions relative to SEQ ID NO:48. The peptide may be a functional variant comprising a maximum of 3 amino acid substitutions, deletions or insertions relative to SEQ ID NO:48. The peptide may be a functional variant comprising a maximum of 2 amino acid substitutions, deletions or insertions relative to SEQ ID NO:48. The peptide may be a functional variant comprising a maximum of 1 amino acid substitution, deletion or insertion relative to SEQ ID NO:48. In such instances, the peptide is capable of binding to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0166] In some examples, the peptide comprises the amino acid sequence of SEQ ID NO:49. In some examples, the peptide consists of the amino acid sequence of SEQ ID NO:49.

[0167] In some preferred examples, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:49 and specifically binds to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0168] The peptide may be a functional variant comprising an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:49. The peptide may be a functional variant comprising a sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:49. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:49. The peptide may be a functional variant comprising a maximum of 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:49. The peptide may be a functional variant comprising a maximum of 4 amino acid substitutions, deletions or insertions relative to SEQ ID NO:49. The peptide may be a functional variant comprising a maximum of 3 amino acid substitutions, deletions or insertions relative to SEQ ID NO:49. The peptide may be a functional variant comprising a maximum of 2 amino acid substitutions, deletions or insertions relative to SEQ ID NO:49. The peptide may be a functional variant comprising a maximum of 1 amino acid substitution, deletion or insertion relative to SEQ ID NO:49. In such instances, the peptide is capable of binding to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0169] In some examples, the peptide comprises the amino acid sequence of SEQ ID NO:50. In some examples, the peptide consists of the amino acid sequence of SEQ ID NO:50.

[0170] In some preferred examples, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:50 and specifically binds to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0171] The peptide may be a functional variant comprising an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:50. The peptide may be a functional variant comprising a sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:50. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:50. The peptide may be a functional variant comprising a maximum of 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:50. The peptide may be a functional variant comprising a maximum of 4 amino acid substitutions, deletions or insertions relative to SEQ ID NO:50. The peptide may be a functional variant comprising a maximum of 3 amino acid substitutions, deletions or insertions relative to SEQ ID NO:50. The peptide may be a functional variant comprising a maximum of 2 amino acid substitutions, deletions or insertions relative to SEQ ID NO:50. The peptide may be a functional variant comprising a maximum of 1 amino acid substitution, deletion or insertion relative to SEQ ID NO:50. In such instances, the peptide is capable of binding to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0172] In some examples, the peptide comprises the amino acid sequence of SEQ ID NO:51. In some examples, the peptide consists of the amino acid sequence of SEQ ID NO:51.

[0173] In some preferred examples, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:51 and specifically binds to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0174] The peptide may be a functional variant comprising an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:51. The peptide may be a functional variant comprising a sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:51. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:51. The peptide may be a functional variant comprising a maximum of 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:51. The peptide may be a functional variant comprising a maximum of 4 amino acid substitutions, deletions or insertions relative to SEQ ID NO:51. The peptide may be a functional variant comprising a maximum of 3 amino acid substitutions, deletions or insertions relative to SEQ ID NO:51. The peptide may be a functional variant comprising a maximum of 2 amino acid substitutions, deletions or insertions relative to SEQ ID NO:51. The peptide may be a functional variant comprising a maximum of 1 amino acid substitution, deletion or insertion relative to SEQ ID NO:51. In such instances, the peptide is capable of binding to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0175] In some examples, the peptide comprises the amino acid sequence of SEQ ID NO:52. In some examples, the peptide consists of the amino acid sequence of SEQ ID NO:52.

[0176] In some preferred examples, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:52 and specifically binds to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0177] The peptide may be a functional variant comprising an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:52. The peptide may be a functional variant comprising a sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:52. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:52. The peptide may be a functional variant comprising a maximum of 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:52. The peptide may be a functional variant comprising a maximum of 4 amino acid substitutions, deletions or insertions relative to SEQ ID NO:52. The peptide may be a functional variant comprising a maximum of 3 amino acid substitutions, deletions or insertions relative to SEQ ID NO:52. The peptide may be a functional variant comprising a maximum of 2 amino acid substitutions, deletions or insertions relative to SEQ ID NO:52. The peptide may be a functional variant comprising a maximum of 1 amino acid substitution, deletion or insertion relative to SEQ ID NO:52. In such instances, the peptide is capable of binding to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0178] In some examples, the peptide comprises the amino acid sequence of SEQ ID NO:53. In some examples, the peptide consists of the amino acid sequence of SEQ ID NO:53.

[0179] In some preferred examples, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:53 and specifically binds to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0180] The peptide may be a functional variant comprising an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:53. The peptide may be a functional variant comprising a sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:53. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:52. The peptide may be a functional variant comprising a maximum of 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:53. The peptide may be a functional variant comprising a maximum of 4 amino acid substitutions, deletions or insertions relative to SEQ ID NO:53. The peptide may be a functional variant comprising a maximum of 3 amino acid substitutions, deletions or insertions relative to SEQ ID NO:53. The peptide may be a functional variant comprising a maximum of 2 amino acid substitutions, deletions or insertions relative to SEQ ID NO:53. The peptide may be a functional variant comprising a maximum of 1 amino acid substitution, deletion or insertion relative to SEQ ID NO:53. In such instances, the peptide is capable of binding to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0181] In some examples, the peptide comprises the amino acid sequence of SEQ ID NO:54. In some examples, the peptide consists of the amino acid sequence of SEQ ID NO:54.

[0182] In some preferred examples, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:54 and specifically binds to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0183] The peptide may be a functional variant comprising an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:54. The peptide may be a functional variant comprising a sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:54. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:54. The peptide may be a functional variant comprising a maximum of 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:54. The peptide may be a functional variant comprising a maximum of 4 amino acid substitutions, deletions or insertions relative to SEQ ID NO:54. The peptide may be a functional variant comprising a maximum of 3 amino acid substitutions, deletions or insertions relative to SEQ ID NO:54. The peptide may be a functional variant comprising a maximum of 2 amino acid substitutions, deletions or insertions relative to SEQ ID NO:54. The peptide may be a functional variant comprising a maximum of 1 amino acid substitution, deletion or insertion relative to SEQ ID NO:54. In such instances, the peptide is capable of binding to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0184] In some examples, the peptide comprises the amino acid sequence of SEQ ID NO:55. In some examples, the peptide consists of the amino acid sequence of SEQ ID NO:55. In some preferred examples, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:55 and specifically binds to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0185] The peptide may be a functional variant comprising an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:55. The peptide may be a functional variant comprising a sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:55. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:55. The peptide may be a functional variant comprising a maximum of 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:55. The peptide may be a functional variant comprising a maximum of 4 amino acid substitutions, deletions or insertions relative to SEQ ID NO:55. The peptide may be a functional variant comprising a maximum of 3 amino acid substitutions, deletions or insertions relative to SEQ ID NO:55. The peptide may be a functional variant comprising a maximum of 2 amino acid substitutions, deletions or insertions relative to SEQ ID NO:55. The peptide may be a functional variant comprising a maximum of 1 amino acid substitution, deletion or insertion relative to SEQ ID NO:55. In such instances, the peptide is capable of binding to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0186] In some examples, the peptide comprises the amino acid sequence of SEQ ID NO:56. In some examples, the peptide consists of the amino acid sequence of SEQ ID NO:56.

[0187] In some preferred examples, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:56 and specifically binds to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0188] The peptide may be a functional variant comprising an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:56. The peptide may be a functional variant comprising a sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:56. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:56. The peptide may be a functional variant comprising a maximum of 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:56. The peptide may be a functional variant comprising a maximum of 4 amino acid substitutions, deletions or insertions relative to SEQ ID NO:56. The peptide may be a functional variant comprising a maximum of 3 amino acid substitutions, deletions or insertions relative to SEQ ID NO:56. The peptide may be a functional variant comprising a maximum of 2 amino acid substitutions, deletions or insertions relative to SEQ ID NO:56. The peptide may be a functional variant comprising a maximum of 1 amino acid substitution, deletion or insertion relative to SEQ ID NO:56. In such instances, the peptide is capable of binding to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0189] In some examples, the peptide comprises the amino acid sequence of SEQ ID NO:57. In some examples, the peptide consists of the amino acid sequence of SEQ ID NO:57.

[0190] In some preferred examples, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:57 and specifically binds to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0191] The peptide may be a functional variant comprising an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:57. The peptide may be a functional variant comprising a sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:57. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:57. The peptide may be a functional variant comprising a maximum of 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:57. The peptide may be a functional variant comprising a maximum of 4 amino acid substitutions, deletions or insertions relative to SEQ ID NO:57. The peptide may be a functional variant comprising a maximum of 3 amino acid substitutions, deletions or insertions relative to SEQ ID NO:57. The peptide may be a functional variant comprising a maximum of 2 amino acid substitutions, deletions or insertions relative to SEQ ID NO:57. The peptide may be a functional variant comprising a maximum of 1 amino acid substitution, deletion or insertion relative to SEQ ID NO:57. In such instances, the peptide is capable of binding to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0192] In some examples, the peptide comprises the amino acid sequence of SEQ ID NO:58. In some examples, the peptide consists of the amino acid sequence of SEQ ID NO:58.

[0193] In some preferred examples, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:58 and specifically binds to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0194] The peptide may be a functional variant comprising an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:58. The peptide may be a functional variant comprising a sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:58. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:54. The peptide may be a functional variant comprising a maximum of 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:58. The peptide may be a functional variant comprising a maximum of 4 amino acid substitutions, deletions or insertions relative to SEQ ID NO:58. The peptide may be a functional variant comprising a maximum of 3 amino acid substitutions, deletions or insertions relative to SEQ ID NO:58. The peptide may be a functional variant comprising a maximum of 2 amino acid substitutions, deletions or insertions relative to SEQ ID NO:58. The peptide may be a functional variant comprising a maximum of 1 amino acid substitution, deletion or insertion relative to SEQ ID NO:58. In such instances, the peptide is capable of binding to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0195] In some examples, the peptide comprises the amino acid sequence of SEQ ID NO:59. In some examples, the peptide consists of the amino acid sequence of SEQ ID NO:59.

[0196] In some preferred examples, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:59 and specifically binds to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0197] The peptide may be a functional variant comprising an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:59. The peptide may be a functional variant comprising a sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:59. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:59. The peptide may be a functional variant comprising a maximum of 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:59. The peptide may be a functional variant comprising a maximum of 4 amino acid substitutions, deletions or insertions relative to SEQ ID NO:59. The peptide may be a functional variant comprising a maximum of 3 amino acid substitutions, deletions or insertions relative to SEQ ID NO:59. The peptide may be a functional variant comprising a maximum of 2 amino acid substitutions, deletions or insertions relative to SEQ ID NO:59. The peptide may be a functional variant comprising a maximum of 1 amino acid substitution, deletion or insertion relative to SEQ ID NO:59. In such instances, the peptide is capable of binding to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0198] In some examples, the peptide comprises the amino acid sequence of SEQ ID NO:60. In some examples, the peptide consists of the amino acid sequence of SEQ ID NO:60.

[0199] In some preferred examples, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:60 and specifically binds to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0200] The peptide may be a functional variant comprising an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:60. The peptide may be a functional variant comprising a sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:60. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:60. The peptide may be a functional variant comprising a maximum of 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:60. The peptide may be a functional variant comprising a maximum of 4 amino acid substitutions, deletions or insertions relative to SEQ ID NO:60. The peptide may be a functional variant comprising a maximum of 3 amino acid substitutions, deletions or insertions relative to SEQ ID NO:60. The peptide may be a functional variant comprising a maximum of 2 amino acid substitutions, deletions or insertions relative to SEQ ID NO:60. The peptide may be a functional variant comprising a maximum of 1 amino acid substitution, deletion or insertion relative to SEQ ID NO:60. In such instances, the peptide is capable of binding to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0201] In some examples, the peptide comprises the amino acid sequence of SEQ ID NO:61. In some examples, the peptide consists of the amino acid sequence of SEQ ID NO:61.

[0202] In some preferred examples, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:61 and specifically binds to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0203] The peptide may be a functional variant comprising an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:61. The peptide may be a functional variant comprising a sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:61. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:61. The peptide may be a functional variant comprising a maximum of 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:61. The peptide may be a functional variant comprising a maximum of 4 amino acid substitutions, deletions or insertions relative to SEQ ID NO:61. The peptide may be a functional variant comprising a maximum of 3 amino acid substitutions, deletions or insertions relative to SEQ ID NO:61. The peptide may be a functional variant comprising a maximum of 2 amino acid substitutions, deletions or insertions relative to SEQ ID NO:61. The peptide may be a functional variant comprising a maximum of 1 amino acid substitution, deletion or insertion relative to SEQ ID NO:61. In such instances, the peptide is capable of binding to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0204] In some examples, the peptide comprises the amino acid sequence of SEQ ID NO:62. In some examples, the peptide consists of the amino acid sequence of SEQ ID NO:62. In some preferred examples, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:62 and specifically binds to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0205] The peptide may be a functional variant comprising an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:62. The peptide may be a functional variant comprising a sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:62. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:61. The peptide may be a functional variant comprising a maximum of 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:62. The peptide may be a functional variant comprising a maximum of 4 amino acid substitutions, deletions or insertions relative to SEQ ID NO:62. The peptide may be a functional variant comprising a maximum of 3 amino acid substitutions, deletions or insertions relative to SEQ ID NO:62. The peptide may be a functional variant comprising a maximum of 2 amino acid substitutions, deletions or insertions relative to SEQ ID NO:62. The peptide may be a functional variant comprising a maximum of 1 amino acid substitution, deletion or insertion relative to SEQ ID NO:62. In such instances, the peptide is capable of binding to a Notchl receptor to inhibit Notchl receptor dimerization and / or activation.

[0206] In some examples the peptide comprises or consists of the amino acid sequence of SEQ ID NO:3, any one of SEQ ID NOs:63-67, a sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or 99% identical thereto, or a functional variant thereof.

[0207] In some examples the peptide comprises or consists of the amino acid sequence of SEQ ID NO:3, any one of SEQ ID NOs:63-67, a sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or 99% identical thereto, or a functional variant thereof and is capable of specifically binding to a Notch2 receptor to inhibit Notch2 receptor dimerization and / or activation.

[0208] In some examples, the peptide comprises the amino acid sequence of KYDKYCADHFK (SEQ ID NO:3). In some examples, the peptide consists of the amino acid sequence of KYDKYCADHFK (SEQ ID NO:3). The peptide consisting of SEQ ID NO:3 may be referred to as “Notch2 inhibitor N26” or “N26”.

[0209] In some preferred examples, the peptide comprises or consists of the amino acid sequence of KYDKYCADHFK (SEQ ID NO:3) and specifically binds to a Notch2 receptor to inhibit Notch2 receptor dimerization and / or activation. The peptide may be a functional variant comprising or consisting of an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:3. The peptide may be a functional variant comprising or consisting of a sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:3. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:3. The peptide may be a functional variant comprising a maximum of 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:3. The peptide may be a functional variant comprising a maximum of 4 amino acid substitutions, deletions or insertions relative to SEQ ID NO:3. The peptide may be a functional variant comprising a maximum of 3 amino acid substitutions, deletions or insertions relative to SEQ ID NO:3. The peptide may be a functional variant comprising a maximum of 2 amino acid substitutions, deletions or insertions relative to SEQ ID NO:3. The peptide may be a functional variant comprising a maximum of 1 amino acid substitution, deletion or insertion relative to SEQ ID NO:3. In such instances, the peptide is capable of binding to a Notch2 receptor to inhibit Notch2 receptor dimerization and / or activation. In some examples, the peptide comprises the amino acid sequence of SEQ ID NO:63. In some examples, the peptide consists of the amino acid sequence of SEQ ID NO:63.

