Peptides for the treatment of disorders of the inner ear or the mastoic process

Abstract

SorCS2 related lipidated cyclic peptides, cyclic peptides, lipidated linear peptides, linear peptides of use in treatment or prophylaxis of diseases or disorders of the ear or mastoid process.

Description

[0001] Novel Uses

[0002] Technical field

[0003] The present invention concerns peptides for use in the treatment or prophylaxis of diseases or disorders of the ear or mastoid process.

[0004] Background

[0005] The sortilin-related Vps10p domain containing receptor 2 (SorCS2) in the Vps1 Op-domain receptor family has emerged within neuroscience as it has been shown to be deeply involved with neuronal viability and function (Glerup, 2014; Glerup, 2016; Leloup, 2018; Ma, 2017; Malik, 2019; Yang, 2021). The SorCS2 receptor mediates the sorting and trafficking of a variety of ligands and receptors, which are crucial to neurite formation, synaptic plasticity and axon growth. Large cohort studies have highlighted the clinical relevance of SorCS2, linking it to several neurodegenerative and psychiatric disorders including bipolar disorder, Alzheimer's disease (AD), Huntington’s disease (HD), Frontotemporal dementia (FTD), depression, schizophrenia, and attention deficit / hyperactivity disorder (ADHD) (Baum, 2008; Ollila, 2009; Christoforou, 2011 ; Alemany, 2015; Reitz, 2015). Additionally, SorCS2 has been functionally linked with the severe neurological proteinopathies of amyotrophic lateral sclerosis (ALS) and HD (Mori, 2015; Ma, 2017; Salasova, 2021) and also pain-related diseases such as neuropathic pain (Richner, 2012; Ma, 2017; Miki, 2018). In proteinopathies, SorCS2 has been shown to mis-localize to disease-aggregates resulting in its deficiency and acceleration of disease progression.

[0006] SorCS2 was further shown to be critical in mediating the signalling by brain-derived neurotrophic factor (BDNF), which plays a central role in neuronal survival and differentiation, and synaptic plasticity through activation of its receptor TrkB. Dysregulation of BDNF / TrkB signalling has been demonstrated to contribute to many pathological processes, including various neurodegenerative diseases (Glerup, 2016; Qui, 2020). BDNF promotes activation of cAMP- response element binding protein (CREB) (Glerup, 2016), which is well-known to improve survival, synaptic formation and growth in neurons. A critical mediator of this is the production of BDNF itself by CREB (Tao, 1998), thereby establishing a positive feedback loop. CREB activation has also been described to induce mitochondrial biogenesis through the upregulation of PGC1a (Wu, 2006; Kang, 2017). PGC1a is a master regulator of mitochondrial biogenesis and function, including oxidative phosphorylation and ROS detoxification (Rius-Perez, 2020; Valle, 2005).

[0007] A recent study identified loss of SorCS2 as the causative factor for hearing loss in a spontaneous deaf mouse line, illustrating that SorCS2 might be critical for maintenance of cochlear morphology and function (Forge et al, 2017).

[0008] The process of hearing begins with sound waves entering the outer ear and traveling through the ear canal to reach the eardrum. The eardrum vibrates, transmitting these vibrations to the bones of the middle ear - the malleus, incus, and stapes. These bones amplify the sound vibrations and send them to the cochlea in the inner ear, a fluid-filled structure with a basilar membrane. The cochlea receives an acoustic signal, and a traveling wave is generated, which first undergoes amplification by the outer hair cells (OHCs), which act as a biological amplifier / compressor and modifies the signal. The basilar membrane of the cochlea is highly frequency-specific and tonotopically organized. The base of the basilar membrane responds to higher-frequency sounds, while the apex responds to low frequencies. The inner hair cells (IHCs) are responsible for sending the majority of auditory signals from the cochlea into the brain for processing. IHCs convert mechanical vibrations caused by sound waves into electrical signals. These electrical signals are then transmitted to the spiral ganglion neurons (SGNs) via neurotransmitter release, which subsequently relays the auditory information to the brain for perception and interpretation.

[0009] The most common type of hearing loss is sensorineural hearing loss, which refers to any cause of hearing loss due to a pathology of the cochlea, auditory nerve, or central nervous system. This differs from conductive hearing loss, which results from the inability of sound waves to reach the inner ear. Sensorineural hearing loss affects more than 320 million people worldwide.

[0010] For many years the focus of hearing loss was on the loss of OHCs and IHCs, but more recently it has been shown that changes in the cochlea can also alter the neural sound-evoked output of the auditory nerve independently of hair cell loss and changes in hearing thresholds (Kohrman et al, 2020). This form of hearing loss has been referred to as hidden hearing loss (HHL) to reflect that the dysfunction is not revealed by standard tests of auditory thresholds.

[0011] One of the best documented mechanisms for HHL is the degeneration of cochlear ribbon synapses linking the IHCs and the SGNs, without hair cell loss and SGNs themselves (cochlear synaptopathy). In mice, acoustic overexposure was shown to leave cochlear sensory cells intact but cause acute and irreversible loss of synaptic ribbons (Kujawa and Liberman, 2009), and these findings have since replicated in a range of mammalian species. Whilst hidden hearing loss can be a result of several environmental factors, most commonly noise exposure, it can also be caused by pharmacological damage after treatment with ototoxic drugs such as cisplatin, salicylate and different antibiotics. For example, doses of gentamycin that spare hair cells have been linked to loss of IHC synapses (Kohrman et al, 2020).

[0012] The SorCS2 signaling pathway has been implicated in various studies of hearing loss. Strong evidence links the neurotrophin BDNF to development and maintenance of ribbon synapses, a feature that has been shown both in vitro and in vivo. BDNF released from the IHC acts on TrkB on SGNs, and genetic disruption of the gene encoding this receptor produces cochlear dysfunction (Fritzsch et al, 2004). Interestingly, evidence suggests also that salicylate treatment leads to downregulation of BDNF and thereby synaptopathy and IHC loss (Singer et al, 2008). In line with this, exogenous administration of BDNF or TrkB agonistic monoclonal antibodies produces beneficial effects in ex vivo cochlear models, while in rodent models of hearing loss beneficial effects have been seen with administration of BDNF (Foster et al, 2022). The major challenge for such therapeutic interventions is getting the drug into the cochlea, but a specific formulation of recombinant BDNF (OTO-413 developed by Otonomy Inc) has shown initial evidence of efficacy via intratympanic administration in rodents and in humans. Further, noise exposure has been demonstrated to reduce the expression and activity of PGC-1a, which affected ROS detoxification and further contributed to oxidative stress in an animal model of noise-induced hidden hearing loss (Liu et al, 2022). PGC1a, has been shown to promote lysosomal biogenesis through regulation of TFEB (master regulator of lysosomal biogenesis) (Ghosh, 2015; Lynch, 2020). TFEB has also been implicated in sensorineural hearing loss; in degenerated SGNs, induced by kanamycin and furosemide administration, the nuclear-to- cytoplasmic TFEB ratio was decreased, and the late stage of autophagic flux was impaired. After autophagy dysfunction was partially ameliorated with an MTOR inhibitor, which promoted TFEB translocation into the nucleus from the cytoplasm, it was found that the lysosomal deficits were significantly relieved, the oxidative stress level was reduced, and the density of surviving SGNs and auditory nerve fibers was increased (Ye et al, 2019).

[0013] These data support the hypothesis that modulation of the SorCS2 pathway could have a therapeutic benefit in patients suffering from inner ear disorders.