[0210] In some preferred examples, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:63 and specifically binds to a Notch2 receptor to inhibit Notch2 receptor dimerization and / or activation.

[0211] The peptide may be a functional variant comprising or consisting of an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:63. The peptide may be a functional variant comprising or consisting of a sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:63. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:63. The peptide may be a functional variant comprising a maximum of 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:63. The peptide may be a functional variant comprising a maximum of 4 amino acid substitutions, deletions or insertions relative to SEQ ID NO:63. The peptide may be a functional variant comprising a maximum of 3 amino acid substitutions, deletions or insertions relative to SEQ ID NO:63. The peptide may be a functional variant comprising a maximum of 2 amino acid substitutions, deletions or insertions relative to SEQ ID NO:63. The peptide may be a functional variant comprising a maximum of 1 amino acid substitution, deletion or insertion relative to SEQ ID NO:63. In such instances, the peptide is capable of binding to a Notch2 receptor to inhibit Notch2 receptor dimerization and / or activation. In some examples, the peptide comprises the amino acid sequence of SEQ ID NO:64. In some examples, the peptide consists of the amino acid sequence of SEQ ID NO:64.

[0212] In some preferred examples, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:64 and specifically binds to a Notch2 receptor to inhibit Notch2 receptor dimerization and / or activation.

[0213] The peptide may be a functional variant comprising or consisting of an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:64. The peptide may be a functional variant comprising or consisting of a sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:64. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:64. The peptide may be a functional variant comprising a maximum of 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:64. The peptide may be a functional variant comprising a maximum of 4 amino acid substitutions, deletions or insertions relative to SEQ ID NO:64. The peptide may be a functional variant comprising a maximum of 3 amino acid substitutions, deletions or insertions relative to SEQ ID NO:64. The peptide may be a functional variant comprising a maximum of 2 amino acid substitutions, deletions or insertions relative to SEQ ID NO:64. The peptide may be a functional variant comprising a maximum of 1 amino acid substitution, deletion or insertion relative to SEQ ID NO:64. In such instances, the peptide is capable of binding to a Notch2 receptor to inhibit Notch2 receptor dimerization and / or activation. In some examples, the peptide comprises the amino acid sequence of SEQ ID NO:65. In some examples, the peptide consists of the amino acid sequence of SEQ ID NO:65.

[0214] In some preferred examples, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:65 and specifically binds to a Notch2 receptor to inhibit Notch2 receptor dimerization and / or activation.

[0215] The peptide may be a functional variant comprising or consisting of an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:65. The peptide may be a functional variant comprising or consisting of a sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:65. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:65. The peptide may be a functional variant comprising a maximum of 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:65. The peptide may be a functional variant comprising a maximum of 4 amino acid substitutions, deletions or insertions relative to SEQ ID NO:65. The peptide may be a functional variant comprising a maximum of 3 amino acid substitutions, deletions or insertions relative to SEQ ID NO:65. The peptide may be a functional variant comprising a maximum of 2 amino acid substitutions, deletions or insertions relative to SEQ ID NO:65. The peptide may be a functional variant comprising a maximum of 1 amino acid substitution, deletion or insertion relative to SEQ ID NO:65. In such instances, the peptide is capable of binding to a Notch2 receptor to inhibit Notch2 receptor dimerization and / or activation. In some examples, the peptide comprises the amino acid sequence of SEQ ID NO:66. In some examples, the peptide consists of the amino acid sequence of SEQ ID NO:66.

[0216] In some preferred examples, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:66 and specifically binds to a Notch2 receptor to inhibit Notch2 receptor dimerization and / or activation.

[0217] The peptide may be a functional variant comprising or consisting of an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:66. The peptide may be a functional variant comprising or consisting of a sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:66. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:66. The peptide may be a functional variant comprising a maximum of 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:66. The peptide may be a functional variant comprising a maximum of 4 amino acid substitutions, deletions or insertions relative to SEQ ID NO:66. The peptide may be a functional variant comprising a maximum of 3 amino acid substitutions, deletions or insertions relative to SEQ ID NO:66. The peptide may be a functional variant comprising a maximum of 2 amino acid substitutions, deletions or insertions relative to SEQ ID NO:66. The peptide may be a functional variant comprising a maximum of 1 amino acid substitution, deletion or insertion relative to SEQ ID NO:66. In such instances, the peptide is capable of binding to a Notch2 receptor to inhibit Notch2 receptor dimerization and / or activation. In some examples, the peptide comprises the amino acid sequence of SEQ ID NO:67. In some examples, the peptide consists of the amino acid sequence of SEQ ID NO:67.

[0218] In some preferred examples, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:67 and specifically binds to a Notch2 receptor to inhibit Notch2 receptor dimerization and / or activation.

[0219] The peptide may be a functional variant comprising or consisting of an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:67. The peptide may be a functional variant comprising or consisting of a sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:67. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:67. The peptide may be a functional variant comprising a maximum of 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:67. The peptide may be a functional variant comprising a maximum of 4 amino acid substitutions, deletions or insertions relative to SEQ ID NO:67. The peptide may be a functional variant comprising a maximum of 3 amino acid substitutions, deletions or insertions relative to SEQ ID NO:67. The peptide may be a functional variant comprising a maximum of 2 amino acid substitutions, deletions or insertions relative to SEQ ID NO:67. The peptide may be a functional variant comprising a maximum of 1 amino acid substitution, deletion or insertion relative to SEQ ID NO:67. In such instances, the peptide is capable of binding to a Notch2 receptor to inhibit Notch2 receptor dimerization and / or activation. In some examples the peptide comprises or consists of the amino acid sequence of SEQ ID NO:2, any one of SEQ ID NOs:5-7, SEQ ID NO:68, SEQ ID NO:69, a sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or 99% identical thereto, or a functional variant thereof.

[0220] In some examples the peptide comprises or consists of the amino acid sequence of SEQ ID NO:2, any one of SEQ ID NOs:5-7, SEQ ID NO:68, SEQ ID NO:69, a sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or 99% identical thereto, or a functional variant thereof and is capable of specifically binding to a Notch3 receptor to inhibit Notch3 receptor dimerization and / or activation.

[0221] In some examples, the peptide comprises the amino acid sequence of EKYCADHFADGR (SEQ ID NO:2). In some examples, the peptide consists of the amino acid sequence of EKYCADHFADGR (SEQ ID NO:2). The peptide consisting of SEQ ID NO:2 may be referred to as “Notch3 inhibitor 23DB4”, “23DB4 or“N34””.

[0222] In some preferred examples, the peptide comprises or consists of the amino acid sequence of EKYCADHFADGR (SEQ ID NO:2) and specifically binds to a Notch3 receptor to inhibit Notch3 receptor dimerization and / or activation.

[0223] The peptide may be a functional variant comprising or consisting of an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:2. The peptide may be a functional variant comprising or consisting of a sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:2. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:2. The peptide may be a functional variant comprising a maximum of 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:2. The peptide may be a functional variant comprising a maximum of 4 amino acid substitutions, deletions or insertions relative to SEQ ID NO:2. The peptide may be a functional variant comprising a maximum of 3 amino acid substitutions, deletions or insertions relative to SEQ ID NO:2. The peptide may be a functional variant comprising a maximum of 2 amino acid substitutions, deletions or insertions relative to SEQ ID NO:2. The peptide may be a functional variant comprising a maximum of 1 amino acid substitution, deletion or insertion relative to SEQ ID NO:2. In such instances, the peptide is capable of binding to a Notch3 receptor to inhibit Notch3 receptor dimerization and / or activation. In some examples, the peptide comprises the amino acid sequence of PVYEKYCADHFADGRCDQ (SEQ ID NO:5). In some examples, the peptide consists of the amino acid sequence of SEQ ID NO:5.

[0224] In some preferred examples, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:5 and specifically binds to a Notch3 receptor to inhibit Notch3 receptor dimerization and / or activation.

[0225] The peptide may be a functional variant comprising or consisting of an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:5. The peptide may be a functional variant comprising or consisting of a sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:5. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:5. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:5. The peptide may be a functional variant comprising a maximum of 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:5. The peptide may be a functional variant comprising a maximum of 4 amino acid substitutions, deletions or insertions relative to SEQ ID NO:5. The peptide may be a functional variant comprising a maximum of 3 amino acid substitutions, deletions or insertions relative to SEQ ID NO:5. The peptide may be a functional variant comprising a maximum of 2 amino acid substitutions, deletions or insertions relative to SEQ ID NO:5. The peptide may be a functional variant comprising a maximum of 1 amino acid substitution, deletion or insertion relative to SEQ ID NO:5. In such instances, the peptide is capable of binding to a Notch3 receptor to inhibit Notch3 receptor dimerization and / or activation.

[0226] In some examples, the peptide comprises the amino acid sequence of PVYEKYCADHFADGR (SEQ ID NO:6). In some examples, the peptide consists of the amino acid sequence of SEQ ID NO:6.

[0227] In some preferred examples, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:6 and specifically binds to a Notch3 receptor to inhibit Notch3 receptor dimerization and / or activation. The peptide may be a functional variant comprising or consisting of an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:6. The peptide may be a functional variant comprising or consisting of a sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:6. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:6. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:6. The peptide may be a functional variant comprising a maximum of 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:6. The peptide may be a functional variant comprising a maximum of 4 amino acid substitutions, deletions or insertions relative to SEQ ID NO:6. The peptide may be a functional variant comprising a maximum of 3 amino acid substitutions, deletions or insertions relative to SEQ ID NO:6. The peptide may be a functional variant comprising a maximum of 2 amino acid substitutions, deletions or insertions relative to SEQ ID NO:6. The peptide may be a functional variant comprising a maximum of 1 amino acid substitution, deletion or insertion relative to SEQ ID NO:6. In such instances, the peptide is capable of binding to a Notch3 receptor to inhibit Notch3 receptor dimerization and / or activation.

[0228] In some examples, the peptide comprises the amino acid sequence of EKYCADHFADGRCDQ (SEQ ID NO:7). In some examples, the peptide consists of the amino acid sequence of SEQ ID NO:7.

[0229] In some preferred examples, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:7 and specifically binds to a Notch3 receptor to inhibit Notch3 receptor dimerization and / or activation.

[0230] The peptide may be a functional variant comprising or consisting of an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:7. The peptide may be a functional variant comprising or consisting of a sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:7. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:7. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:7. The peptide may be a functional variant comprising a maximum of 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:7. The peptide may be a functional variant comprising a maximum of 4 amino acid substitutions, deletions or insertions relative to SEQ ID NO:7. The peptide may be a functional variant comprising a maximum of 3 amino acid substitutions, deletions or insertions relative to SEQ ID NO:7. The peptide may be a functional variant comprising a maximum of 2 amino acid substitutions, deletions or insertions relative to SEQ ID NO:7. The peptide may be a functional variant comprising a maximum of 1 amino acid substitution, deletion or insertion relative to SEQ ID NO:7. In such instances, the peptide is capable of binding to a Notch3 receptor to inhibit Notch3 receptor dimerization and / or activation.

[0231] In some examples, the peptide comprises the amino acid sequence of SEQ ID NO:68. In some examples, the peptide consists of the amino acid sequence of SEQ ID NO:68.

[0232] In some preferred examples, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:68 and specifically binds to a Notch3 receptor to inhibit Notch3 receptor dimerization and / or activation.

[0233] The peptide may be a functional variant comprising or consisting of an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:68. The peptide may be a functional variant comprising or consisting of a sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:68. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:68. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:68. The peptide may be a functional variant comprising a maximum of 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:68. The peptide may be a functional variant comprising a maximum of 4 amino acid substitutions, deletions or insertions relative to SEQ ID NO:68. The peptide may be a functional variant comprising a maximum of 3 amino acid substitutions, deletions or insertions relative to SEQ ID NO:68. The peptide may be a functional variant comprising a maximum of 2 amino acid substitutions, deletions or insertions relative to SEQ ID NO:68. The peptide may be a functional variant comprising a maximum of 1 amino acid substitution, deletion or insertion relative to SEQ ID NO:68. In such instances, the peptide is capable of binding to a Notch3 receptor to inhibit Notch3 receptor dimerization and / or activation.

[0234] In some examples, the peptide comprises the amino acid sequence of SEQ ID NO:69. In some examples, the peptide consists of the amino acid sequence of SEQ ID NO:69.

[0235] In some preferred examples, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:69 and specifically binds to a Notch3 receptorto inhibit Notch3 receptor dimerization and / or activation.

[0236] The peptide may be a functional variant comprising or consisting of an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:69. The peptide may be a functional variant comprising or consisting of a sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:69. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:69. The peptide may be a functional variant comprising up to 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:69. The peptide may be a functional variant comprising a maximum of 5 amino acid substitutions, deletions or insertions relative to SEQ ID NO:69. The peptide may be a functional variant comprising a maximum of 4 amino acid substitutions, deletions or insertions relative to SEQ ID NO:69. The peptide may be a functional variant comprising a maximum of 3 amino acid substitutions, deletions or insertions relative to SEQ ID NO:69. The peptide may be a functional variant comprising a maximum of 2 amino acid substitutions, deletions or insertions relative to SEQ ID NO:69. The peptide may be a functional variant comprising a maximum of 1 amino acid substitution, deletion or insertion relative to SEQ ID NO:69. In such instances, the peptide is capable of binding to a Notch3 receptor to inhibit Notch3 receptor dimerization and / or activation.

[0237] Peptide Secondary Structure

[0238] In some embodiments the peptide of the invention forms a secondary structure. Suitably, the peptide forms a helix, such as an alpha helix. Suitably, the peptide comprises a core helical structure. The secondary structure of the peptide may competitively bind to the Notch receptor dimerization motif, thereby inhibiting Notch receptor dimerization. The secondary structure of the peptide may competitively bind to the Notch receptor dimerization motif, thereby inhibiting Notch receptor activation. The secondary structure of the peptide may competitively bind to the Notch receptor dimerization motif, thereby inhibiting Notch receptor signalling. The secondary structure of the peptide may contribute to the specificity of the peptide for a specific Notch receptor i.e. Notchl, Notch2, Notch3 or Notch4.

[0239] The peptide may form a secondary structure which mimics the secondary structure of the dimerization motif of the Notchl receptor. In this context, “mimics” means that the secondary structure is the same as the secondary structure of the dimerization motif of the Notchl receptor. Without wishing to be bound by theory, this may allow the peptide to competitively bind with the dimerization motif of the Notchl receptor, thereby preventing Notchl receptor dimerization and / or activation. For example, peptides of SEQ ID NOs:4, 8, or 40-62 may mimic Notchl. In a preferred example, the peptide of SEQ ID NO: 4 mimics the structure of the dimerization motif of Notchl. In a preferred example, the peptide of SEQ ID NO: 8 mimics the structure of the dimerization motif of Notchl.