[0014] Modulators of the SorCS2 pathway have been described and demonstrated as having utility as medicaments. W02017101956 relates to linear peptides and methods for modulating the phosphorylation of the Vps10 domain-containing receptor SorCSI , SorCS2 or SorCS3. WO2022029281 describes cyclic peptides and methods for modulating SorCSI , SorCS2 or SorCS3. International Patent Application PCT / EP2023 / 053211 (publication number WO2023152229) describes peptides and methods for modulating SorCS2.

[0015] There remains a need for the provision of medicaments of use in the treatment or prophylaxis of diseases or disorders of the ear or mastoid process. Such medicaments may demonstrate advantages over known approaches, such as one or more of the following aspects:

[0016] (i) in vivo efficacy

[0017] (iii) pharmacokinetic properties;

[0018] (iv) physiochemical properties; and / or

[0019] (vii) safety profile or therapeutic index (Tl).

[0020] Summary of the Invention

[0021] Provided is a method for the treatment or prophylaxis of a disease or disorder of the ear or mastoid process in a subject, the method comprising the administration of a peptide or a pharmaceutically acceptable salt thereof, wherein the peptide is:

[0022] (i) a lipidated cyclic peptide comprising the sequence:

[0023] X2- X3- E - H - X4- E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0024] X2represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E, A or a conservatively substituted variant of said peptide;

[0025] (ii) a cyclic peptide comprising the sequence:

[0026] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0027] X2represents P, D, Q, K, G X3 represents I, L, A, T, V

[0028] X4 represents E, A or a conservatively substituted variant of said peptide, wherein when X2represents P then X3 is other than V;

[0029] (iii) a cyclic peptide comprising 10 or fewer amino acid residues within the cycle and comprising the sequence:

[0030] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0031] X2represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E, A or a conservatively substituted variant of said peptide;

[0032] (iv) a lipidated linear peptide comprising the sequence:

[0033] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0034] X2represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E, A or a conservatively substituted variant of said peptide;

[0035] (v) a linear peptide comprising the sequence:

[0036] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0037] X2represents P, D, Q, K, G

[0038] X3 represents I, L, A, T, V X4 represents E, A or a conservatively substituted variant of said peptide, wherein when X2represents P then X3 is other than V; or

[0039] (vi) a linear peptide comprising 10 or fewer amino acid residues within the backbone and comprising the sequence:

[0040] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0041] X2represents P, D, Q, K, G

[0042] X3 represents I, L, A, T, V

[0043] X4 represents E, A or a conservatively substituted variant of said peptide. Also, provided is a peptide or a pharmaceutically acceptable salt thereof for use in the treatment or prophylaxis of a disease or disorder of the ear or mastoid process, wherein the peptide is:

[0044] (i) a lipidated cyclic peptide comprising the sequence:

[0045] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0046] X2represents P, D, Q, K, G

[0047] X3 represents I, L, A, T, V

[0048] X4 represents E, A or a conservatively substituted variant of said peptide;

[0049] (ii) a cyclic peptide comprising the sequence:

[0050] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0051] X2represents P, D, Q, K, G

[0052] X3 represents I, L, A, T, V

[0053] X4 represents E, A or a conservatively substituted variant of said peptide, wherein when X2represents P then X3 is other than V;

[0054] (iii) a cyclic peptide comprising 10 or fewer amino acid residues within the cycle and comprising the sequence:

[0055] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein: X2represents P, D, Q, K, G

[0056] X3represents I, L, A, T, V

[0057] X4represents E, A or a conservatively substituted variant of said peptide;

[0058] (iv) a lipidated linear peptide comprising the sequence:

[0059] X2- X3- E - H - X4- E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0060] X2represents P, D, Q, K, G

[0061] X3represents I, L, A, T, V

[0062] X4represents E, A or a conservatively substituted variant of said peptide;

[0063] (v) a linear peptide comprising the sequence:

[0064] X2- X3- E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0065] X2represents P, D, Q, K, G

[0066] X3 represents I, L, A, T, V

[0067] X4represents E, A or a conservatively substituted variant of said peptide, wherein when X2represents P then X3 is other than V; or

[0068] (vi) a linear peptide comprising 10 or fewer amino acid residues within the backbone and comprising the sequence:

[0069] X2- X3- E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0070] X2represents P, D, Q, K, G

[0071] X3 represents I, L, A, T, V

[0072] X4represents E, A or a conservatively substituted variant of said peptide. Further provided is a pharmaceutical composition for the treatment or prophylaxis of a disease or disorder of the ear or mastoid process, said pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof, wherein the peptide is:

[0073] (i) a lipidated cyclic peptide comprising the sequence:

[0074] X2- X3- E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein: X2represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E, A or a conservatively substituted variant of said peptide;

[0075] (ii) a cyclic peptide comprising the sequence:

[0076] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0077] X2represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E, A or a conservatively substituted variant of said peptide, wherein when X2represents P then X3 is other than V;

[0078] (iii) a cyclic peptide comprising 10 or fewer amino acid residues within the cycle and comprising the sequence:

[0079] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0080] X2represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E, A or a conservatively substituted variant of said peptide;

[0081] (iv) a lipidated linear peptide comprising the sequence:

[0082] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0083] X2represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E, A or a conservatively substituted variant of said peptide;

[0084] (v) a linear peptide comprising the sequence:

[0085] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0086] X2represents P, D, Q, K, G

[0087] X3 represents I, L, A, T, V

[0088] X4 represents E, A or a conservatively substituted variant of said peptide, wherein when X2 represents P then X3 is other than V; or

[0089] (vi) a linear peptide comprising 10 or fewer amino acid residues within the backbone and comprising the sequence:

[0090] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0091] X2 represents P, D, Q, K, G

[0092] X3 represents I, L, A, T, V

[0093] X4 represents E, A or a conservatively substituted variant of said peptide. Additionally provided is the use of a peptide or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis of a disease or disorder of the ear or mastoid process, wherein the peptide is:

[0094] (i) a lipidated cyclic peptide comprising the sequence:

[0095] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0096] X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E, A or a conservatively substituted variant of said peptide;

[0097] (ii) a cyclic peptide comprising the sequence:

[0098] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0099] X2 represents P, D, Q, K, G

[0100] X3 represents I, L, A, T, V

[0101] X4 represents E, A or a conservatively substituted variant of said peptide, wherein when X2 represents P then X3 is other than V;

[0102] (iii) a cyclic peptide comprising 10 or fewer amino acid residues within the cycle and comprising the sequence:

[0103] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0104] X2 represents P, D, Q, K, G X3 represents I, L, A, T, V

[0105] X4 represents E, A or a conservatively substituted variant of said peptide;

[0106] (iv) a lipidated linear peptide comprising the sequence:

[0107] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0108] X2represents P, D, Q, K, G

[0109] X3 represents I, L, A, T, V

[0110] X4 represents E, A or a conservatively substituted variant of said peptide;

[0111] (v) a linear peptide comprising the sequence:

[0112] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0113] X2represents P, D, Q, K, G

[0114] X3 represents I, L, A, T, V

[0115] X4 represents E, A or a conservatively substituted variant of said peptide, wherein when X2represents P then X3 is other than V; or

[0116] (vi) a linear peptide comprising 10 or fewer amino acid residues within the backbone and comprising the sequence:

[0117] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0118] X2represents P, D, Q, K, G

[0119] X3 represents I, L, A, T, V

[0120] X4 represents E, A or a conservatively substituted variant of said peptide.