[0240] The peptide may form a secondary structure which mimics the secondary structure of the dimerization motif of the Notch2 receptor. In this context, “mimics” means that the secondary structure is the same as the secondary structure of the dimerization motif of the Notch2 receptor. Without wishing to be bound by theory, this may allow the peptide to competitively bind with the dimerization motif of the Notch2 receptor, thereby preventing Notch2 receptor dimerization and / or activation. For example, peptides of SEQ ID NOs:3, or 63-67 may mimic Notch2. In a preferred example, the peptide of SEQ ID NO: 3 mimics the structure of the dimerization motif of Notch2. The peptide may form a secondary structure which mimics the secondary structure of the dimerization motif of the Notch3 receptor. In this context, “mimics” means that the secondary structure is the same as the secondary structure of the dimerization motif of the Notch3 receptor. Without wishing to be bound by theory, this may allow the peptide to competitively bind with the dimerization motif of the Notch3 receptor, thereby preventing Notch3 receptor dimerization and / or activation. For example, peptides of SEQ ID NOs:2, 5-7, 68 or 69 may mimic Notch3. In a preferred example, the peptide of SEQ ID NO:2 mimics the structure of the dimerization motif of Notch3. In a preferred example, the peptide of SEQ ID NO:5 mimics the structure of the dimerization motif of Notch3. In a preferred example, the peptide of SEQ ID NO: 6 mimics the structure of the dimerization motif of Notch3. In a preferred example, the peptide of SEQ ID NO:7 mimics the structure of the dimerization motif of Notch3.

[0241] Notch receptor

[0242] The peptides of the invention are capable of binding to a Notch receptor and inhibiting Notch receptor dimerization and / or activation. The peptides of the invention are capable of binding to a Notch receptor and inhibiting Notch receptor signalling.

[0243] The Notch receptor may be Notch1, Notch2, Notch3 and / or Notch4. In some embodiments, the peptide of the invention can bind to different Notch receptors, such as Notch1, Notch2, Notch3 and / or Notch4. In some examples, the peptide binds to Notchl and Notch2, but does not bind to Notch3 or Notch4. In some examples, the peptide binds to Notchl and Notch3, but does not bind to Notch2 or Notch4. In some examples, the peptide binds to Notchl and Notch4, but does not bind to Notch2 or Notch3. In some examples, the peptide binds to Notch2 and Notch3, but does not bind to Notchl or Notch4. In some examples, the peptide binds to Notch2 and Notch4, but does not bind to Notchl or Notch3. In some examples, the peptide binds to Notch3 and Notch4, but does not bind to Notchl or Notch2. Alternatively, the peptide may specifically bind to a specific Notch receptor. In some examples, the peptide specifically binds to the Notchl receptor, but does not bind to Notch2, Notch3 or Notch4. In some examples, the peptide specifically binds to the Notch2 receptor, but does not bind to Notchl, Notch3 or Notch4. In some examples, the peptide specifically binds to the Notch3 receptor, but does not bind Notchl, Notch2 or Notch4. In some examples, the peptide specifically binds the Notch4 receptor, but does not bind to Notchl, Notch2, or Notch3. Suitable peptide sequences for binding to each Notch receptor are identified elsewhere herein. Advantageously in some cases, the peptide is specific for a particular Notch receptor and thereby provides targeted inhibition of only one type of Notch receptor, leaving the other Notch receptors functional. This means that the peptide can be used as a targeted therapy with fewer side effects caused by off-target binding.

[0244] Suitably, the Notch receptor is a mammalian Notch receptor. Suitable mammalian Notch receptors may be selected from: a primate, preferably a human, a mouse, rat, hamster, dog, cat, horse, pig, goat, sheep, and cow Notch receptor. In some preferred examples, the Notch receptor is a human Notch receptor.

[0245] In some examples, the Notch receptor is not a human Notch receptor. For example, the Notch receptor may be an insect Notch receptor, a rodent Notch receptor, an avian Notch receptor, an amphibian Notch receptor, or a fish Notch receptor. In some examples, the Notch receptor may be a fly, mouse, rat, hamster, chicken, xenopus or zebrafish Notch receptor.

[0246] Suitably, the Notch receptor comprises a binding site. In some embodiments, the peptide binds to the Notch receptor at the binding site. Suitably, the peptide binds to the binding site to inhibit Notch receptor dimerization. Suitably, the peptide binds to the binding site and inhibits Notch receptor activation. Suitably, the peptide binds to the binding site and inhibits Notch receptor signalling. Suitably, the peptide binds to the binding site and inhibits Notch receptor dimerization and activation.

[0247] The binding site may be in the extracellular domain of the Notch receptor. The binding site may be in the extracellular domain, adjacent to the cell membrane or substantially adjacent to the cell membrane. In this context, “adjacent to the cell membrane” means close to the cell membrane or directly next to the cell membrane. The binding site may be in the extracellular domain of the Notch receptor, approximately 200 amino acids from the transmembrane domain.

[0248] The binding site may be in the negative regulatory region (NRR) of the extracellular domain of the Notch receptor. The NRR region contains three LIN-12 / Notch repeat (LNR) domains,, and the heterodimerization domain. The NRR region may also be referred to as the ECR-E region. The structure of the Notch3 extracellular domain is shown in Fig. 1C. The general structure shown in Fig. 1C is shared by other Notch receptors, such as Notchl, Notch2 and Notch4.

[0249] Suitably the binding site is in the NRR of the Notchl receptor between amino acid positions 1442 and 1732 of the Notchl receptor, wherein the amino acid positions are numbered relative to SEQ ID NO:29. Suitably the binding site is in the NRR of the Notchl receptor between amino acid positions 1450 and 1700 of the Notchl receptor, wherein the amino acid positions are numbered relative to SEQ ID NO:29. Suitably the binding site is in the NRR of the Notchl receptor between amino acid positions 1450 and 1600 of the Notchl receptor, wherein the amino acid positions are numbered relative to SEQ ID NO:29. Suitably the binding site is in the NRR of the Notchl receptor between amino acid positions 1500 and 1600 of the Notchl receptor, wherein the amino acid positions are numbered relative to SEQ ID NO:29. Suitably the binding site is in the NRR of the Notchl receptor between amino acid positions 1500 and 1550 of the Notchl receptor, wherein the amino acid positions are numbered relative to SEQ ID NO:29. Suitably the binding site is in the NRR of the Notchl receptor between amino acid positions 1520 and 1550 of the Notchl receptor, wherein the amino acid positions are numbered relative to SEQ ID NO:29. Suitably the binding site is in the NRR of the Notchl receptor between amino acid positions 1530 and 1540 of the Notchl receptor, wherein the amino acid positions are numbered relative to SEQ ID NO:29. In some examples, the binding site is at amino acid positions 1535-1539 of the Notchl receptor, wherein the amino acid positions are numbered relative to SEQ ID NO:29.

[0250] Suitably the binding site is in the third LNRofthe NRR of the Notch 1 receptor. Suitably the binding site is in the third LNR of the NRR between amino acid positions 1532 to 1571 of the Notch 1 receptor, wherein the amino acid positions are numbered relative to SEQ ID NO:29. In some examples, the binding site is in the third LNR of the NRR at amino acid positions 1535-1539 of the Notchl receptor, wherein the amino acid positions are numbered relative to SEQ ID NO:29. Suitably the binding site is in the NRR of the Notch2 receptor between amino acid positions 1418 and 1677 of the Notch2 receptor, wherein the amino acid positions are numbered relative to SEQ ID NO:30. Suitably the binding site is in the NRR of the Notch2 receptor between amino acid positions 1420 and 1650 of the Notch2 receptor, wherein the amino acid positions are numbered relative to SEQ ID NO:30. Suitably the binding site is in the NRR of the Notch2 receptor between amino acid positions 1450 and 1600 of the Notch2 receptor, wherein the amino acid positions are numbered relative to SEQ ID NO:30. Suitably the binding site is in the NRR of the Notch2 receptor between amino acid positions 1450 and 1550 of the Notch2 receptor, wherein the amino acid positions are numbered relative to SEQ ID NO:30. Suitably the binding site is in the NRR of the Notch2 receptor between amino acid positions 1500 and 1550 of the Notch2 receptor, wherein the amino acid positions are numbered relative to SEQ ID NO:30. Suitably the binding site is in the NRR of the Notch2 receptor between amino acid positions 1500 and 1520 of the Notch2 receptor, wherein the amino acid positions are numbered relative to SEQ ID NO:30. Suitably the binding site is in the NRR of the Notch2 receptor between amino acid positions 1505 and 1515 of the Notch2 receptor, wherein the amino acid positions are numbered relative to SEQ ID NO:30. In some examples, the binding site is at amino acid positions 1508-1512 of the Notch2 receptor, wherein the amino acid positions are numbered relative to SEQ ID NO:30.

[0251] Suitably the binding site is in the NRR of the Notch3 receptor between amino acid positions 1380 and 1640 of the Notch3 receptor, wherein the amino acid positions are numbered relative to SEQ ID NO:31. Suitably the binding site is in the NRR of the Notch3 receptor between amino acid positions 1400 and 1600 of the Notch3 receptor, wherein the amino acid positions are numbered relative to SEQ ID NO:31. Suitably the binding site is in the NRR of the Notch3 receptor between amino acid positions 1400 and 1550 of the Notch3 receptor, wherein the amino acid positions are numbered relative to SEQ ID NO:31. Suitably the binding site is in the NRR of the Notch3 receptor between amino acid positions 1450 and 1550 of the Notch3 receptor, wherein the amino acid positions are numbered relative to SEQ ID NO:31. Suitably the binding site is in the NRR of the Notch3 receptor between amino acid positions 1450 and 1500 of the Notch3 receptor, wherein the amino acid positions are numbered relative to SEQ ID NO:31. Suitably the binding site is in the NRR of the Notch3 receptor between amino acid positions 1465 and 1495 of the Notch3 receptor, wherein the amino acid positions are numbered relative to SEQ ID NO:31. Suitably the binding site is in the NRR of the Notch3 receptor between amino acid positions 1470 and 1480 of the Notch3 receptor, wherein the amino acid positions are numbered relative to SEQ ID NO:31. In some examples, the binding site is at amino acid positions 1474-1478 of the Notch3 receptor, wherein the amino acid positions are numbered relative to SEQ ID NO:31.

[0252] Suitably the binding site is in the NRR of the Notch4 receptor between amino acid positions of 1163 and 1310 of the Notch4 receptor, wherein the amino acid positions are numbered relative to SEQ ID NO:33. Suitably the binding site is in the NRR of the Notch4 receptor between amino acid positions 1170 and 1300 of the Notch4 receptor, wherein the amino acid positions are numbered relative to SEQ ID NO:33. Suitably the binding site is in the NRR of the Notch4 receptor between amino acid positions 1200 and 1300 of the Notch4 receptor, wherein the amino acid positions are numbered relative to SEQ ID NO:33. Suitably the binding site is in the NRR of the Notch4 receptor between amino acid positions 1225 and 1275 of the Notch4 receptor, wherein the amino acid positions are numbered relative to SEQ ID NO:33. Suitably the binding site is in the NRR of the Notch4 receptor between amino acid positions 1240 and 1270 of the Notch4 receptor, wherein the amino acid positions are numbered relative to SEQ ID NO:33. Suitably the binding site is in the NRR of the Notch4 receptor between amino acid positions 1255 and 1265 of the Notch4 receptor, wherein the amino acid positions are numbered relative to SEQ ID NO:33. In some examples, the binding site is at amino acid positions 1257-1261 of the Notch4 receptor, wherein the amino acid positions are numbered relative to SEQ ID NO:33.

[0253] Binding Site Motif

[0254] The binding site may correspond to the dimerization motif of a Notch receptor. In this context, “correspond to” the dimerization motif means that the binding site comprises or consists of the dimerization motif i.e. that the peptide binds to the Notch receptor at the dimerization motif. The binding site may include the dimerization motif of the Notch receptor, and may further comprise additional amino acids at the N and / or C terminal sides of the dimerization motif.

[0255] The binding site may comprise an amino acid motif comprising the sequence YCXDH (SEQ ID NO: 23), wherein X is an amino acid selected from H, A, K and R. In preferred examples, the binding site may comprise an amino acid motif comprising the sequence YCXDH (SEQ ID NO: 23), wherein X is an amino acid selected from H, A, and K. The binding site may comprise an amino acid motif comprising the sequence YCXDH (SEQ ID NO: 23), wherein X is an amino acid selected from H, A, and R. The binding site may comprise an amino acid motif comprising the sequence YCXDH (SEQ ID NO: 23), wherein X is an amino acid selected from A, K and R. The binding site may comprise an amino acid motif comprising the sequence YCXDH (SEQ ID NO: 23), wherein X is an amino acid selected from H and A. The binding site may comprise an amino acid motif comprising the sequence YCXDH (SEQ ID NO: 23), wherein X is an amino acid selected from H and K. The binding site may comprise an amino acid motif comprising the sequence YCXDH (SEQ ID NO: 23), wherein X is an amino acid selected from H and R. The binding site may comprise an amino acid motif comprising the sequence YCXDH (SEQ ID NO: 23), wherein X is an amino acid selected from A and K. The binding site may comprise an amino acid motif comprising the sequence YCXDH (SEQ ID NO: 23), wherein X is an amino acid selected from A and K. The binding site may comprise an amino acid motif comprising the sequence YCXDH (SEQ ID NO: 23), wherein X is an amino acid selected from K and R. The binding site may comprise an amino acid motif comprising the sequence YCADH (SEQ ID NO:9). The binding site may comprise an amino acid motif comprising the sequence YCHDH (SEQ ID NO:14). The binding site may comprise an amino acid motif comprising the sequence YCKDH (SEQ ID NO:10). The binding site may comprise an amino acid motif comprising the sequence YCRDH (SEQ ID NO: 15).

[0256] The binding site may comprise an amino acid motif comprising the sequence YCXDHF (SEQ ID NO:24), wherein X is an amino acid selected from H, A, and K. The binding site may comprise an amino acid motif comprising the sequence YCXDHF (SEQ ID NO:24), wherein X is an amino acid selected from H and A. The binding site may comprise an amino acid motif comprising the sequence YCXDHF (SEQ ID NO:24), wherein X is an amino acid selected from H, and K. The binding site may comprise an amino acid motif comprising the sequence YCXDHF (SEQ ID NO:24), wherein X is an amino acid selected from A and K. The binding site may comprise and amino acid motif comprising the sequence YCADHF (SEQ ID NO:71). The binding site may comprise the amino acid motif YCHDHF (SEQ ID NQ:70). The binding site may comprise and amino acid motif comprising the sequence comprising the sequence YCKDHF (SEQ ID NO:72). In some examples, the binding site comprises an amino acid motif comprising the sequence X1YCX2DH (SEQ ID NO:80), wherein Xi is an amino acid selected from Q and K, and X2is selected from H, A, and K. The binding site may comprise an amino acid motif comprising the sequence X1YCX2DH (SEQ ID NO:80), wherein Xi is an amino acid selected from Q and K, and X2is selected from H and A. The binding site may comprise an amino acid motif comprising the sequence X1YCX2DH (SEQ ID NO:80), wherein Xi is an amino acid selected from Q and K, and X2is selected from H and K. The binding site may comprise an amino acid motif comprising the sequence X1YCX2DH (SEQ ID NO:80), wherein X1is an amino acid selected from Q and K, and X2is selected from A and K. The binding site may comprise an amino acid motif comprising the sequence QYCHDH (SEQ ID NO: 81), The binding site may comprise an amino acid motif comprising the sequence QYCKDH (SEQ ID NO:82). The binding site may comprise an amino acid motif comprising the sequence QYCADH (SEQ ID NO:83). The binding site may comprise an amino acid motif comprising the sequence KYCADH (SEQ ID NO:84). The binding site may comprise an amino acid motif comprising the sequence KYCHDH (SEQ ID NO:85). The binding site may comprise an amino acid motif comprising the sequence KYCKDH (SEQ ID NO:86). The binding site may comprise an amino acid motif comprising the sequence X1YCX2DHF (SEQ ID NO:25), wherein X1is an amino acid selected from Q and K, and X2is selected from H, A, and K. The binding site may comprise an amino acid motif comprising the sequence X1YCX2DHF (SEQ ID NO:25), wherein X1is an amino acid selected from Q and K, and X2is selected from H and A. The binding site may comprise an amino acid motif comprising the sequence X1YCX2DHF (SEQ ID NO:25), wherein X1is an amino acid selected from Q and K, and X2is selected from H and K. The binding site may comprise an amino acid motif comprising the sequence X1YCX2DHF (SEQ ID NO:25), wherein X1is an amino acid selected from Q and K, and X2is selected from A and K. The binding site may comprise an amino acid motif comprising the sequence QYCHDHF (SEQ ID NO:73). The binding site may comprise an amino acid motif comprising the sequence QYCKDHF (SEQ ID NO:74). The binding site may comprise an amino acid motif comprising the sequence QYCADHF (SEQ ID NO: 77). The binding site may comprise an amino acid motif comprising the sequence KYCADHF (SEQ ID NO:75). The binding site may comprise an amino acid motif comprising the sequence KYCHDHF (SEQ ID NO: 78). The binding site may comprise an amino acid motif comprising the sequence KYCKDHF (SEQ ID NO: 79).

[0257] In some examples, the binding site comprises an amino acid motif comprising the sequence X1X2YCX3DH (SEQ ID NO:17 / SEQ ID:26), wherein X1is selected from E and D, X2is selected from K and Q, and X3is selected A, K, H and R. In some examples, the binding site comprises an amino acid motif comprising the sequence X1X2YCX3DH (SEQ ID NO: 17), wherein X1is selected from E and D, X2is selected from K and Q, and X3is selected A, K, and H. In some examples, the binding site comprises an amino acid motif comprising the sequence X1X2YCX3DH (SEQ ID NO: 17), wherein X1is selected from E and D, X2is selected from K and Q, and X3is selected A, K, and R. In some examples, the binding site comprises an amino acid motif comprising the sequence X1X2YCX3DH (SEQ ID NO: 17), wherein X1is selected from E and D, X2is selected from K and Q, and X3is selected K, H, and R. In some examples, the binding site comprises an amino acid motif comprising the sequence X1X2YCX3DH (SEQ ID NO: 17), wherein X1is selected from E and D, X2is selected from K and Q, and X3is selected A and K. In some examples, the binding site comprises an amino acid motif comprising the sequence X1X2YCX3DH (SEQ ID NO:17), wherein X1is selected from E and D, X2is selected from K and Q, and X3is selected A and H. In some examples, the binding site comprises an amino acid motif comprising the sequence X1X2YCX3DH (SEQ ID NO:17), wherein X1is selected from E and D, X2is selected from K and Q, and X3is selected A and R. In some examples, the binding site comprises an amino acid motif comprising the sequence X1X2YCX3DH (SEQ ID NO: 17), wherein X1is selected from E and D, X2is selected from K and Q, and X3is selected K and H. In some examples, the binding site comprises an amino acid motif comprising the sequence X1X2YCX3DH (SEQ ID NO: 17), wherein X1is selected from E and D, X2is selected from K and Q, and X3is selected K and R. In some examples, the binding site comprises an amino acid motif comprising the sequence X1X2YCX3DH (SEQ ID NO:17), wherein X1is selected from E and D, X2is selected from K and Q, and X3is selected H and R.

[0258] In one embodiment, the binding site comprises an amino acid motif comprising the sequence DQYCKDH (SEQ ID NO:18). In one embodiment, the binding site comprises an amino acid motif comprising the sequence DKYCADH (SEQ ID NO:19). In one embodiment, the binding site comprises an amino acid motif comprising the sequence EKYCADH (SEQ ID NQ:20). In one embodiment, the binding site comprises an amino acid motif comprising the sequence DQYCHDH (SEQ ID NO: 21). In one embodiment, the binding site comprises an amino acid motif comprising the sequence DQYCRDH (SEQ ID NO:22). In one embodiment, the binding site comprises an amino acid motif comprising the sequence EKYCKDH (SEQ ID NO:87). In one embodiment, the binding site comprises an amino acid motif comprising the sequence EKYCHDH (SEQ ID NO:88). In one embodiment, the binding site comprises an amino acid motif comprising the sequence EKYCRDH (SEQ ID NO:89). In one embodiment, the binding site comprises an amino acid motif comprising the sequence EQYCADH (SEQ ID NO:90). In one embodiment, the binding site comprises an amino acid motif comprising the sequence EQYCKDH (SEQ ID NO:91). In one embodiment, the binding site comprises an amino acid motif comprising the sequence EQYCHDH (SEQ ID NO:92). In one embodiment, the binding site comprises an amino acid motif comprising the sequence EQYCRDH (SEQ ID NO:93). In one embodiment, the binding site comprises an amino acid motif comprising the sequence DKYCKDH (SEQ ID NO:94). In one embodiment, the binding site comprises an amino acid motif comprising the sequence DKYCHDH (SEQ ID NO:95). In one embodiment, the binding site comprises an amino acid motif comprising the sequence DKYCRDH (SEQ ID NO:96). In one embodiment, the binding site comprises an amino acid motif comprising the sequence DQYCADH (SEQ ID NO:97).

[0259] The binding site may comprise an amino acid motif comprising the sequence YX1X2YCX3DH (SEQ ID NO:27) wherein X1is an amino acid selected from D and E, X2is selected from Q and K, and X3is selected from H, A, K and R. The binding site may comprise an amino acid motif comprising the sequence YX1X2YCX3DH (SEQ ID NO:27) wherein X1is an amino acid selected from D and E, X2is selected from Q and K, and X3is selected from H, A and K. The binding site may comprise an amino acid motif comprising the sequence YX1X2YCX3DH (SEQ ID NO:27) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, and X3is selected from H, A and R. The binding site may comprise an amino acid motif comprising the sequence YX1X2YCX3DH (SEQ ID NO:27) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, and X3is selected from H, K and R. The binding site may comprise an amino acid motif comprising the sequence YXIX2YCX3DH (SEQ ID NO:27) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, and X3is selected from A, K and R. The binding site may comprise an amino acid motif comprising the sequence YXIX2YCX3DH (SEQ ID NO:27) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, and X3is selected from H and A. The binding site may comprise an amino acid motif comprising the sequence YXIX2YCX3DH (SEQ ID NO:27) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, and X3is selected from H and K. The binding site may comprise an amino acid motif comprising the sequence YXIX2YCX3DH (SEQ ID NO:27) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, and X3is selected from H and R. The binding site may comprise an amino acid motif comprising the sequence YXIX2YCX3DH (SEQ ID NO:27) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, and X3is selected from A and K, The binding site may comprise an amino acid motif comprising the sequence YXIX2YCX3DH (SEQ ID NO:27) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, and X3is selected from A and R. The binding site may comprise an amino acid motif comprising the sequence YXIX2YCX3DH (SEQ ID NO:27) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, and X3is selected from K and R. Suitably, the binding site comprises an amino acid motif comprising the sequence YDQYCHDH (SEQ ID NO:99). Suitably, the binding site comprises an amino acid motif comprising the sequence YDQYCADH (SEQ ID NO:100). Suitably, the binding site comprises an amino acid motif comprising the sequence YDQYCKDH (SEQ ID NO:101 / SEQ ID NO:76). Suitably, the binding site comprises an amino acid motif comprising the sequence YDQYCRDH (SEQ ID NO: 102). Suitably, the binding site comprises an amino acid motif comprising the sequence YDKYCHDH (SEQ ID NO:103), Suitably, the binding site comprises an amino acid motif comprising the sequence YDKYCADH (SEQ ID NO: 104). Suitably, the binding site comprises an amino acid motif comprising the sequence YDKYCKDH (SEQ ID NO: 105). Suitably, the binding site comprises an amino acid motif comprising the sequence YDKYCRDH (SEQ ID NO:106). Suitably, the binding site comprises an amino acid motif comprising the sequence YEQYCHDH (SEQ ID NO:107). Suitably, the binding site comprises an amino acid motif comprising the sequence YEQYCADH (SEQ ID NO: 108). Suitably, binding site comprises an amino acid motif comprising the sequence YEQYCKDH (SEQ ID NO: 109). Suitably, the binding site comprises an amino acid motif comprising the sequence YEQYCRDH (SEQ ID NO:110). Suitably, the binding site comprises an amino acid motif comprising the sequence YEQYCHDH (SEQ ID NO:111). Suitably, the binding site comprises an amino acid motif comprising the sequence YEQYCADH (SEQ ID NO:112). Suitably, the binding site comprises an amino acid motif comprising the sequence YEQYCKDH (SEQ ID NO: 113). Suitably, the binding site comprises an amino acid motif comprising the sequence YEQYCRDH (SEQ ID NO: 114).

[0260] The binding site may comprise an amino acid motif comprising the sequence YX1X2YCX3DHF (SEQ ID NO:98) wherein X1is an amino acid selected from D and E, X2is selected from Q and K, and X3is selected from H, A, K and R. The binding site may comprise an amino acid motif comprising the sequence YX1X2YCX3DHF (SEQ ID NO:98) wherein X1is an amino acid selected from D and E, X2is selected from Q and K, and X3is selected from H, A and K. The binding site may comprise an amino acid motif comprising the sequence YX1X2YCX3DHF (SEQ ID NO:98) wherein X1is an amino acid selected from D and E, X2is selected from Q and K, and X3is selected from H, A and R. The binding site may comprise an amino acid motif comprising the sequence YX1X2YCX3DHF (SEQ ID NO:98) wherein X1is an amino acid selected from D and E, X2is selected from Q and K, and X3is selected from H, K and R. The binding site may comprise an amino acid motif comprising the sequence YX1X2YCX3DHF (SEQ ID NO:98) wherein X1is an amino acid selected from D and E, X2is selected from Q and K, and X3is selected from A, K and R. The binding site may comprise an amino acid motif comprising the sequence YX1X2YCX3DHF (SEQ ID NO:98) wherein X1is an amino acid selected from D and E, X2is selected from Q and K, and X3is selected from H and A. The binding site may comprise an amino acid motif comprising the sequence YX1X2YCX3DHF (SEQ ID NO:98) wherein X1is an amino acid selected from D and E, X2is selected from Q and K, and X3is selected from H and K. The binding site may comprise an amino acid motif comprising the sequence YX1X2YCX3DHF (SEQ ID NO:98) wherein X1is an amino acid selected from D and E, X2is selected from Q and K, and X3is selected from H and R. The binding site may comprise an amino acid motif comprising the sequence YX1X2YCX3DHF (SEQ ID NO:98) wherein X1is an amino acid selected from D and E, X2is selected from Q and K, and X3is selected from A and K, The binding site may comprise an amino acid motif comprising the sequence YX1X2YCX3DHF (SEQ ID NO:98) wherein X1is an amino acid selected from D and E, X2is selected from Q and K, and X3is selected from A and R. The binding site may comprise an amino acid motif comprising the sequence YX1X2YCX3DHF (SEQ ID NO:98) wherein X1is an amino acid selected from D and E, X2is selected from Q and K, and X3is selected from K and R. Suitably, the binding site comprises an amino acid motif comprising the sequence YDQYCHDHF (SEQ ID NO: 115). Suitably, the binding site comprises an amino acid motif comprising the sequence YDQYCADHF (SEQ ID NO: 116). Suitably, the binding site comprises an amino acid motif comprising the sequence YDQYCKDHF (SEQ ID NO:117). Suitably, the binding site comprises an amino acid motif comprising the sequence YDQYCRDHF (SEQ ID NO: 118). Suitably, the binding site comprises an amino acid motif comprising the sequence YDKYCHDHF (SEQ ID NO: 119), Suitably, the binding site comprises an amino acid motif comprising the sequence YDKYCADHF (SEQ ID NO:120). Suitably, the binding site comprises an amino acid motif comprising the sequence YDKYCKDHF (SEQ ID NO: 121). Suitably, the binding site comprises an amino acid motif comprising the sequence YDKYCRDHF (SEQ ID NO:122). Suitably, the binding site comprises an amino acid motif comprising the sequence YEQYCHDHF (SEQ ID NO:123). Suitably, the binding site comprises an amino acid motif comprising the sequence YEQYCADHF (SEQ ID NO: 124). Suitably, the binding site comprises an amino acid motif comprising the sequence YEQYCKDHF (SEQ ID NO: 125). Suitably, the binding site comprises an amino acid motif comprising the sequence YEQYCRDHF (SEQ ID NO:126). Suitably, the binding site comprises an amino acid motif comprising the sequence YEQYCHDHF (SEQ ID NO:127). Suitably, the binding site comprises an amino acid motif comprising the sequence YEQYCADHF (SEQ ID NO: 128). Suitably, the binding site comprises an amino acid motif comprising the sequence YEQYCKDHF (SEQ ID NO: 129). Suitably, the binding site comprises an amino acid motif comprising the sequence YEQYCRDHF (SEQ ID NO:130). The binding site may comprise an amino acid motif comprising the sequence X1X2YCX3DHX4(SEQ ID NO:28) wherein X1is an amino acid selected from D and E, X2is selected from Q and K, and X3is selected from H, A, K and R, and X4is selected from F and Y. The binding site may comprise an amino acid motif comprising the sequence X1X2YCX3DHX4(SEQ ID NO:28) wherein X1is an amino acid selected from D and E, X2is selected from Q and K, X3is selected from H, A and K, and X4is selected from F and Y. The binding site may comprise an amino acid motif comprising the sequence X1X2YCX3DHX4(SEQ ID NO:28) wherein X1is an amino acid selected from D and E, X2is selected from Q and K, X3is selected from H, A and R, and X4is selected from F and Y. The binding site may comprise an amino acid motif comprising the sequence XIX2YCX3DHX4(SEQ ID NO:28) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, X3 is selected from H, K and R, and X4 is selected from F and Y. The binding site may comprise an amino acid motif comprising the sequence X1X2YCX3DHX4 (SEQ ID NO:28) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, X3is selected from A, K and R, and X4is selected from F and Y. The binding site may comprise an amino acid motif comprising the sequence X1X2YCX3DHX4 (SEQ ID NO:28) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, X3is selected from H and A, and X4is selected from F and Y. The binding site may comprise an amino acid motif comprising the sequence X1X2YCX3DHX4 (SEQ ID NO:28) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, X3is selected from H and K, and X4is selected from F and Y. The binding site may comprise an amino acid motif comprising the sequence X1X2YCX3DHX4(SEQ ID NO:28) wherein X1is an amino acid selected from D and E, X2is selected from Q and K, X3is selected from H and R, and X4is selected from F and Y. The binding site may comprise an amino acid motif comprising the sequence XIX2YCX3DHX4(SEQ ID NO:28) wherein Xi is an amino acid selected from D and E, X2is selected from Q and K, X3is selected from A and K, and X4is selected from F and Y. The binding site may comprise an amino acid motif comprising the sequence X1X2YCX3DHX4(SEQ ID NO:28) wherein X1is an amino acid selected from D and E, X2is selected from Q and K, X3is selected from A and R, and X4is selected from F and Y. The binding site may comprise an amino acid motif comprising the sequence X1X2YCX3DHX4(SEQ ID NO:28) wherein X1is an amino acid selected from D and E, X2is selected from Q and K, X3is selected from K and R, and X4is selected from F and Y. Suitably, the binding site comprises an amino acid motif comprising the sequence DQYCHDHF (SEQ ID NO: 16) Suitably, the binding site comprises an amino acid motif comprising the sequence DQYCADHF (SEQ ID NO:131). Suitably, the binding site comprises an amino acid motif comprising the sequence DQYCKDHF (SEQ ID NO: 11) Suitably, the binding site comprises an amino acid motif comprising the sequence DQYCRDHF (SEQ ID NO:132). Suitably, the binding site comprises an amino acid motif comprising the sequence DQYCHDHY (SEQ ID NO: 133). Suitably, the binding site comprises an amino acid motif comprising the sequence DQYCADHY (SEQ ID NO:134) Suitably, the binding site comprises an amino acid motif comprising the sequence DQYCKDHY (SEQ ID NO: 135). Suitably, the binding site comprises an amino acid motif comprising the sequence DQYCRDHY (SEQ ID NO:32) Suitably, the binding site comprises an amino acid motif comprising the sequence DKYCHDHF (SEQ ID NO: 136). Suitably, the binding site comprises an amino acid motif comprising the sequence. Suitably, the binding site comprises an amino acid motif comprising the sequence DKYCADHF (SEQ ID NO:12). Suitably, the binding site comprises an amino acid motif comprising the sequence DKYCKDHF (SEQ ID NO:137). Suitably, the binding site comprises an amino acid motif comprising the sequence DKYCRDHF (SEQ ID NO:138). Suitably, the binding site comprises an amino acid motif comprising the sequence DKYCHDHY (SEQ ID NO:139). Suitably, the binding site comprises an amino acid motif comprising the sequence DKYCADHY (SEQ ID NO:140). Suitably, the binding site comprises an amino acid motif comprising the sequence DKYCKDHY (SEQ ID NO:141). Suitably, the binding site comprises an amino acid motif comprising the sequence DKYCRDHY (SEQ ID NO: 142). Suitably, the binding site comprises an amino acid motif comprising the sequence. Suitably, the binding site comprises an amino acid motif comprising the sequence EQYCHDHF (SEQ ID NO: 143). Suitably, the binding site comprises an amino acid motif comprising the sequence EQYCADHF (SEQ ID NO:144). Suitably, the binding site comprises an amino acid motif comprising the sequence EQYCKDHF (SEQ ID NO:145). Suitably, the binding site comprises an amino acid motif comprising the sequence EQYCRDHF (SEQ ID NO:146). Suitably, the binding site comprises an amino acid motif comprising the sequence EQYCHDHY (SEQ ID NO:147). Suitably, the binding site comprises an amino acid motif comprising the sequence EQYCADHY (SEQ ID NO:148). Suitably, the binding site comprises an amino acid motif comprising the sequence EQYCKDHY (SEQ ID NO:149). Suitably, the binding site comprises an amino acid motif comprising the sequence EQYCRDHY (SEQ ID NQ:150). Suitably, the binding site comprises an amino acid motif comprising the sequence EKYCHDHF (SEQ ID NO: 151). Suitably, the binding site comprises an amino acid motif comprising the sequence EKYCADHF (SEQ ID NO:13). Suitably, the binding site comprises an amino acid motif comprising the sequence EKYCKDHF (SEQ ID NO:152). Suitably, the binding site comprises an amino acid motif comprising the sequence EKYCRDHF (SEQ ID NO: 153). Suitably, the binding site comprises an amino acid motif comprising the sequence EKYCHDHY (SEQ ID NO:154). Suitably, the binding site comprises an amino acid motif comprising the sequence EKYCADHY (SEQ ID NO:155). Suitably, the binding site comprises an amino acid motif comprising the sequence EKYCKDHY (SEQ ID NO:156). Suitably, the binding site comprises an amino acid motif comprising the sequence EKYCRDHY (SEQ ID NO:157).