[0121] Brief Description of the Figures

[0122] Fig. 1A to Fig. 1C: Purification and qualitative check of CLP1 : HPLC chromatogram for CLP1 with UV detection at 220 nm (Fig. 1A), LCMS chromatogram (Fig. 1 B) and full scan acquisition positive ion mode spectrum (Fig. 1C).

[0123] Fig. 2A and Fig. 2B: CLP1 increases levels of CREB transcriptional targets: 1 uM of peptide CLP1 significantly increased the levels of downstream targets of CREB: neurotrophic factor BDNF (Fig. 2A), mitochondrial master regulator PGC1a (Fig. 2B) in mouse primary neurons after 16- and 24-hours. Peptide CPX showed no effect at these timepoints. Means±SEM.

[0124] Fig. 3A and Fig. 3B: CLP1 clears soluble mutated HTT in Huntington’s patient-derived fibroblasts : peptides CLP1 and CPX significantly reduced mutated Huntingtin (mHTT) levels in Huntington’s patient-derived fibroblasts (GM04719) by 50% and 25%, respectively, after

[0125] 24 hours of treatment (Fig. 3A). A significant decrease in total HTT levels was also observed (Fig.

[0126] 3B).

[0127] Fig. 4A to Fig. 4G: Chemical and physical stability of CLP1 in three buffers: the stability of CLP1 in buffer systems with pH 4.5 (Fig. 4A), pH 6.5 (Fig. 4B) and pH 7.5 (Fig. 4C) after 14 days at 40°C. CLP1 did not show any fibrillation in any of the buffers using ThT assay, demonstrating good physical stability at pH 4.5 (Fig. 4D), pH 6.5 (Fig. 4E) and pH 7.5 (Fig. 4F) relative to positive control (Fig. 4G).

[0128] Fig. 5A to Fig. 5C: CLP1 is stable in plasma and brain homogenates: CLP1 and CPX demonstrated limited degradation in human plasma (Fig. 5A), mouse plasma (Fig. 5B). CLP1 displayed higher stability than CPX in mouse brain homogenate (Fig. 5C).

[0129] Fig. 6A to Fig. 6D: CLP1 metabolic stability in liver S9 fractions: stability of CLP1 in Liver S9 fractions from 5 different species - intrinsic clearance of CLP1 (Fig. 6A), intrinsic clearance of 7-ethoxycoumarin positive control (Fig. 6B), remaining percentage of CLP1 (Fig. 6C) and remaining percentage of 7-ethoxycoumarin positive control (Fig. 6D).

[0130] Fig. 7A and Fig. 7B: Brain free fraction of CLP1 : brain free fraction of CLP1 in mouse brain (Fig. 7A) and human brain (Fig. 7B) measured by LCMS.

[0131] Fig. 8A to Fig. 8C: Pharmacokinetics of CLP1 in wild-type mice: plasma (Fig. 8A), whole brain (Fig. 8B) and cerebrospinal fluid (Fig. 8C) concentrations of CLP1 from 1 to 24 hours postinjection by LCMS / MS.

[0132] Fig. 9A to Fig. 9C: Single-injection of CLP1 in wild-type mice: CLP1 showed strong tendency to increase BDNF after 4 hours (Fig. 9A). Post-hoc analysis showed a significant timedependent effect (p=0.0438) of CLP1 on BDNF levels by two-way ANOVA analysis (not shown). CLP1 significantly increased PGC1a at 2-4 hours post injection (Fig. 9B) and transcription factor

[0133] EB (TFEB) at 2-8 hours post injection (Fig. 80). Means±SEM.

[0134] Fig. 10A and Fig. 10B: 7-day daily treatment of CLP1 in wild-type mice: CLP1 and CPX significantly increased PGC1a at both 0.2 mg / kg and 2 mg / kg daily doses for CLP1 and 13 mg / kg for CPX (Fig. 10A) and GRN at both 0.2 mg / kg and 2 mg / kg daily doses for CLP1 and 13 mg / kg for CPX (Fig. 10C). CLP1 (0.2 mg / kg) and CPX (13 mg / kg) significantly increased BDNF-levels following single subcutaneous dose per day (Fig. 10B).

[0135] Fig. 11A to Fig. 11 F: CLP1 improves behavior in R6 / 2 mouse model of Huntington’s disease a schematic of the PoC study from Example 11 (Fig 11 A). CLP1 and CPX did not change bodyweight (Fig. 11 B). CLP1 significantly improved clasping behavior at week 9 and 14 in R6 / 2 treated mice, while CPX improved clasping at 9 weeks only (Fig. 11 C). No significant effects were observed in rotarod (Fig. 11 D). Kaplan-Meier curve shows cumulative survival (Fig. 11 E), in which CLP1 increased the mean survival of treated R6 / 2 mice by 7 days and median survival by 13 days (Fig. 11 F) in this severe model of Huntington’s disease.

[0136] Fig. 12A to Fig. 12D: CLP1 improves behavior in a mouse model of Parkinson’s (MPTP model): a schematic of the experimental design from Example 12 (Fig. 12A). Behavioral and biochemical analysis was assessed at day 10. Treatment with CLP1 increased distance travelled in the open-field test, significantly for 2 mg / kg (Fig. 12B). CLP1 completely rescued grip strength at both 0.2 and 2 mg / kg dosing (Fig. 12C). Body weight of animals after MPTP injection were reduced at first and gradually increased during the study, while MPTP significantly changed body weight at endpoint from non-treated mice (sham), CLP1 treated mice do not show a significant change in bodyweight at end point compared to sham group (Fig. 12D).

[0137] Fig. 13A and Fig. 13B: CLP1 increases neuronal survival in a mouse model of Parkinson’s (MPTP model): Tyrosine hydroxylase (TH)+ neurons in the substantia nigra pars compacta (SNpc) from 6 mice were immunostained and counted as a measure of dopaminergic neuronal survival. The number of positive cells was expressed as average of three brain sections. Representative images from each group are shown (Fig. 13A). TH-stain guantifications show a significant effect of CLP1 (0.2 mg / kg) on survival of TH+ neurons (Fig. 13B).

[0138] Fig. 14A to Fig. 14F: CLP1 clears and reduces spreading of human a-synuclein PFFs in vivo: a schematic of the experimental design from Example 13 is shown (Fig. 14A). The injection site was amygdala and both ipsilateral and contralateral spread of PFFs in substantia nigra pars compacta and amygdala was assessed after 32-days of treatment (Fig. 14B). Representative images of substantia nigra (Fig. 14C) and amygdala (Fig. 14D) are shown. CLP1 significantly reduced number of PFF inclusions in both substantia nigra (SN) ipsilateral and amygdala contralateral, while showing a clear tendency to reduce ipsilateral inclusion in amygdala as well (Fig. 14E). One brain was immunostained for TH+ neurons and imaged (Fig. 14F). The TH-stain clearly shows loss of dopaminergic striatal dopaminergic terminals in vehicle treated rat, as signal was almost completely lost at site of injection. CLP1 -treatment notably preserved the dopaminergic terminals.

[0139] Fig. 15: FSL data: 8-week old FSL rats were treated once per day with 0.2 mg / kg or 2 mg / kg of CLP1 or 13 mg / kg of CPX for 8 days in 4.38 mM L-His, 140 mM NaCI, 0.2% Tween-20 and 1500111 hyaluronidase (pH 6.15). After treatment, the levels of BDNF in the hippocampus were evaluated by western blotting normalized to beta-actin. The graph depicts the densitometric guantification of western blot bands. BDNF levels were normalised to BDNF levels in control rats (FRL).