[0261] Notch 1

[0262] In some embodiments, the Notch receptor is Notchl. In some examples, the Notch receptor is human Notchl. The amino acid sequence of the wild type human Notch 1 receptor is shown in SEQ ID NO: 29. In some examples, the Notchl receptor comprises or consists of the amino acid sequence of SEQ ID NO:29. In some examples, the Notchl receptor may comprise an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:29.

[0263] In some examples, the peptide specifically binds to Notchl. In some embodiments, the peptide does not bind to other Notch receptors.

[0264] Suitably, the Notchl receptor comprises a binding site to which the peptide binds as defined hereinabove. Suitable Notch 1 binding sites are described in detail above, any of which may be bound by a peptide of the invention. In some embodiments, the Notchl receptor comprises a binding site comprising an amino acid motif having the sequence YCKDH (SEQ ID NO:10). In some embodiments, the Notchl receptor may comprise a binding site comprising an amino acid motif comprising the sequence DQYCKDHF (SEQ ID NO:11).

[0265] In some embodiments, the peptide comprises an amino acid motif comprising or consisting of the sequence YCKDH (SEQ ID NO: 10) and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif having the sequence YCKDH (SEQ ID NO: 10) to inhibit Notchl receptor dimerization and / or activation. In some embodiments, the peptide comprises an amino acid motif comprising or consisting of the sequence YCKDH (SEQ ID NO: 10) and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif comprising the sequence DQYCKDHF (SEQ ID NO:11). In some embodiments, the peptide comprises an amino acid motif comprising or consisting of the sequence YCKDH (SEQ ID NO:10) and is capable of binding to a Notch1 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:29.

[0266] In some embodiments, the peptide comprises an amino acid motif comprising or consisting of the sequence DQYCKDHF (SEQ ID NO:11) and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif having the sequence YCKDH (SEQ ID NO: 10) to inhibit Notchl receptor dimerization and / or activation. In some embodiments, the peptide comprises an amino acid motif comprising or consisting of the sequence DQYCKDHF (SEQ ID NO:11) and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif comprising the sequence DQYCKDHF (SEQ ID NO:11). In some embodiments, the peptide comprises an amino acid motif comprising or consisting of the sequence DQYCKDHF (SEQ ID NO:11) and is capable of binding to a Notch1 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:29.

[0267] In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:4 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:4, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif having the sequence YCKDH (SEQ ID NO:10) to inhibit Notchl receptor dimerization and / or activation. In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:4 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:4, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif comprising the sequence DQYCKDHF (SEQ ID NO:11). In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:4 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:4, and is capable of binding to a Notch1 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:29.

[0268] In some embodiments, the peptide comprises or consists of amino acid sequence of SEQ ID NO:8 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:8, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif having the sequence YCKDH (SEQ ID NO:10) to inhibit Notchl receptor dimerization and / or activation. In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:8 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:8, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif comprising the sequence DQYCKDHF (SEQ ID NO:11). In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:8 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:8, and is capable of binding to a Notch1 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:29.

[0269] In some embodiments, the peptide comprises or consists of amino acid sequence of SEQ ID NO:40 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NQ:40, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif having the sequence YCKDH (SEQ ID NO:10) to inhibit Notchl receptor dimerization and / or activation. In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NQ:40 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NQ:40, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif comprising the sequence DQYCKDHF (SEQ ID NO:11). In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NQ:40 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NQ:40, and is capable of binding to a Notch1 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:29.

[0270] In some embodiments, the peptide comprises or consists of amino acid sequence of SEQ ID NO:41 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:41, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif having the sequence YCKDH (SEQ ID NO:10) to inhibit Notchl receptor dimerization and / or activation. In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:41 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:41, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif comprising the sequence DQYCKDHF (SEQ ID NO:11). In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:41 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:41, and is capable of binding to a Notch1 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:29.

[0271] In some embodiments, the peptide comprises or consists of amino acid sequence of SEQ ID NO:42 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:42, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif having the sequence YCKDH (SEQ ID NO:10) to inhibit Notch1 receptor dimerization and / or activation. In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:42 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:42, and is capable of binding to a Notch1 receptor at a binding site comprising an amino acid motif comprising the sequence DQYCKDHF (SEQ ID NO:11). In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:42 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:42, and is capable of binding to a Notch1 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:29.

[0272] In some embodiments, the peptide comprises or consists of amino acid sequence of SEQ ID NO:43 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:43, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif having the sequence YCKDH (SEQ ID NO:10) to inhibit Notchl receptor dimerization and / or activation. In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:43 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:43, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif comprising the sequence DQYCKDHF (SEQ ID NO:11). In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:43 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:43, and is capable of binding to a Notch1 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:29.

[0273] In some embodiments, the peptide comprises or consists of amino acid sequence of SEQ ID NO:44 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:44, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif having the sequence YCKDH (SEQ ID NO:10) to inhibit Notchl receptor dimerization and / or activation. In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:44 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:44, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif comprising the sequence DQYCKDHF (SEQ ID NO:11). In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:44 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:44, and is capable of binding to a Notch1 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:29.

[0274] In some embodiments, the peptide comprises or consists of amino acid sequence of SEQ ID NO:45 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:45, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif having the sequence YCKDH (SEQ ID NO:10) to inhibit Notchl receptor dimerization and / or activation. In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:45 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:45, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif comprising the sequence DQYCKDHF (SEQ ID NO:11). In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:45 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:45, and is capable of binding to a Notch1 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:29.

[0275] In some embodiments, the peptide comprises or consists of amino acid sequence of SEQ ID NO:46 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:46, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif having the sequence YCKDH (SEQ ID NO:10) to inhibit Notchl receptor dimerization and / or activation. In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:46 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:46, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif comprising the sequence DQYCKDHF (SEQ ID NO:11). In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:46 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:46, and is capable of binding to a Notch1 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:29.

[0276] In some embodiments, the peptide comprises or consists of amino acid sequence of SEQ ID NO:47 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:47, and is capable of binding to a Notch1 receptor at a binding site comprising an amino acid motif having the sequence YCKDH (SEQ ID NO:10) to inhibit Notch1 receptor dimerization and / or activation. In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:47 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:47, and is capable of binding to a Notch1 receptor at a binding site comprising an amino acid motif comprising the sequence DQYCKDHF (SEQ ID NO:11). In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:47 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:47, and is capable of binding to a Notch1 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:29.

[0277] In some embodiments, the peptide comprises or consists of amino acid sequence of SEQ ID NO:48 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:48, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif having the sequence YCKDH (SEQ ID NO:10) to inhibit Notchl receptor dimerization and / or activation. In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:48 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:48, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif comprising the sequence DQYCKDHF (SEQ ID NO:11). In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:48 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:48, and is capable of binding to a Notch1 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:29.

[0278] In some embodiments, the peptide comprises or consists of amino acid sequence of SEQ ID NO:49 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:49, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif having the sequence YCKDH (SEQ ID NO:10) to inhibit Notchl receptor dimerization and / or activation. In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:49 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:49, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif comprising the sequence DQYCKDHF (SEQ ID NO:11). In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:49 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:49, and is capable of binding to a Notch1 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:29.

[0279] In some embodiments, the peptide comprises or consists of amino acid sequence of SEQ ID NO:50 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:50, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif having the sequence YCKDH (SEQ ID NO:10) to inhibit Notchl receptor dimerization and / or activation. In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:50 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:50, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif comprising the sequence DQYCKDHF (SEQ ID NO:11). In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:50 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:50, and is capable of binding to a Notch1 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:29.

[0280] In some embodiments, the peptide comprises or consists of amino acid sequence of SEQ ID NO:51 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:51, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif having the sequence YCKDH (SEQ ID NO:10) to inhibit Notchl receptor dimerization and / or activation. In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:51 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:51, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif comprising the sequence DQYCKDHF (SEQ ID NO:11). In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:51 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:51, and is capable of binding to a Notch1 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:29. In some embodiments, the peptide comprises or consists of amino acid sequence of SEQ ID NO:52 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:52, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif having the sequence YCKDH (SEQ ID NO:10) to inhibit Notchl receptor dimerization and / or activation. In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:52 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:52, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif comprising the sequence DQYCKDHF (SEQ ID NO:11). In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:52 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:52, and is capable of binding to a Notch1 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:29.

[0281] In some embodiments, the peptide comprises or consists of amino acid sequence of SEQ ID NO:53 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:53, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif having the sequence YCKDH (SEQ ID NO:10) to inhibit Notchl receptor dimerization and / or activation. In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:53 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:53, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif comprising the sequence DQYCKDHF (SEQ ID NO:11). In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:53 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:53, and is capable of binding to a Notch1 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:29.

[0282] In some embodiments, the peptide comprises or consists of amino acid sequence of SEQ ID NO:54 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:54, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif having the sequence YCKDH (SEQ ID NO:10) to inhibit Notchl receptor dimerization and / or activation. In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:54 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:54, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif comprising the sequence DQYCKDHF (SEQ ID NO:11). In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:54 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:54, and is capable of binding to a Notch1 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:29.

[0283] In some embodiments, the peptide comprises or consists of amino acid sequence of SEQ ID NO:55 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:55, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif having the sequence YCKDH (SEQ ID NO:10) to inhibit Notchl receptor dimerization and / or activation. In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:55 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:55, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif comprising the sequence DQYCKDHF (SEQ ID NO:11). In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:55 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:55, and is capable of binding to a Notch1 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:29.

[0284] In some embodiments, the peptide comprises or consists of amino acid sequence of SEQ ID NO:56 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:56, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif having the sequence YCKDH (SEQ ID NO:10) to inhibit Notchl receptor dimerization and / or activation. In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:56 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:56, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif comprising the sequence DQYCKDHF (SEQ ID NO:11). In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:56 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:56, and is capable of binding to a Notch1 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:29.

[0285] In some embodiments, the peptide comprises or consists of amino acid sequence of SEQ ID NO:57 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:57, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif having the sequence YCKDH (SEQ ID NO:10) to inhibit Notchl receptor dimerization and / or activation. In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:57 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:57, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif comprising the sequence DQYCKDHF (SEQ ID NO:11). In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:57 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:57, and is capable of binding to a Notch1 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:29.

[0286] In some embodiments, the peptide comprises or consists of amino acid sequence of SEQ ID NO:58 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:58, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif having the sequence YCKDH (SEQ ID NO:10) to inhibit Notchl receptor dimerization and / or activation. In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:58 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:58, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif comprising the sequence DQYCKDHF (SEQ ID NO:11). In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:58 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:58, and is capable of binding to a Notch1 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:29.

[0287] In some embodiments, the peptide comprises or consists of amino acid sequence of SEQ ID NO:59 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:59, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif having the sequence YCKDH (SEQ ID NO:10) to inhibit Notchl receptor dimerization and / or activation. In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:59 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:59, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif comprising the sequence DQYCKDHF (SEQ ID NO:11). In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:59 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:59, and is capable of binding to a Notch1 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:29.

[0288] In some embodiments, the peptide comprises or consists of amino acid sequence of SEQ ID NO:60 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:60, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif having the sequence YCKDH (SEQ ID NO:10) to inhibit Notchl receptor dimerization and / or activation. In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:60 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:60, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif comprising the sequence DQYCKDHF (SEQ ID NO:11). In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:60 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:60, and is capable of binding to a Notch1 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:29.