[0140] Fig. 16A to Fig. 16F: CLP1 increases time spent awake in Wistar Kyoto rats: effect of ketamine and CLP1 on wakefulness (Fig. 16A), NREM (Fig. 16B) and REM (Fig. 16C) sleep between 0-3 hours post injection, and wakefulness (Fig. 16D), NREM (Fig. 16E) and REM (Fig.

[0141] 16F) sleep between 11-12 hours post injection.

[0142] Fig. 17A to Fig. 17D: Brain and plasma-stability of CLP1 to CLP10 and LLP1 to LLP10: the stability of peptides CLP1 and LLP1 to LLP10 in plasma (Fig. 17A) and mouse brain homogenate (Fig. 17C) and stability of peptides CLP1 to CLP10 in plasma (Fig. 17B) and mouse brain homogenate (Fig. 17D).

[0143] Fig. 18A to Fig. 18D: Effects of CLP1 to CLP10 and LLP1 to LLP10 on CREB-targeted genes effect on BDNF for CLP1 to CLP10 (Fig 18A) and CLP1 and LLP1 to LLP10 (Fig 18B) and PGC1a for CLP1 to CLP10 (Fig. 18C) and CLP1 and LLP1 to LLP10 (Fig. 18D) levels after

[0144] 8-24 hours of stimulation with respective peptides in primary cortical neurons.

[0145] Fig. 19A and Fig. 19B: CLP1 and CLP10 clear soluble mutated HTT in Huntington’s

[0146] :-derived fibroblasts : peptides CLP1 and CLP10 significantly reduced mutated

[0147] Huntingtin (mHTT) levels in Huntington’s patient-derived fibroblasts (GM04719) by 50% after 24 hours of treatment (measured using MW1 antibody specific for polyglutamine stretch) (Fig. 19A) and showed a decrease in total HTT levels (Fig. 19B).

[0148] Fig. 20A to Fig. 20D: Pharmacokinetics of selected peptides in wild-type mice: plasma (Fig. 20A) and whole brain (Fig. 20C) concentrations of cyclic peptides from 1 to 48 hours by LCMS / MS. Calculated PK measures for plasma (Fig. 20B) and brain (Fig. 20D).

[0149] Fig. 21 A to Fig. 21 C: In vivo efficacy of selected peptides in wild-type mice: CLP1 significantly increased BDNF levels (Fig. 21 A) and tropomyosin receptor kinase B (TrkB) levels along with CLP4 (Fig. 21 C). All variants significantly increased levels of PGC1a (Fig. 21 B).

[0150] Fig. 22A to Fig. 22D: Physical stability of CLP10 in three buffers: CLP10 demonstrated fibrillation in buffer at pH 4.5 (Fig. 22A) while being stable in both pH 6.5 (Fig. 22B) and pH 7.5 (Fig. 22C) buffer systems using ThT assay. Positive control is shown in Fig. 22D.

[0151] Fig. 23A and Fig. 23B: Brain free fraction of CLP1 and CLP10: brain free fraction of CLP1 and CLP10 in mouse brain (Fig. 23A) and human brain (Fig. 23B) measured by LCMS.

[0152] Fig. 24A and Fig. 24B: Pharmacokinetics of CLP10: CLP10 levels are stable in both plasma (Fig. 24A) and brain (Fig. 24B) 24 hours post injection.

[0153] Fig. 25: Lipidated peptides LLP11 , LLP12 and CLP11 increase BDNF in vivo: BDNF levels in wild-type mice between 4-8 hours post-injection.

[0154] Fig. 26: Identification of shorter seguences with activity (CP13 to CP17): the activity of CLP1 and non-lipidated cyclic peptides (CP13 to CP17 and CPX).

[0155] Fig. 27A and Fig. 27B: Stability of cyclic non-lipidated peptides CP1 to CP12: stability of peptides in mouse brain (Fig. 27A) and plasma (Fig. 27B).

[0156] Fig. 28A to Fig. 28C: In vivo efficacy of non-lipidated cyclic peptides CP5 to CP12: CP6, CP7 and CP10 significantly increased TFEB (Fig. 28A). CP5, CP7 and CP9 significantly increased BDNF (Fig. 28B). CP5, CP6, CP7, CP8 and CP10 significantly increased PGC1a levels (Fig. 28C).

[0157] Fig. 29: Impact of amino acid variation on activity (CP18 to CP22): BDNF levels of primary cortical neurons after treatment with non-lipidated cyclic peptides (CP18 to CP22 and CPX) compared to CLP1.

[0158] Fig. 30: Impact of different lipidations on activity (CLP12 to CLP15): BDNF levels of primary cortical neurons after treatment with lipidated cyclic peptides (CLP12 to CP15) compared to CLPI .

[0159] Fig. 31 A to Fig. 31 C: CLP1 increases GRN and rescues lysosomal deficits in a GRN- heterozygous mouse model of FTP: Daily subcutaneous administration of CLP1 (0.2 mg / kg) for 7 days in GRN heterozygous mice increases GRN levels (Fig. 31A) and normalises lysosomal proteins LAMP1 (Fig. 31 B) and p62 (Fig. 31C).

[0160] Fig. 32A to Fig. 32I: CLP1 rescues behavioral phenotype in the Huntington’s Disease model zQ175: zQ175 mice display reduced bodyweight compared to wild-type littermates and treatment has no effect on bodyweight (Fig. 32A). Latency to fall in rotarod behavioral assessment throughout study (Fig. 32B). At 12 months of age, the latency to fall of the treatment groups (CPX and CLP1) trended higher compared with zQ175+vehicle. Number of errors made in Transverse beam test while traversing (Fig. 32C). CLP1 rescues number of errors made at 12 months of age, which is also significant compared to CPX-treated group. Principal component analysis plot of home-cage analysis data (Fig. 32D) and hierarchical dendrogram analysis (Fig. 32E) demonstrate rescue of behavioural phenotype in zQ175 HD mouse model by CLP1 treatment, whereas CPX treatment also leads to notable rescue. Individual behavior parameters for CPX and CLP1 (Fig. 32F and Fig. 32G respectively). zQ175 mice all display higher NfL levels in CSF and blood compared to WT (Fig. 32H and Fig. 32I) and treatment with CLP1 and CPX show a trend to decrease this.

[0161] Fig. 33A and Fig. 33B: CLP1 increases GBA in human iPSC-derived dopaminergic neurons: TFEB and GCase levels in hIPSC-derived dopaminergic neurons following treatment with CLP1.

[0162] Brief Description of the Sequences

[0163] SEQ ID NO: 1 Cyclic lipidated peptide CLP1

[0164] SEQ ID NO: 2 Cyclic lipidated peptide CLP2

[0165] SEQ ID NO: 3 Cyclic lipidated peptide CLP3

[0166] SEQ ID NO: 4 Cyclic lipidated peptide CLP4

[0167] SEQ ID NO: 5 Cyclic lipidated peptide CLP5

[0168] SEQ ID NO: 6 Cyclic lipidated peptide CLP6

[0169] SEQ ID NO: 7 Cyclic lipidated peptide CLP7 SEQ ID NO: 8 Cyclic lipidated peptide CLP8

[0170] SEQ ID NO: 9 Cyclic lipidated peptide CLP9

[0171] SEQ ID NO: 10 Cyclic lipidated peptide CLP10

[0172] SEQ ID NO: 11 Cyclic lipidated peptide CLP11

[0173] SEQ ID NO: 12 Cyclic lipidated peptide CLP12

[0174] SEQ ID NO: 13 Cyclic lipidated peptide CLP13

[0175] SEQ ID NO: 14 Cyclic lipidated peptide CLP14

[0176] SEQ ID NO: 15 Cyclic lipidated peptide CLP15

[0177] SEQ ID NO: 16 Linear lipidated peptide LLP1

[0178] SEQ ID NO: 17 Linear lipidated peptide LLP2

[0179] SEQ ID NO: 18 Linear lipidated peptide LLP3

[0180] SEQ ID NO: 19 Linear lipidated peptide LLP4

[0181] SEQ ID NO: 20 Linear lipidated peptide LLP5

[0182] SEQ ID NO: 21 Linear lipidated peptide LLP6

[0183] SEQ ID NO: 22 Linear lipidated peptide LLP7

[0184] SEQ ID NO: 23 Linear lipidated peptide LLP8

[0185] SEQ ID NO: 24 Linear lipidated peptide LLP9

[0186] SEQ ID NO: 25 Linear lipidated peptide LLP10

[0187] SEQ ID NO: 26 Linear lipidated peptide LLP11

[0188] SEQ ID NO: 27 Linear lipidated peptide LLP12

[0189] SEQ ID NO: 28 Cyclic peptide CP1

[0190] SEQ ID NO: 29 Cyclic peptide CP2

[0191] SEQ ID NO: 30 Cyclic peptide CP3

[0192] SEQ ID NO: 31 Cyclic peptide CP4

[0193] SEQ ID NO: 32 Cyclic peptide CP5

[0194] SEQ ID NO: 33 Cyclic peptide CP6

[0195] SEQ ID NO: 34 Cyclic peptide CP7

[0196] SEQ ID NO: 35 Cyclic peptide CP8

[0197] SEQ ID NO: 36 Cyclic peptide CP9

[0198] SEQ ID NO: 37 Cyclic peptide CP10

[0199] SEQ ID NO: 38 Cyclic peptide CP11

[0200] SEQ ID NO: 39 Cyclic peptide CP12

[0201] SEQ ID NO: 40 Cyclic peptide CP13

[0202] SEQ ID NO: 41 Cyclic peptide CP14

[0203] SEQ ID NO: 42 Cyclic peptide CP15

[0204] SEQ ID NO: 43 Cyclic peptide CP16

[0205] SEQ ID NO: 44 Cyclic peptide CP17 SEQ ID NO: 45 Cyclic peptide CP18

[0206] SEQ ID NO: 46 Cyclic peptide CP19

[0207] SEQ ID NO: 47 Cyclic peptide CP20

[0208] SEQ ID NO: 48 Cyclic peptide CP21

[0209] SEQ ID NO: 49 Cyclic peptide CP22

[0210] SEQ ID NO: 50 Native SorCS2 fragment

[0211] SEQ ID NO: 51 Variable peptide sequence 1

[0212] SEQ ID NO: 52 Variable peptide sequence 2

[0213] SEQ ID NO: 53 Variable peptide sequence 3

[0214] SEQ ID NO: 54 Variable peptide sequence 4

[0215] SEQ ID NO: 55 Variable peptide sequence 5

[0216] SEQ ID NO: 56 Variable peptide sequence 6

[0217] SEQ ID NO: 57 Variable peptide sequence 7

[0218] SEQ ID NO: 58 Variable peptide sequence 8

[0219] SEQ ID NO: 59 Variable peptide sequence 9

[0220] SEQ ID NO: 60 Variable peptide sequence 10

[0221] SEQ ID NO: 61 Variable peptide sequence 11

[0222] SEQ ID NO: 62 Variable peptide sequence 12

[0223] SEQ ID NO: 63 Cyclic peptide CPX

[0224] Detailed Description of the Invention

[0225] Provided is a method for the treatment or prophylaxis of a disease or disorder of the ear or mastoid process in a subject, the method comprising the administration of a peptide or a pharmaceutically acceptable salt thereof, wherein the peptide is:

[0226] (i) a lipidated cyclic peptide comprising the sequence:

[0227] X2- X3- E - H - X4- E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0228] X2represents P, D, Q, K, G

[0229] X3represents I, L, A, T, V

[0230] X4represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 ;

[0231] (ii) a cyclic peptide comprising the sequence:

[0232] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0233] X2represents P, D, Q, K, G Xa represents I, L, A, T, V

[0234] X4 represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 , wherein when X2represents P then X3 is other than V;

[0235] (iii) a cyclic peptide comprising 10 or fewer amino acid residues within the cycle and comprising the sequence:

[0236] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0237] X2represents P, D, Q, K, G

[0238] X3 represents I, L, A, T, V

[0239] X4 represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 ;

[0240] (iv) a lipidated linear peptide comprising the sequence:

[0241] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0242] X2represents P, D, Q, K, G

[0243] X3 represents I, L, A, T, V

[0244] X4 represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 ;

[0245] (v) a linear peptide comprising the sequence:

[0246] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0247] X2represents P, D, Q, K, G

[0248] X3 represents I, L, A, T, V

[0249] X4 represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 , wherein when X2represents P then X3 is other than V; or

[0250] (vi) a linear peptide comprising 10 or fewer amino acid residues within the backbone and comprising the sequence:

[0251] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0252] X2represents P, D, Q, K, G

[0253] X3 represents I, L, A, T, V X4 represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51.

[0254] Also, provided is a peptide or a pharmaceutically acceptable salt thereof for use in the treatment or prophylaxis of a disease or disorder of the ear or mastoid process, wherein the peptide is:

[0255] (i) a lipidated cyclic peptide comprising the sequence:

[0256] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0257] X2represents P, D, Q, K, G

[0258] X3 represents I, L, A, T, V

[0259] X4 represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 ;

[0260] (ii) a cyclic peptide comprising the sequence:

[0261] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0262] X2represents P, D, Q, K, G

[0263] X3 represents I, L, A, T, V

[0264] X4 represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 , wherein when X2represents P then X3 is other than V;

[0265] (iii) a cyclic peptide comprising 10 or fewer amino acid residues within the cycle and comprising the sequence:

[0266] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0267] X2represents P, D, Q, K, G

[0268] X3 represents I, L, A, T, V

[0269] X4 represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 ;

[0270] (iv) a lipidated linear peptide comprising the sequence:

[0271] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0272] X2represents P, D, Q, K, G

[0273] A3 represents I, L, A, T, V X4represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 ;

[0274] (v) a linear peptide comprising the sequence:

[0275] X2- X3- E - H - X4- E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0276] X2represents P, D, Q, K, G

[0277] X3represents I, L, A, T, V X4represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 , wherein when X2represents P then X3 is other than V; or

[0278] (vi) a linear peptide comprising 10 or fewer amino acid residues within the backbone and comprising the sequence:

[0279] X2- X3- E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0280] X2represents P, D, Q, K, G

[0281] X3 represents I, L, A, T, V X4represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51.

[0282] Further provided is a pharmaceutical composition for the treatment or prophylaxis of a disease or disorder of the ear or mastoid process, said pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof, wherein the peptide is:

[0283] (i) a lipidated cyclic peptide comprising the sequence:

[0284] X2- X3- E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0285] X2represents P, D, Q, K, G

[0286] X3 represents I, L, A, T, V X4represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 ;

[0287] (ii) a cyclic peptide comprising the sequence:

[0288] X2- X3- E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0289] X2represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 , wherein when X2represents P then X3 is other than V;

[0290] (iii) a cyclic peptide comprising 10 or fewer amino acid residues within the cycle and comprising the sequence:

[0291] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0292] X2represents P, D, Q, K, G

[0293] X3 represents I, L, A, T, V

[0294] X4 represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 ;

[0295] (iv) a lipidated linear peptide comprising the sequence:

[0296] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0297] X2represents P, D, Q, K, G

[0298] X3 represents I, L, A, T, V

[0299] X4 represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 ;

[0300] (v) a linear peptide comprising the sequence:

[0301] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0302] X2represents P, D, Q, K, G

[0303] X3 represents I, L, A, T, V

[0304] X4 represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 , wherein when X2represents P then X3 is other than V; or

[0305] (vi) a linear peptide comprising 10 or fewer amino acid residues within the backbone and comprising the sequence:

[0306] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0307] X2represents P, D, Q, K, G

[0308] X3 represents I, L, A, T, V

[0309] X4 represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51.