[0289] In some embodiments, the peptide comprises or consists of amino acid sequence of SEQ ID NO:61 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:61, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif having the sequence YCKDH (SEQ ID NO:10) to inhibit Notchl receptor dimerization and / or activation. In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:61 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:61, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif comprising the sequence DQYCKDHF (SEQ ID NO:11). In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:61 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:61, and is capable of binding to a Notch1 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:29.

[0290] In some embodiments, the peptide comprises or consists of amino acid sequence of SEQ ID NO:62 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:62, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif having the sequence YCKDH (SEQ ID NO:10) to inhibit Notchl receptor dimerization and / or activation. In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:62 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:62, and is capable of binding to a Notchl receptor at a binding site comprising an amino acid motif comprising the sequence DQYCKDHF (SEQ ID NO:11). In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:62 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:62, and is capable of binding to a Notch1 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:29.

[0291] Notch2

[0292] In some embodiments, the Notch receptor is Notch2. In some examples, the Notch receptor is human Notch2. The amino acid sequence of the wild type human Notch 2 receptor is shown in SEQ ID NO: 30. In some examples, the Notch2 receptor comprises or consists of the amino acid sequence of SEQ ID NO:30. In some examples, the Notchl receptor may comprise an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:30.

[0293] In some examples, the peptide specifically binds to Notch2. In some embodiments, the peptide does not bind to other Notch receptors.

[0294] Suitably, the Notch2 receptor comprises a binding site to which the peptide binds as defined hereinabove. Suitable Notch2 binding sites are described in detail above, any of which may be bound by a peptide of the invention. In some embodiments, the Notch2 receptor comprises an amino acid motif having the sequence YCADH (SEQ ID NO:9). In some embodiments, the Notch2 receptor may comprise a binding site comprising an amino acid motif comprising the sequence DKYCADHF (SEQ ID NO: 12). In some embodiments, the peptide comprises an amino acid motif comprising or consisting of the sequence YCADH (SEQ ID NO:9) and is capable of binding to a Notch2 receptor at a binding site comprising an amino acid motif having the sequence YCADH (SEQ ID NO:9) to inhibit Notch2 receptor dimerization and / or activation. In some embodiments, the peptide comprises an amino acid motif comprising or consisting of the sequence YCADH (SEQ ID NO:9) and is capable of binding to a Notch2 receptor at a binding site comprising an amino acid motif comprising the sequence DKYCADHF (SEQ ID NO:12). In some embodiments, the peptide comprises an amino acid motif comprising or consisting of the sequence YCADH (SEQ ID NO:9) and is capable of binding to a Notch2 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:30.

[0295] In some embodiments, the peptide comprises an amino acid motif comprising or consisting of the sequence DKYCADHF (SEQ ID NO: 12) and is capable of binding to a Notch2 receptor at a binding site comprising an amino acid motif having the sequence YCADH (SEQ ID NO:9) to inhibit Notch2 receptor dimerization and / or activation. In some embodiments, the peptide comprises an amino acid motif comprising or consisting of the sequence DKYCADHF (SEQ ID NO:12) and is capable of binding to a Notch2 receptor at a binding site comprising an amino acid motif comprising the sequence DKYCADHF (SEQ ID NO: 12). In some embodiments, the peptide comprises an amino acid motif comprising or consisting of the sequence DKYCADHF (SEQ ID NO: 12) and is capable of binding to a Notch2 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:30.

[0296] In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:3 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:3, and is capable of binding to a Notch2 receptor at a binding site comprising an amino acid motif having the sequence YCADH (SEQ ID NO:9) to inhibit Notch2 receptor dimerization and / or activation. In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:3 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:3, and is capable of binding to a Notch2 receptor at a binding site comprising an amino acid motif comprising the sequence DKYCADHF (SEQ ID NO:12). In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:3 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 3, and is capable of binding to a Notch2 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:30. In some embodiments, the peptide comprises or consists of the sequence amino acid sequence of SEQ ID NO:63 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:63, and is capable of binding to a Notch2 receptor at a binding site comprising an amino acid motif having the sequence YCADH (SEQ ID NO:9) to inhibit Notch2 receptor dimerization and / or activation. In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:63 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:63, and is capable of binding to a Notch2 receptor at a binding site comprising an amino acid motif comprising the sequence DKYCADHF (SEQ ID NO:12). In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:63 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:63, and is capable of binding to a Notch2 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:30.

[0297] In some embodiments, the peptide comprises or consists of the sequence amino acid sequence of SEQ ID NO:64 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:64, and is capable of binding to a Notch2 receptor at a binding site comprising an amino acid motif having the sequence YCADH (SEQ ID NO:9) to inhibit Notch2 receptor dimerization and / or activation. In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:64 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:64, and is capable of binding to a Notch2 receptor at a binding site comprising an amino acid motif comprising the sequence DKYCADHF (SEQ ID NO:12). In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:64 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:64, and is capable of binding to a Notch2 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:30.

[0298] In some embodiments, the peptide comprises or consists of the sequence amino acid sequence of SEQ ID NO:65 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:65, and is capable of binding to a Notch2 receptor at a binding site comprising an amino acid motif having the sequence YCADH (SEQ ID NO:9) to inhibit Notch2 receptor dimerization and / or activation. In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:65 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:65, and is capable of binding to a Notch2 receptor at a binding site comprising an amino acid motif comprising the sequence DKYCADHF (SEQ ID NO:12). In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:65 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:65, and is capable of binding to a Notch2 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:30.

[0299] In some embodiments, the peptide comprises or consists of the sequence amino acid sequence of SEQ ID NO:66 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:66, and is capable of binding to a Notch2 receptor at a binding site comprising an amino acid motif having the sequence YCADH (SEQ ID NO:9) to inhibit Notch2 receptor dimerization and / or activation. In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:66 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:66, and is capable of binding to a Notch2 receptor at a binding site comprising an amino acid motif comprising the sequence DKYCADHF (SEQ ID NO:12). In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:66 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:66, and is capable of binding to a Notch2 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:30.

[0300] In some embodiments, the peptide comprises or consists of the sequence amino acid sequence of SEQ ID NO:67 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:67, and is capable of binding to a Notch2 receptor at a binding site comprising an amino acid motif having the sequence YCADH (SEQ ID NO:9) to inhibit Notch2 receptor dimerization and / or activation. In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:67 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:67, and is capable of binding to a Notch2 receptor at a binding site comprising an amino acid motif comprising the sequence DKYCADHF (SEQ ID NO:12). In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:67 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:67, and is capable of binding to a Notch2 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:30.

[0301] Notch3

[0302] In some embodiments, the Notch receptor is Notch3. In some examples, the Notch receptor is human Notch3. The amino acid sequence of the wild type human Notch 3 receptor is shown in SEQ ID NO: 31. In some examples, the Notch3 receptor comprises or consists of the amino acid sequence of SEQ ID NO:31. In some examples, the Notchl receptor may comprise an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:31.

[0303] In some examples, the peptide specifically binds to Notch3. In some embodiments, the peptide does not bind to other Notch receptors.

[0304] Suitably, the Notch3 receptor comprises a binding site to which the peptide binds as defined hereinabove. Suitable Notch 3 binding sites are described in detail above, any of which may be bound by a peptide of the invention. In some embodiments, the Notch3 receptor comprises a binding site comprising an amino acid motif having the sequence YCADH (SEQ ID NO:9). In some embodiments, the Notch3 receptor may comprise a binding site comprising an amino acid motif comprising the sequence EKYCADHF (SEQ ID NO:13).

[0305] In some embodiments, the peptide comprises an amino acid motif comprising or consisting of the sequence YCADH (SEQ ID NO:9) and is capable of binding to a Notch3 receptor at a binding site comprising an amino acid motif having the sequence YCADH (SEQ ID NO:9) to inhibit Notch3 receptor dimerization and / or activation. In some embodiments, the peptide comprises an amino acid motif comprising or consisting of the sequence YCADH (SEQ ID NO:9) and is capable of binding to a Notch3 receptor at a binding site comprising an amino acid motif comprising the sequence EKYCADHF (SEQ ID NO:13). In some embodiments, the peptide comprises an amino acid motif comprising or consisting of the sequence YCADH (SEQ ID NO:9) and is capable of binding to a Notch3 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:31.

[0306] In some embodiments, the peptide comprises an amino acid motif comprising or consisting of the sequence EKYCADHF (SEQ ID NO: 13) and is capable of binding to a Notch3 receptor at a binding site comprising an amino acid motif having the sequence YCADH (SEQ ID NO:9) to inhibit Notch3 receptor dimerization and / or activation. In some embodiments, the peptide comprises an amino acid motif comprising or consisting of the sequence EKYCADHF (SEQ ID NO:13) and is capable of binding to a Notch3 receptor at a binding site comprising an amino acid motif comprising the sequence EKYCADHF (SEQ ID NO: 13). In some embodiments, the peptide comprises an amino acid motif comprising or consisting of the sequence EKYCADHF (SEQ ID NO: 13) and is capable of binding to a Notch3 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:31.

[0307] In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:2 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:2, and is capable of binding to a Notch3 receptor at a binding site comprising an amino acid motif having the sequence YCADH (SEQ ID NO:9) to inhibit Notch3 receptor dimerization and / or activation. In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:2 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:2, and is capable of binding to a Notch3 receptor at a binding site comprising an amino acid motif comprising the sequence EKYCADHF (SEQ ID NO:13). In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:2 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:2, and is capable of binding to a Notch3 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:31.

[0308] In some embodiments, the peptide comprises or consists of the sequence amino acid sequence of SEQ ID NO:5 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:5, and is capable of binding to a Notch3 receptor at a binding site comprising an amino acid motif having the sequence YCADH (SEQ ID NO:9) to inhibit Notch3 receptor dimerization and / or activation. In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:5 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:5, and is capable of binding to a Notch3 receptor at a binding site comprising an amino acid motif comprising the sequence EKYCADHF (SEQ ID NO: 13). In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:5 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:5, and is capable of binding to a Notch3 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:31.

[0309] In some embodiments, the peptide comprises or consists of the sequence amino acid sequence of SEQ ID NO:6 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:6, and is capable of binding to a Notch3 receptor at a binding site comprising an amino acid motif having the sequence YCADH (SEQ ID NO:9) to inhibit Notch3 receptor dimerization and / or activation. In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:6 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:6, and is capable of binding to a Notch3 receptor at a binding site comprising an amino acid motif comprising the sequence EKYCADHF (SEQ ID NO: 13). In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:6 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:6, and is capable of binding to a Notch3 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:31.

[0310] In some embodiments, the peptide comprises or consists of the sequence amino acid sequence of SEQ ID NO:7 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:7, and is capable of binding to a Notch3 receptor at a binding site comprising an amino acid motif having the sequence YCADH (SEQ ID NO:9) to inhibit Notch3 receptor dimerization and / or activation. In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:7 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:7, and is capable of binding to a Notch3 receptor at a binding site comprising an amino acid motif comprising the sequence EKYCADHF (SEQ ID NO: 13). In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:7 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:7, and is capable of binding to a Notch3 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:31.

[0311] In some embodiments, the peptide comprises or consists of the sequence amino acid sequence of SEQ ID NO:68 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:68, and is capable of binding to a Notch3 receptor at a binding site comprising an amino acid motif having the sequence YCADH (SEQ ID NO:9) to inhibit Notch3 receptor dimerization and / or activation. In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:68 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:68, and is capable of binding to a Notch3 receptor at a binding site comprising an amino acid motif comprising the sequence EKYCADHF (SEQ ID NO:13). In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:68 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:68, and is capable of binding to a Notch3 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:31.

[0312] In some embodiments, the peptide comprises or consists of the sequence amino acid sequence of SEQ ID NO:69 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:69, and is capable of binding to a Notch3 receptor at a binding site comprising an amino acid motif having the sequence YCADH (SEQ ID NO:9) to inhibit Notch3 receptor dimerization and / or activation. In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:69 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:69, and is capable of binding to a Notch3 receptor at a binding site comprising an amino acid motif comprising the sequence EKYCADHF (SEQ ID NO:13). In some embodiments, the peptide comprises or consists of the amino acid sequence of SEQ ID NO:69 or an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:69, and is capable of binding to a Notch3 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:31.

[0313] Notch4

[0314] In some embodiments, the Notch receptor is Notch4. In some examples, the Notch receptor is human Notch4. The amino acid sequence of the wild type human Notch 4 receptor is shown in SEQ ID NO: 33. In some examples, the Notch4 receptor comprises or consists of the amino acid sequence of SEQ ID NO:33. In some examples, the Notchl receptor may comprise an amino acid sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:33.

[0315] In some examples, the peptide specifically binds to Notch4. In some embodiments, the peptide does not bind to other Notch receptors.

[0316] Suitably, the Notch4 receptor comprises a binding site to which the peptide binds as defined hereinabove. Suitable Notch4 binding sites are described in detail above, any of which may be bound by a peptide of the invention. In some embodiments, the Notch4 receptor comprises a binding site comprising an amino acid motif having the sequence YCHDH (SEQ ID NO:14). In some embodiments, the Notch4 receptor may comprise a binding site comprising an amino acid motif comprising the sequence DQYCHDHF (SEQ ID NO:16). In some embodiments, the peptide comprises an amino acid motif comprising or consisting of the sequence YCHDH (SEQ ID NO: 14) and is capable of binding to a Notch4 receptor at a binding site comprising an amino acid motif having the sequence YCHDH (SEQ ID NO: 14) to inhibit Notch4 receptor dimerization and / or activation. In some embodiments, the peptide comprises an amino acid motif comprising or consisting of the sequence YCHDH (SEQ ID NO: 14) and is capable of binding to a Notch4 receptor at a binding site comprising an amino acid motif comprising the sequence DQYCHDHF (SEQ ID NO:16). In some embodiments, the peptide comprises an amino acid motif comprising or consisting of the sequence YCHDH (SEQ ID NO: 14) and is capable of binding to a Notch4 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:33.

[0317] In some embodiments, the peptide comprises an amino acid motif comprising or consisting of the sequence DQYCHDHF (SEQ ID NO:16) and is capable of binding to a Notch4 receptor at a binding site comprising an amino acid motif having the sequence YCHDH (SEQ ID NO: 14) to inhibit Notch4 receptor dimerization and / or activation. In some embodiments, the peptide comprises an amino acid motif comprising or consisting of the sequence DQYCHDHF (SEQ ID NO: 16) and is capable of binding to a Notch4 receptor at a binding site comprising an amino acid motif comprising the sequence DQYCHDHF (SEQ ID NO:16). In some embodiments, the peptide comprises an amino acid motif comprising or consisting of the sequence DQYCHDHF (SEQ ID NO: 16) and is capable of binding to a Notch4 receptor comprising or consisting of the amino acid sequence of SEQ ID NO:33.

[0318] Modified Notch Receptor

[0319] Also provided herein is a modified Notch receptor, comprising a deletion of an amino acid motif in its extracellular domain. The deleted motif comprises the sequence YCXDH (SEQ ID NO:23), wherein X is an amino acid selected from H, A, K and R. In some examples, the modified Notch receptor is not capable of dimerization. In some examples, the modified Notch receptor is able to dimerize at a reduced rate compared to an unmodified or wild type Notch receptor. In some examples, the modified Notch receptor is not capable of activation. In some examples, the modified Notch receptor binds to a ligand with reduced efficiency compared to an unmodified or wild type Notch receptor. In some examples, the modified Notch receptor binds to a ligand with reduced affinity compared to an unmodified or wild type Notch receptor. In some examples, the modified Notch receptor is not capable of binding to a ligand, such as Jagged (JAG)1, JAG2, Delta-Like (DLL)1, DLL3, and / or DLL4. In some examples, the modified Notch receptor is activated at a reduced rate compared to an unmodified or wild type Notch receptor.