[0310] Additionally provided is the use of a peptide or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis of a disease or disorder of the ear or mastoid process, wherein the peptide is:

[0311] (i) a lipidated cyclic peptide comprising the sequence:

[0312] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0313] X2represents P, D, Q, K, G

[0314] X3 represents I, L, A, T, V

[0315] X4 represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 ;

[0316] (ii) a cyclic peptide comprising the sequence:

[0317] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0318] X2represents P, D, Q, K, G

[0319] X3 represents I, L, A, T, V

[0320] X4 represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 , wherein when X2represents P then X3 is other than V;

[0321] (iii) a cyclic peptide comprising 10 or fewer amino acid residues within the cycle and comprising the sequence:

[0322] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0323] X2represents P, D, Q, K, G

[0324] X3 represents I, L, A, T, V

[0325] X4 represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 ;

[0326] (iv) a lipidated linear peptide comprising the sequence:

[0327] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0328] X2represents P, D, Q, K, G

[0329] X3 represents I, L, A, T, V

[0330] X4 represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 ;

[0331] (v) a linear peptide comprising the sequence:

[0332] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0333] X2represents P, D, Q, K, G

[0334] X3 represents I, L, A, T, V X4 represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 , wherein when X2represents P then X3 is other than V; or

[0335] (vi) a linear peptide comprising 10 or fewer amino acid residues within the backbone and comprising the sequence:

[0336] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0337] X2represents P, D, Q, K, G

[0338] X3 represents I, L, A, T, V X4 represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51.

[0339] Peptides In one embodiment, the peptide is a lipidated cyclic peptide comprising the sequence:

[0340] X2- X3 - E - H - X4 - E (SEQ ID No. 51) position 1 2 3 4 5 6 wherein:

[0341] X2represents P, D, Q, K, G

[0342] X3 represents I, L, A, T, V

[0343] X4 represents E, A or a salt thereof, or comprising a conservatively substituted variant of SEQ ID No. 51 or a salt thereof.

[0344] The lipidated cyclic peptide may comprise the sequence:

[0345] X2- X3 - E - H - X4 - E (SEQ ID No. 51) position 1 2 3 4 5 6 wherein:

[0346] X2represents P, D, Q, K, G

[0347] X3 represents I, L, A, T, V

[0348] X4 represents E, A or a salt thereof. In particular wherein the peptide is backbone cyclised and all residues of the peptide backbone are joined exclusively by peptide bonds.

[0349] In another embodiment, the peptide is a cyclic peptide comprising the sequence:

[0350] X2- X3- E - H - X4- E (SEQ ID No. 51) position 1 2 3 4 5 6 wherein:

[0351] X2represents P, D, Q, K, G

[0352] X3represents I, L, A, T, V

[0353] X4represents E, A or a salt thereof, or comprising a conservatively substituted variant of SEQ ID No. 51 or a salt thereof, wherein when X2represents P then X3 is other than V.

[0354] The cyclic peptide may comprise the sequence:

[0355] X2- X3- E - H - X4 - E (SEQ ID No. 51) position 1 2 3 4 5 6 wherein:

[0356] X2represents P, D, Q, K, G

[0357] X3 represents I, L, A, T, V

[0358] X4represents E, A or a salt thereof, wherein when X2represents P then X3 is other than V. In particular wherein the peptide is backbone cyclised and all residues of the peptide backbone are joined exclusively by peptide bonds.

[0359] In another embodiment, the peptide is a cyclic peptide comprising 10 or fewer amino acid residues within the cycle and comprising the sequence:

[0360] X2- X3- E - H - X4 - E (SEQ ID No. 51) position 1 2 3 4 5 6 wherein:

[0361] X2represents P, D, Q, K, G

[0362] X3 represents I, L, A, T, V

[0363] X4represents E, A or a salt thereof, or comprising a conservatively substituted variant of SEQ ID No. 51 or a salt thereof.

[0364] The cyclic peptide may comprise 10 or fewer amino acid residues within the cycle and comprise the sequence:

[0365] X2- X3- E - H - X4 - E (SEQ ID No. 51) position 1 2 3 4 5 6 wherein:

[0366] X2represents P, D, Q, K, G Xa represents I, L, A, T, V X4 represents E, A or a salt thereof. In particular wherein the peptide is backbone cyclised and all residues of the peptide backbone are joined exclusively by peptide bonds.

[0367] In another embodiment, the peptide is a lipidated linear peptide comprising the sequence:

[0368] X2- X3 - E - H - X4 - E (SEQ ID No. 51) position 1 2 3 4 5 6 wherein:

[0369] X2represents P, D, Q, K, G

[0370] X3 represents I, L, A, T, V

[0371] X4 represents E, A or a salt thereof, or comprising a conservatively substituted variant of SEQ ID No. 51 or a salt thereof.

[0372] The lipidated linear peptide may comprise the sequence:

[0373] X2- X3 - E - H - X4 - E (SEQ ID No. 51) position 1 2 3 4 5 6 wherein:

[0374] X2represents P, D, Q, K, G

[0375] X3 represents I, L, A, T, V

[0376] X4 represents E, A or a salt thereof. In particular wherein all residues of the peptide backbone are joined exclusively by peptide bonds.

[0377] In another embodiment, the peptide is a linear peptide comprising the sequence:

[0378] X2- X3 - E - H - X4 - E (SEQ ID No. 51) position 1 2 3 4 5 6 wherein:

[0379] X2represents P, D, Q, K, G

[0380] X3 represents I, L, A, T, V

[0381] X4 represents E, A or a salt thereof, or comprising a conservatively substituted variant of SEQ ID No. 51 or a salt thereof, wherein when X2represents P then X3 is other than V.

[0382] The linear peptide may comprise the sequence: X2- X3 - E - H - X4 - E (SEQ ID No. 51) position 1 2 3 4 5 6 wherein:

[0383] X2represents P, D, Q, K, G Xa represents I, L, A, T, V

[0384] X4 represents E, A or a salt thereof, or comprising a conservatively substituted variant of SEQ ID No. 51 or a salt thereof, wherein when X2represents P then X3 is other than V. In particular wherein all residues of the peptide backbone are joined exclusively by peptide bonds.

[0385] In another embodiment, the peptide is a linear peptide comprising 10 or fewer amino acid residues within the backbone and comprising the sequence:

[0386] X2- X3 - E - H - X4 - E (SEQ ID No. 51) position 1 2 3 4 5 6 wherein: X2represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E, A or a salt thereof, or comprising a conservatively substituted variant of SEQ ID No. 51 or a salt thereof.

[0387] The linear peptide may comprise 10 or fewer amino acid residues within the backbone and comprise the sequence:

[0388] X2- X3 - E - H - X4 - E (SEQ ID No. 51) position 1 2 3 4 5 6 wherein: X2represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E, A or a salt thereof. In particular wherein all residues of the peptide backbone are joined exclusively by peptide bonds.

[0389] A "peptide" is a polymer of amino acid residues, typically joined exclusively by peptide bonds.

[0390] In some embodiments, the peptides may be modified. Particular modifications include N- terminal acetylation and / or C-terminal amidation. In some embodiments the peptides do not contain side chain modifications. In other embodiments the peptides are not modified.

[0391] Certain peptides described herein are cyclic. A peptide can typically be cyclised in four different ways: side chain-to-side chain, tail-to-side chain (i.e. C-terminus to side chain), side chain-to-head (i.e. N-terminus to side chain) and head-to-tail. As used herein, the term “head-to- tail cyclised peptide” is used interchangeably with the term ’’backbone cyclised peptide”.

[0392] In one embodiment, the cyclic peptide is a backbone cyclised peptide. In one embodiment, the cyclic peptide is formed by the formation of an amide bond between its N- terminus- and its C-terminus-parts, i.e. head-to tail cyclization. In some embodiments the peptide is cyclised side chain-to-side chain and the backbone of the peptide is joined exclusively by peptide bonds. In some embodiments the peptide is cyclised tail-to-side chain and the backbone of the peptide is joined exclusively by peptide bonds. In some embodiments the peptide is cyclised side chain-to-head and the backbone of the peptide is joined exclusively by peptide bonds.

[0393] In some embodiments the peptide is backbone cyclised and the backbone of the peptide is joined exclusively by peptide bonds.

[0394] In some embodiments cyclic peptides comprise 25 or fewer amino acid residues within the cycle, such as 20 or fewer amino acid residues within the cycle (e.g. comprising 20 amino acid residues within the cycle), especially 15 or fewer amino acid residues within the cycle (e.g. comprising 15 amino acid residues within the cycle), in particular 12 or fewer amino acid residues within the cycle (e.g. comprising 12 amino acid residues within the cycle), for example 11 or fewer amino acid residues within the cycle (e.g. comprising 11 amino acid residues within the cycle).

[0395] In some embodiments cyclic peptides comprise 6 or more amino acid residues within the cycle, such as 7 or more amino acid residues within the cycle (e.g. comprising 7 amino acid residues within the cycle), especially 8 or more amino acid residues within the cycle (e.g. comprising 8 amino acid residues within the cycle), in particular 9 or more amino acid residues within the cycle (e.g. comprising 9 amino acid residues within the cycle), for example 10 or more amino acid residues within the cycle (e.g. comprising 10 amino acid residues within the cycle). In certain embodiments cyclic peptides comprise 11 or more amino acid residues within the cycle (e.g. comprising 11 amino acid residues within the cycle).

[0396] In some embodiments linear peptides comprise 25 or fewer amino acid residues within the backbone, such as 20 or fewer amino acid residues within the backbone (e.g. comprising 20 amino acid residues within the backbone), especially 15 or fewer amino acid residues within the backbone (e.g. comprising 15 amino acid residues within the backbone), in particular 12 or fewer amino acid residues within the backbone (e.g. comprising 12 amino acid residues within the backbone) for example 11 or fewer amino acid residues within the backbone (e.g. comprising 11 amino acid residues within the backbone).

[0397] In some embodiments linear peptides comprise 6 or more amino acid residues within the backbone, such as 7 or more amino acid residues within the backbone (e.g. comprising 7 amino acid residues within the backbone), especially 8 or more amino acid residues within the backbone (e.g. comprising 8 amino acid residues within the backbone), in particular 9 or more amino acid residues within the backbone (e.g. comprising 9 amino acid residues within the backbone), for example 10 or more amino acid residues within the backbone (e.g. comprising 10 amino acid residues within the backbone). In certain embodiments linear peptides comprise 11 or more amino acid residues within the backbone (e.g. comprising 11 amino acid residues within the backbone).

[0398] In some embodiments all residues within a cyclic peptide are within the cycle.

[0399] In some embodiments peptides comprise the sequence:

[0400] E - X2- X3- E - H - X4- E (SEQ ID No. 52) position 0 1 2 3 4 5 6 wherein:

[0401] X2represents P, D, Q, K, G

[0402] X3represents I, L, A, T, V

[0403] X4represents E, A or a salt thereof, or comprise a conservatively substituted variant of SEQ ID No. 52 or a salt thereof.

[0404] In some embodiments peptides comprise the sequence:

[0405] E - X2- X3 - E - H - X4 - E (SEQ ID No. 52) position 0 1 2 3 4 5 6 wherein:

[0406] X2represents P, D, Q, K, G

[0407] X3 represents I, L, A, T, V

[0408] X4represents E, A or a salt thereof.

[0409] In some embodiments peptides comprise the sequence:

[0410] X2- X3- E - H - X4 - E - D (SEQ ID No. 53) position 1 2 3 4 5 6 7 wherein:

[0411] X2represents P, D, Q, K, G

[0412] X3 represents I, L, A, T, V

[0413] X4represents E, A or a salt thereof, or comprise a conservatively substituted variant of SEQ ID No. 53 or a salt thereof.

[0414] In some embodiments peptides comprise the sequence:

[0415] X2- X3- E - H - X4 - E - D (SEQ ID No. 53) position 1 2 3 4 5 6 7 wherein:

[0416] X2represents P, D, Q, K, G

[0417] X3 represents I, L, A, T, V

[0418] X4represents E, A or a salt thereof. In some embodiments peptides comprise the sequence:

[0419] T- E- X2- X3- E- H- X4- E (SEQ ID No.54) position -1 0 1 2 3 4 5 6 wherein:

[0420] X2represents P, D, Q, K, G

[0421] X3 represents I, L, A, T, V

[0422] X4represents E, A or a salt thereof, or comprise a conservatively substituted variant of SEQ ID No.54 or a salt thereof.

[0423] In some embodiments peptides comprise the sequence: T- E- X2- X3- E- H- X4- E (SEQ ID No.54) position -1 0 1 2 3 4 5 6 wherein:

[0424] X2represents P, D, Q, K, G

[0425] X3represents I, L, A, T, V

[0426] X4represents E, A or a salt thereof.

[0427] In some embodiments peptides comprise the sequence:

[0428] E- X2- X3- E- H- X4- E- D (SEQ ID No.55) position 0 1 2 3 4 5 6 7 wherein:

[0429] X2represents P, D, Q, K, G

[0430] X3 represents I, L, A, T, V

[0431] X4represents E, A or a salt thereof, or comprise a conservatively substituted variant of SEQ ID No.55 or a salt thereof.

[0432] In some embodiments peptides comprise the sequence: E- X2- X3- E- H- X4- E- D (SEQ ID No.55) position 0 1 2 3 4 5 6 7 wherein:

[0433] X2represents P, D, Q, K, G

[0434] X3 represents I, L, A, T, V

[0435] X4represents E, A or a salt thereof.

[0436] In some embodiments peptides comprise the sequence: X2- X3- E- H- X4- E- D- V (SEQ ID No.56) position 1 2 3 4 5 6 7 8 wherein:

[0437] X2represents P, D, Q, K, G

[0438] X3 represents I, L, A, T, V

[0439] X4represents E, A or a salt thereof, or comprise a conservatively substituted variant of SEQ ID No.56 or a salt thereof.

[0440] In some embodiments peptides comprise the sequence: X2- X3- E- H- X4- E- D- V (SEQ ID No.56) position 1 2 3 4 5 6 7 8 wherein:

[0441] X2represents P, D, Q, K, G

[0442] X3represents I, L, A, T, V

[0443] X4represents E, A or a salt thereof.