[0320] The modified Notch receptor may be Notchl. In some examples, the amino acid motif YCKDH (SEQ ID NO:10) is deleted from the extracellular domain of the modified Notchl receptor. Therefore, the extracellular domain of the modified Notchl receptor does not comprise the amino acid motif of SEQ ID NO:10. In some examples, the modified Notchl receptor lacks the binding site at amino acid positions 1535-1539, wherein the amino acid positions are numbered relative to SEQ ID NO:29. In some examples the modified Notchl receptor comprises or consists of the amino acid sequence of SEQ ID NO:164. In some examples the modified Notchl receptor consists of the amino acid sequence of SEQ ID NO:164. In some examples, the modified Notchl receptor is activated at a reduced rate compared to an unmodified or wild type Notchl receptor. Suitably, the modified Notchl receptor is not capable of activation. In some examples, the modified Notchl receptor is able to dimerize at a reduced rate compared to an unmodified or wild type Notchl receptor. Suitably, the modified Notchl receptor is not capable of dimerization. Suitably, the modified Notchl receptor is not capable of binding to a ligand such as DLL4, DLL1, DLL3, JAG1 and / or JAG2. Preferably, the modified Notchl receptor is not capable of dimerization or is able to dimerize at a reduced rate compared to an unmodified or wild type Notchl receptor and thus is not capable of binding to a ligand or binds to a ligand at a reduced rate. In some examples, the modified Notchl receptor is not capable of dimerization or is able to dimerize at a reduced rate compared to an unmodified or wild type Notchl receptor and thus binds to a ligand with reduced affinity compared to an unmodified or wild type Notchl receptor. Preferably, the modified Notchl receptor is not capable of activation or is activated at a reduced rate compared to an unmodified or wild type Notchl receptor and thus is not capable binding to a ligand or is able to bind to a ligand at a reduced rate compared to an unmodified or wild type Notchl receptor. In some examples, the modified Notchl receptor is not capable of activation or is activated at a reduced rate compared to an unmodified or wild type Notchl receptor and thus binds to a ligand with reduced affinity compared to an unmodified or wild type Notchl receptor.

[0321] The modified Notch receptor may be Notch2. In some examples, the amino acid motif YCADH (SEQ ID NO:9) is deleted from the extracellular domain of the modified Notch2 receptor. Therefore, the extracellular domain of the modified Notch2 receptor does not comprise the amino acid motif of SEQ ID NO:9. In some examples, the modified Notch2 receptor lacks the binding site at amino acid positions 1508-1512, wherein the amino acid positions are numbered relative to SEQ ID NO:30. In some examples the modified Notch2 receptor comprises or consists of the amino acid sequence of SEQ ID NO:165. In some examples the modified Notch2 receptor consists of the amino acid sequence of SEQ ID NO: 165. In some examples, the modified Notch2 receptor is activated at a reduced rate compared to an unmodified or wild type Notch2 receptor. Suitably, the modified Notch2 receptor is not capable of activation. In some examples, the modified Notch2 receptor is activated at a reduced rate compared to an unmodified or wild type Notch2 receptor. Suitably, the modified Notch2 receptor is not capable of activation. In some examples, the modified Notch2 receptor is able to dimerize at a reduced rate compared to an unmodified or wild type Notch2 receptor. Suitably, the modified Notch2 receptor is not capable of dimerization. Suitably, the modified Notch2 receptor is not capable of binding to a ligand such as DLL4, DLL1, DLL3, JAG1, and / or JAG2. Preferably, the modified Notch2 receptor is not capable of dimerization or is able to dimerize at a reduced rate compared to an unmodified or wild type Notch2 receptor and thus is not capable of binding to a ligand or binds to a ligand at a reduced rate. In some examples, the modified Notch2 receptor is not capable of dimerization or is able to dimerize at a reduced rate compared to an unmodified or wild type Notch2 receptor and thus binds to a ligand with reduced affinity compared to an unmodified or wild type Notch2 receptor. Preferably, the modified Notch2 receptor is not capable of activation or is activated at a reduced rate compared to an unmodified or wild type Notch2 receptor and thus is not capable binding to a ligand or is able to bind to a ligand at a reduced rate compared to an unmodified or wild type Notch2 receptor. In some examples, the modified Notch2 receptor is not capable of activation or is activated at a reduced rate compared to an unmodified or wild type Notch2 receptor and thus binds to a ligand with reduced affinity compared to an unmodified or wild type Notch2 receptor.

[0322] The modified Notch receptor may be Notch3. In some examples, the amino acid motif YCADH (SEQ ID NO:9) is deleted from the extracellular domain of the modified Notch3 receptor. Therefore, the extracellular domain of the modified Notch3 receptor does not comprise the amino acid motif of SEQ ID NO:9. In some examples, the modified Notch3 receptor lacks the binding site at amino acid positions 1474-1478, wherein the amino acid positions are numbered relative to SEQ ID NO:31. In some examples the modified Notch3 receptor comprises or consists of the amino acid sequence of SEQ ID NO:163. In some examples the modified Notch3 receptor consists of the amino acid sequence of SEQ ID NO: 163. In some examples, the modified Notch3 receptor is activated at a reduced rate compared to an unmodified or wild type Notch3 receptor. Suitably, the modified Notch3 receptor is not capable of activation. In some examples, the modified Notch3 receptor is able to dimerize at a reduced rate compared to an unmodified or wild type Notch3 receptor. Suitably, the modified Notch3 receptor is not capable of dimerization. Suitably, the modified Notch3 receptor is not capable of binding to a ligand such as DLL4, DLL1, DLL3, JAG1 and / or JAG2. Preferably, the modified Notch3 receptor is not capable of dimerization or is able to dimerize at a reduced rate compared to an unmodified or wild type Notch3 receptor and thus is not capable of binding to a ligand or binds to a ligand at a reduced rate. In some examples, the modified Notch3 receptor is not capable of dimerization or is able to dimerize at a reduced rate compared to an unmodified or wild type Notch3 receptor and thus binds to a ligand with reduced affinity compared to an unmodified or wild type Notch3 receptor. Preferably, the modified Notch3 receptor is not capable of activation or is activated at a reduced rate compared to an unmodified or wild type Notch3 receptor and thus is not capable binding to a ligand or is able to bind to a ligand at a reduced rate compared to an unmodified or wild type Notch3 receptor. In some examples, the modified Notch3 receptor is not capable of activation or is activated at a reduced rate compared to an unmodified or wild type Notch3 receptor and thus binds to a ligand with reduced affinity compared to an unmodified or wild type Notch3 receptor. The modified Notch receptor may be Notch4. In some examples the amino acid motif YCHDH (SEQ ID NO:14) is deleted from the extracellular domain of the modified Notch4 receptor. Therefore, the extracellular domain of the modified Notch4 receptor does not comprise the amino acid motif of SEQ ID NO:14. In some examples, the modified Notch4 receptor lacks the binding site at amino acid positions 1257-1261, wherein the amino acid positions are numbered relative to SEQ ID NO:33. In some examples the modified Notch4 receptor comprises or consists of the amino acid sequence of SEQ ID NO: 166. In some examples the modified Notch4 receptor consists of the amino acid sequence of SEQ ID NO:166. In some examples, the modified Notch4 receptor is activated at a reduced rate compared to an unmodified or wild type Notch4 receptor. Suitably, the modified Notch4 receptor is not capable of activation. In some examples, the modified Notch4 receptor is able to dimerize at a reduced rate compared to an unmodified or wild type Notch4 receptor. Suitably, the modified Notch4 receptor is not capable of dimerization. Suitably, the modified Notch4 receptor is not capable of binding to a ligand such as DLL4, DLL1, DLL3, JAG1 and / or JAG2. Preferably, the modified Notch4 receptor is not capable of dimerization or is able to dimerize at a reduced rate compared to an unmodified or wild type Notch4 receptor and thus is not capable of binding to a ligand or binds to a ligand at a reduced rate. In some examples, the modified Notch4 receptor is not capable of dimerization or is able to dimerize at a reduced rate compared to an unmodified or wild type Notch4 receptor and thus binds to a ligand with reduced affinity compared to an unmodified or wild type Notch4 receptor. Preferably, the modified Notch4 receptor is not capable of activation or is activated at a reduced rate compared to an unmodified or wild type Notch4 receptor and thus is not capable binding to a ligand or is able to bind to a ligand at a reduced rate compared to an unmodified or wild type Notch4 receptor. In some examples, the modified Notch4 receptor is not capable of activation or is activated at a reduced rate compared to an unmodified or wild type Notch4 receptor and thus binds to a ligand with reduced affinity compared to an unmodified or wild type Notch4 receptor. In some examples, the modified Notch receptor further comprises a molecular tag, suitably at the N or C terminus thereof. For example, a His tag or a HA-epitope tag.

[0323] Also disclosed is a method for modifying a Notch receptor, the method comprising editing a polynucleotide encoding a Notch receptor to delete the polynucleotide sequence encoding the amino acid motif YCXDH (SEQ ID NO:23), wherein X is an amino acid selected from H, A, K and R, from the extracellular domain of the Notch receptor.

[0324] The method for modifying a Notch receptor may comprise using site-directed mutagenesis. The skilled person is aware of methods for site-directed mutagenesis, for example using Phusion High-Fidelity DNA polymerase. The method for modifying a Notch receptor may comprise gene-editing, also referred to as genome editing. The skilled person is aware of methods for gene-editing or genome editing, for example using CRISPR / Cas9. Genes may be edited using any technique known in the art.

[0325] Various non-limiting examples of genome editing methods and RNA editing agents used to introduce nucleic acid alterations may be used in the method of modifying the Notch receptors. Such techniques are well known in the art, a summary of possible such techniques is provided below:

[0326] Genome Editing using engineered endonucleases - this approach refers to a reverse genetics method using artificially engineered nucleases to typically cut and create specific doublestranded breaks (DSBs) at a desired location(s) in the genome, which are then repaired by cellular endogenous processes such as, homologous recombination (HR) or non-homologous end-joining (NHEJ). NHEJ directly joins the DNA ends in a double-stranded break (DSB) with or without minimal ends trimming, while HR utilizes a homologous donor sequence as a template (i.e. the sister chromatid formed during S-phase) for regenerating / copying the missing DNA sequence at the break site. In order to introduce specific nucleotide modifications to the genomic DNA, a donor DNA repair template containing the desired sequence must be present during HR (exogenously provided single stranded or double stranded DNA).

[0327] Genome editing cannot be performed using traditional restriction endonucleases since most restriction enzymes recognize a few base pairs on the DNA as their target and these sequences often will be found in many locations across the genome resulting in multiple cuts which are not limited to a desired location. To overcome this challenge and create site-specific single- or doublestranded breaks (DSBs), several distinct classes of nucleases have been discovered and bioengineered to date. These include the meganucleases, Zinc finger nucleases (ZFNs), transcription-activator like effector nucleases (TALENs) and CRISPR / Cas9 system.

[0328] Meganucleases - Meganucleases are commonly grouped into four families: the LAGLIDADG family, the GIY-YIG family, the His-Cys box family and the HNH family. These families are characterized by structural motifs, which affect catalytic activity and recognition sequence. For instance, members of the LAGLIDADG family are characterized by having either one or two copies of the conserved LAGLIDADG motif. The four families of meganucleases are widely separated from one another with respect to conserved structural elements and, consequently, DNA recognition sequence specificity and catalytic activity. Meganucleases are found commonly in microbial species and have the unique property of having very long recognition sequences (> 14bp) thus making them naturally very specific for cutting at a desired location. This can be exploited to make site-specific double-stranded breaks (DSBs) in genome editing. One of skill in the art can use these naturally occurring meganucleases, however the number of such naturally occurring meganucleases is limited. To overcome this challenge, mutagenesis and high throughput screening methods have been used to create meganuclease variants that recognize unique sequences. For example, various meganucleases have been fused to create hybrid enzymes that recognize a new sequence.

[0329] Alternatively, DNA interacting amino acids of the meganuclease can be altered to design sequence specific meganucleases. Alternatively, meganucleases with site specific cutting characteristics can be obtained using commercially available technologies e.g., Precision Biosciences' Directed Nuclease Editor™ genome editing technology.

[0330] ZFNs and TALENs - Two distinct classes of engineered nucleases, zinc-finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs), have both proven to be effective at producing targeted double- stranded breaks (DSBs).

[0331] ZFNs and TALENs restriction endonuclease technology utilizes a non-specific DNA cutting enzyme which is linked to a specific DNA binding domain (either a series of zinc finger domains or TALE repeats, respectively). Typically a restriction enzyme whose DNA recognition site and cleaving site are separate from each other is selected. The cleaving portion is separated and then linked to a DNA binding domain, thereby yielding an endonuclease with very high specificity for a desired sequence. An exemplary restriction enzyme with such properties is Fokl. Additionally Fokl has the advantage of requiring dimerization to have nuclease activity and this means the specificity increases dramatically as each nuclease partner recognizes a unique DNA sequence. To enhance this effect, Fokl nucleases have been engineered that can only function as heterodimers and have increased catalytic activity. The heterodimer functioning nucleases avoid the possibility of unwanted homodimer activity and thus increase specificity of the doublestranded break (DSB).

[0332] Thus, for example to target a specific site, ZFNs and TALENs are constructed as nuclease pairs, with each member of the pair designed to bind adjacent sequences at the targeted site. Upon transient expression in cells, the nucleases bind to their target sites and the Fokl domains heterodimerize to create a double- stranded break (DSB). Repair of these double- stranded breaks (DSBs) through the non-homologous end-joining (NHEJ) pathway often results in small deletions or small sequence insertions (Indels). Since each repair made by NHEJ is unique, the use of a single nuclease pair can produce an allelic series with a range of different insertions or deletions at the target site. In general NHEJ is relatively accurate (about 75-85% of DSBs in human cells are repaired by NHEJ within about 30 min from detection) in gene editing erroneous NHEJ is relied upon as when the repair is accurate the nuclease will keep cutting until the repair product is mutagenic and the recognition / cut site / P AM motif is gone / mutated or that the transiently introduced nuclease is no longer present. The deletions typically range anywhere from a few base pairs to a few hundred base pairs in length, but larger deletions have been successfully generated in cell culture by using two pairs of nucleases simultaneously. In addition, when a fragment of DNA with homology to the targeted region is introduced in conjunction with the nuclease pair, the double-stranded break (DSB) can be repaired via homologous recombination (HR) (e.g. in the presence of a donor template) to generate specific modifications.

[0333] Although the nuclease portions of both ZFNs and TALENs have similar properties, the difference between these engineered nucleases is in their DNA recognition peptide. ZFNs rely on Cys2-His2 zinc fingers and TALENs on TALES. Both of these DNA recognizing peptide domains have the characteristic that they are naturally found in combinations in their proteins. Cys2-His2 Zinc fingers are typically found in repeats that are 3 bp apart and are found in diverse combinations in a variety of nucleic acid interacting proteins. TALES on the other hand are found in repeats with a one-to-one recognition ratio between the amino acids and the recognized nucleotide pairs. Because both zinc fingers and TALES happen in repeated patterns, different combinations can be tried to create a wide variety of sequence specificities. Approaches for making site-specific zinc finger endonucleases include, e.g., modular assembly (where Zinc fingers correlated with a triplet sequence are attached in a row to cover the required sequence), OPEN (low- stringency selection of peptide domains vs. triplet nucleotides followed by high- stringency selections of peptide combination vs. the final target in bacterial systems), and bacterial one-hybrid screening of zinc finger libraries, among others. ZFNs can also be designed and obtained commercially from e.g., Sangamo Biosciences™ (Richmond, CA).

[0334] T-GEE system (TargetGene's Genome Editing Engine) - A programmable nucleoprotein molecular complex containing a polypeptide moiety and a specificity conferring nucleic acid (SCNA) which assembles in-vivo, in a target cell, and is capable of interacting with the predetermined target nucleic acid sequence is provided. The programmable nucleoprotein molecular complex is capable of specifically modifying and / or editing a target site within the target nucleic acid sequence and / or modifying the function of the target nucleic acid sequence. Nucleoprotein composition comprises (a) polynucleotide molecule encoding a chimeric polypeptide and comprising (i) a functional domain capable of modifying the target site, and (ii) a linking domain that is capable of interacting with a specificity conferring nucleic acid, and (b) specificity conferring nucleic acid (SCNA) comprising (i) a nucleotide sequence complementary to a region of the target nucleic acid flanking the target site, and (ii) a recognition region capable of specifically attaching to the linking domain of the polypeptide. The composition enables modifying a predetermined nucleic acid sequence target precisely, reliably and cost-effectively with high specificity and binding capabilities of molecular complex to the target nucleic acid through base-pairing of specificity-conferring nucleic acid and a target nucleic acid. The composition is less genotoxic, modular in their assembly, utilize single platform without customization, practical for independent use outside of specialized core-facilities, and has shorter development time frame and reduced costs.

[0335] CRISPR-Cas system and all its variants (also referred to herein as “CRISPR”) - Many bacteria and archea contain endogenous RNA-based adaptive immune systems that can degrade nucleic acids of invading phages and plasmids. These systems consist of clustered regularly interspaced short palindromic repeat (CRISPR) nucleotide sequences that produce RNA components and CRISPR associated (Cas) genes that encode protein components. The CRISPR RNAs (crRNAs) contain short stretches of homology to the DNA of specific viruses and plasmids and act as guides to direct Cas nucleases to degrade the complementary nucleic acids of the corresponding pathogen. Studies of the type II CRISPR / Cas system of Streptococcus pyogenes have shown that three components form a RNA / protein complex and together are sufficient for sequencespecific nuclease activity: the Cas9 nuclease, a crRNA containing 20 base pairs of homology to the target sequence, and a trans-activating crRNA (tracrRNA) (Jinek et al. Science (2012) 337: 816-821).

[0336] It was further demonstrated that a synthetic chimeric guide RNA (sgRNA) composed of a fusion between crRNA and tracrRNA could direct Cas9 to cleave DNA targets that are complementary to the crRNA in vitro. It was also demonstrated that transient expression of Cas9 in conjunction with synthetic sgRNAs can be used to produce targeted double- stranded breaks (DSBs) in a variety of different species (Cho et ah, 2013; Cong et ah, 2013; DiCarlo et ah, 2013; Hwang et al., 2013a, b; Jinek et ah, 2013; Mali et ah, 2013).

[0337] The CRISPR / Cas system for genome editing contains two distinct components: a sgRNA and an endonuclease e.g. Cas9. The sgRNA (also referred to herein as short guide RNA (sgRNA)) is typically a 20- nucleotide sequence encoding a combination of the target homologous sequence (crRNA) and the endogenous bacterial RNA that links the crRNA to the Cas9 nuclease (tracrRNA) in a single chimeric transcript. The gRNA / Cas9 complex is recruited to the target sequence by the base pairing between the sgRNA sequence and the complement genomic DNA / RNA. For successful binding of Cas9, the genomic target sequence must also contain the correct Protospacer Adjacent Motif (PAM) sequence immediately following the target sequence. The binding of the gRNA / Cas9 complex localizes the Cas9 to the genomic target sequence so that the Cas9 can cut both strands of the DNA causing a double-strand break (DSB). The double- stranded breaks (DSBs) produced by CRISPR / Cas can undergo homologous recombination or NHEJ and are susceptible to specific sequence modification during DNA repair.

[0338] The Cas9 nuclease has two functional domains: RuvC and HNH, each cutting a different DNA strand. When both of these domains are active, the Cas9 causes double strand breaks (DSBs) in the genomic DNA or RNA.

[0339] A significant advantage of CRISPR / Cas is that the high efficiency of this system is coupled with the ability to easily create synthetic sgRNAs. This creates a system that can be readily modified to target modifications at different genomic sites and / or to target different modifications at the same site. Additionally, protocols have been established which enable simultaneous targeting of multiple genes. The majority of cells carrying the mutation present biallelic mutations in the targeted genes.

[0340] However, apparent flexibility in the base-pairing interactions between the sgRNA sequence and the genomic DNA target sequence allows imperfect matches to the target sequence to be cut by Cas9.

[0341] Modified versions of the Cas9 enzyme containing a single inactive catalytic domain, either RuvC-or HNH-, are called ‘nickases’. With only one active nuclease domain, the Cas9 nickase cuts only one strand of the target DNA, creating a single-strand break or 'nick'. A single strand break, or nick, is mostly repaired by single strand break repair mechanism involving proteins such as but not only, PARP (sensor) and XRCC1 / LIG III complex (ligation). If a single strand break (SSB) is generated by topoisomerase I poisons or by drugs that trap PARP1 on naturally occurring SSBs then these could persist and when the cell enters into S-phase and the replication fork encounter such SSBs they will become single ended DSBs which can only be repaired by HR. However, two proximal, opposite strand nicks introduced by a Cas9 nickase are treated as a double-strand break, in what is often referred to as a 'double nick' CRISPR system. A double-nick, which is basically non-parallel DSB, can be repaired like other DSBs by HR or NHEJ depending on the desired effect on the gene target and the presence of a donor sequence and the cell cycle stage (HR is of much lower abundance and can only occur in S and G2 stages of the cell cycle). Thus, if specificity and reduced off-target effects are crucial, using the Cas9 nickase to create a doublenick by designing two sgRNAs with target sequences in close proximity and on opposite strands of the genomic DNA would decrease off-target effect as either sgRNA alone will result in nicks that are not likely to change the genomic DNA, even though these events are not impossible.

[0342] Modified versions of the Cas9 enzyme containing two inactive catalytic domains (dead Cas9, or dCas9) have no nuclease activity while still able to bind to DNA based on sgRNA specificity. The dCas9 can be utilized as a platform for DNA transcriptional regulators to activate or repress gene expression by fusing the inactive enzyme to known regulatory domains. For example, the binding of dCas9 alone to a target sequence in genomic DNA can interfere with gene transcription.

[0343] Additional variants of Cas9 which may be used by some embodiments of the invention include, but are not limited to, CasX and Cpfl (also known as Cas12a). CasX enzymes comprise a distinct family of RNA-guided genome editors which are smaller in size compared to Cas9 and are found in bacteria (which is typically not found in humans), hence, are less likely to provoke the immune system / response in a human. Also, CasX utilizes a different PAM motif compared to Cas9 and therefore can be used to target sequences in which Cas9 PAM motifs are not found.

[0344] The CRISPR system may be fused with various effector domains, such as DNA cleavage domains. The DNA cleavage domain can be obtained from any endonuclease or exonuclease. Non-limiting examples of endonucleases from which a DNA cleavage domain can be derived include, but are not limited to, restriction endonucleases and homing endonucleases (see, for example, New England Biolabs Catalog or Belfort et al. (1997) Nucleic Acids Res.). In exemplary embodiments, the cleavage domain of the CRISPR system is a Fokl endonuclease domain or a modified Fokl endonuclease domain. In addition, the use of Homing Endonucleases (HE) is another alternative. Hes are small proteins (< 300 amino acids) found in bacteria, archaea, and in unicellular eukaryotes. A distinguishing characteristic of Hes is that they recognize relatively long sequences (14-40 bp) compared to other site-specific endonucleases such as restriction enzymes (4-8 bp). Hes have been historically categorized by small conserved amino acid motifs. At least five such families have been identified: LAGLIDADG; GIY-YIG; HNH; His-Cys Box and PD-(D / E)xK, which are related to EdxHD enzymes and are considered by some as a separate family. At a structural level, the HNH and His-Cys Box share a common fold (designated bba-metal) as do the PD-(D / E)xK and EdxHD enzymes. The catalytic and DNA recognition strategies for each of the families vary and lend themselves to different degrees to engineering for a variety of applications. Exemplary Homing Endonucleases which may be used according to some embodiments of the invention include, without being limited to, l-Crel, I-Tevl, l-Hmul, I- Ppol and l-Ssp68031.

[0345] The method for modifying a Notch receptor may comprise editing a polynucleotide according to SEQ ID NO:158 encoding a Notchl receptor to delete the polynucleo...

Claims

1. Claims1. An isolated peptide having a total length of up to 30 amino acids, wherein the peptide is capable of binding to a Notch receptor and inhibiting Notch receptor dimerization and / or activation.

2. The peptide according to claim 1, wherein the peptide is capable of binding to the Notch receptor at a binding site.

3. The peptide according to claim 2, wherein the binding site is in the extracellular domain of the Notch receptor.

4. The peptide according to any one of claims 2 or 3, wherein the binding site is in the negative regulatory region (NRR) of the extracellular domain of the Notch receptor.

5. The peptide according to any one of claims 2 to 4, wherein the binding site comprises an amino acid motif comprising the sequence YCXDH (SEQ ID NO:23), wherein X is an amino acid selected from A, K, H, and R, preferably wherein X is selected from A, K and H.

6. The peptide according to any preceding claim, wherein the peptide has a total length of between 11-25, 11-20, or 11-15 amino acids, preferably wherein the peptide has a total length of 11-14 amino acids.

7. The peptide according to any preceding claim, wherein the peptide comprises an amino acid motif comprising the sequence YCXDH (SEQ ID NO:23) wherein X is an amino acid selected from A, K, H and R, preferably wherein X is selected from A and K.

8. The peptide according to any preceding claim, wherein the peptide comprises an amino acid motif comprising the sequence X1X2YCX3DHF (SEQ ID NO: 1), wherein X1is selected from E and D, X2is selected from K and Q, and X3is selected from A and K.

9. The peptide according to any preceding claim, wherein the peptide comprises or consists of an amino acid sequence selected from: EKYCADHFADGR (SEQ ID NO:2), KYDKYCADHFK (SEQ ID NO:3), PLYDQYCKDHFSDG (SEQ ID NO:4), PVYEKYCADHFADGRCDQ (SEQ ID NO:5), PVYEKYCADHFADGR (SEQ ID NO:6), EKYCADHFADGRCDQ (SEQ ID NO:7), and NPLYDQYCKDHFSDG(SEQ ID NO:8), a sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto, or a functional variant thereof.

10. The peptide according to any preceding claim, wherein the Notch receptor is selected from Notch1, Notch2, Notch3 and / or Notch4.

11. The peptide according to any preceding claim, wherein the Notch receptor is Notch3 and the peptide comprises or consists of an amino acid sequence selected from: EKYCADHFADGR (SEQ ID NO:2), PVYEKYCADHFADGRCDQ (SEQ ID NO:5), PVYEKYCADHFADGR (SEQ ID NO:6), and EKYCADHFADGRCDQ (SEQ ID NO:7), a sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto, or a functional variant thereof, preferably wherein the peptide comprises or consists of the amino acid sequence EKYCADHFADGR (SEQ ID NO:2), a sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto, or a functional variant thereof.

12. The peptide according to any of claims 1 to 10, wherein the Notch receptor is Notch1 and the peptide comprises or consists of an amino acid sequence selected from: PLYDQYCKDHFSDG (SEQ ID NO:4) and NPLYDQYCKDHFSDG (SEQ ID NO:8), a sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto, or a functional variant thereof, preferably wherein the peptide comprises or consists of the amino acid sequence PLYDQYCKDHFSDG (SEQ ID NO:4), a sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto, or a functional variant thereof.

13. The peptide according to any of claims 1 to 10, wherein the Notch receptor is Notch2 and the peptide comprises or consists of the amino acid sequence KYDKYCADHFK (SEQ ID NO:3), a sequence at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto, or a functional variant thereof.

14. A polynucleotide encoding a peptide according to any preceding claim.

15. An expression construct or expression vector comprising a polynucleotide according to claim 14 adapted for expression in a host cell.

16. A cell or cell culture adapted to express a peptide according to any one of claims 1 to 13 and comprising a polynucleotide according to claim 14 or comprising an expression construct or expression vector according to claim 15.

17. A composition comprising a peptide according to any one of claims 1 to 13.

18. The composition according to claim 17, wherein the composition is a pharmaceutical composition comprising the peptide as a first therapeutic agent and one or more pharmaceutically acceptable excipients.

19. The composition according to claim 17 or 18, further comprising a second therapeutic agent.

20. The peptide according to any one of claims 1 to 13 or the composition according to any one of claims 17 to 19 for use as a medicament.

21. The peptide according to any one of claims 1 to 13 or the composition according to any one of claims 17 to 19 for use in the treatment of a disease or disorder associated with aberrant Notch signalling.

22. The peptide or composition for use according to claim 21, wherein the disease or disorder is selected from cancer, a monogenic disease, a cardiovascular disease, a neuromuscular disorder, a bone disorder, and an inflammatory disease.

23. The peptide or composition for use according to claim 21 or 22, wherein the disease or disorder is cancer, preferably selected from leukaemia, T-cell acute lymphoblastic leukeamia, lymphoma, breast cancer, gastrointestinal cancer, colorectal cancer, prostate cancer, pancreatic cancer such as pancreatic ductal adenocarcinoma, brain tumours, liver cancer, such as hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), a brain tumor such as glioblastoma, skin cancer, melanoma, bladder cancer, and lung cancer.

24. The peptide or composition for use according to claim 21 or 22, wherein the disease or disorder is a monogenic disease, preferably selected from CADASIL, bicuspid aortic valve disease, Hypoplastic Left Heart Syndrome, Thoracic aorticsyndrome, Adams-Oliver syndrome, Hajdu-Cheney disease and Alagille syndrome.

25. The peptide or composition for use according to claim 21 or 22 wherein the disease or disorder is a cardiovascular disease, preferably selected from pulmonary arterial hypertension and Chronic Obstructive Pulmonary Disease.

26. The peptide according to any one of claims 1 to 13 or the composition according to any one of claims 17 to 19 for use in inhibiting tumour angiogenesis.

27. An in vitro or ex vivo method of inhibiting Notch dimerization and / or activation in a cell, comprising contacting said cell with an effective amount of a peptide according to any one of claims 1 to 13, or a composition according to claim 17.

28. The method according to claim 27, wherein the cell is a T-cell acute lymphoblastic leukaemia (T-ALL) cell.

29. A modified Notch receptor protein comprising a deletion of an amino acid motif in the extracellular domain thereof, wherein the amino acid motif comprises the sequence YCXDH (SEQ ID NO:23), wherein X is an amino acid selected from A, K, H and R.

30. The modified Notch receptor according to claim 29, wherein the modified Notch receptor is selected from Notch 1, Notch2, Notch3 or Notch4.

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