[0444] In some embodiments peptides comprise the sequence:

[0445] Xi - T - E X2- X3- E- H- X4- E (SEQ ID No.57) position -2 -1 0 1 2 3 4 5 6 wherein:

[0446] Xi represents M, K

[0447] X2represents P, D, Q, K, G

[0448] X3 represents I, L, A, T, V

[0449] X4represents E, A or a salt thereof, or comprise a conservatively substituted variant of SEQ ID No.57 or a salt thereof.

[0450] In some embodiments peptides comprise the sequence:

[0451] Xi - T - E - X2- X3- E- H - X4- E (SEQ ID No.57) position -2 -1 0 1 2 3 4 5 6 wherein:

[0452] Xi represents M, K

[0453] X2represents P, D, Q, K, G

[0454] X3 represents I, L, A, T, V

[0455] X4represents E, A or a salt thereof.

[0456] In some embodiments peptides comprise the sequence:

[0457] T- E- X2- X3- E- H - X4- E- D (SEQ ID No.58) position -1 0 1 2 3 4 5 6 7 wherein: X2represents P, D, Q, K, G

[0458] X3 represents I, L, A, T, V

[0459] X4represents E, A or a salt thereof, or comprise a conservatively substituted variant of SEQ ID No.58 or a salt thereof.

[0460] In some embodiments peptides comprise the sequence: T- E- X2- X3- E- H- X4- E- D (SEQ ID No.58) position -1 0 1 2 3 4 5 6 7 wherein:

[0461] X2represents P, D, Q, K, G

[0462] X3represents I, L, A, T, V

[0463] X4represents E, A or a salt thereof.

[0464] In some embodiments peptides comprise the sequence:

[0465] E- X2- X3- E- H- X4- E- D - V (SEQ ID No.59) position 0 1 2 3 4 5 6 7 8 wherein:

[0466] X2represents P, D, Q, K, G

[0467] X3 represents I, L, A, T, V

[0468] X4represents E, A or a salt thereof, or comprise a conservatively substituted variant of SEQ ID No.59 or a salt thereof.

[0469] In some embodiments peptides comprise the sequence: E- X2- X3- E- H- X4- E- D- V (SEQ ID No.59) position 0 1 2 3 4 5 6 7 8 wherein:

[0470] X2represents P, D, Q, K, G

[0471] X3 represents I, L, A, T, V

[0472] X4represents E, A or a salt thereof.

[0473] In some embodiments peptides comprise the sequence: (SEQ ID No.60)

[0474] Xi - T - E - X2- X3- E - H - X4- E - D position -2 -1 0 1 2 3 4 5 6 7 wherein:

[0475] Xi represents M, K

[0476] X2represents P, D, Q, K, G X3 represents I, L, A, T, V

[0477] X4 represents E, A or a salt thereof, or comprise a conservatively substituted variant of SEQ ID No.60 or a salt thereof.

[0478] In some embodiments peptides comprise the sequence:

[0479] (SEQ ID No.60)

[0480] Xi - T - E - X2- X3- E - H - X4- E - D position -2 -1 0 1 2 3 4 5 6 7 wherein:

[0481] Xi represents M, K

[0482] X2represents P, D, Q, K, G

[0483] X3represents I, L, A, T, V

[0484] X4 represents E, A or a salt thereof.

[0485] In some embodiments peptides comprise the sequence:

[0486] (SEQ ID No.61)

[0487] T- E- X2- X3- E- H- X4- E- D- V position -1 0 1 2 3 4 5 6 7 8 wherein:

[0488] X2represents P, D, Q, K, G

[0489] X3 represents I, L, A, T, V

[0490] X4 represents E, A or a salt thereof, or comprise a conservatively substituted variant of SEQ ID No.61 or a salt thereof.

[0491] In some embodiments peptides comprise the sequence:

[0492] (SEQ ID No.61)

[0493] T- E- X2- X3- E- H- X4- E- D- V position -1 0 1 2 3 4 5 6 7 8 wherein:

[0494] X2represents P, D, Q, K, G

[0495] X3 represents I, L, A, T, V

[0496] X4 represents E, A or a salt thereof.

[0497] In some embodiments peptides comprise the sequence:

[0498] (SEQ ID No.62)

[0499] Xi - T - E - X2- X3- E - H - X4- E - D - V position -2 -1 0 1 2 3 4 5 6 7 8 wherein:

[0500] Xi represents M, K

[0501] X2represents P, D, Q, K, G

[0502] X3 represents I, L, A, T, V

[0503] X4 represents E, A or a salt thereof, or comprise a conservatively substituted variant of SEQ ID No. 62 or a salt thereof.

[0504] In some embodiments peptides comprise the sequence:

[0505] (SEQ ID No. 62)

[0506] Xi - T - E - X2- X3- E - H - X4- E - D - V position -2 -1 0 1 2 3 4 5 6 7 8 wherein:

[0507] Xi represents M, K

[0508] X2represents P, D, Q, K, G

[0509] X3represents I, L, A, T, V

[0510] X4represents E, A or a salt thereof.

[0511] In some embodiments Xi represents M. In other embodiments Xi represents K.

[0512] In some embodiments X2represents P. In other embodiments X2represents D. In further embodiments X2represents Q. In additional embodiments X2represents K. In certain embodiments X2represents G.

[0513] In some embodiments X3 represents I. In other embodiments X3 represents L. In further embodiments X3 represents A. In additional embodiments X3 represents T. In certain embodiments X3 represents V.

[0514] In some embodiments X4represents E. In further embodiments X4represents A.

[0515] As will be appreciated by the skilled person, certain amino acid residues may be replaced by other amino acid residues without notably impacting function (e.g. stability and / or activity). Such substitutions are generally known as conservative substitutions. Typically, a conservatively substituted variant maintains at least 50%, such as at least 80% and especially at least 90% (e.g. at least 100%) of the relevant functional capability of the non-substituted reference sequence. For example, the functional capability to increase BDNF, PGC1a, TFEB and / or phospho-CREB (Ser133), such as using an assay as described herein (e.g. Example 10). Alternatively, the functional capability may be ti / 2, AUG or Cmax, such as using an assay as described herein (e.g. Example 9), especially ti / 2in brain.

[0516] The functional capability may be the functional capability to increase BDNF, PGC1a, TFEB and / or phospho-CREB (Ser133), such as using an assay as described herein (e.g. Example 10) and also the functional capability may be ti / 2, AUC and / or Cmax, such as using an assay as described herein (e.g. Example 9), especially ti / 2 in brain.

[0517] A conservatively substituted variant may comprise two conservative substitutions. A conservatively substituted variant may comprise two conservative substitutions within the region of the specified sequence (e.g. SEQ ID No: 51 to 62). Alternatively, a conservatively substituted variant may comprise one conservative substitution. A conservatively substituted variant may comprise one conservative substitution within the region of the specified sequence (e.g. SEQ ID No: 51 to 62).

[0518] In some embodiments, peptides do not contain conservative substitutions.

[0519] Specific conservative substitutions may be determined empirically, although commonly suitable replacements are known, for example as shown in Table 1.

[0520] Table 1 - Common conservative substitutions

[0521] Consequently, in some embodiments a variant comprises a substitution of Xi at position -2. Xi may be a replacement for M, such as I, (K), L, R, T, V. Alternatively, Xi may be a replacement for K such as E, (M), N, Q, R, T. Xi may be replaced by E, N, Q, R, T I, L or V.

[0522] In some embodiments a variant comprises a substitution of T at position -1 , such as replacement by A, K, M, N, R or S, especially A, K, M, N or R.

[0523] In some embodiments a variant comprises a substitution of E at position 0, such as replacement by A, D, G, K, Q or V, especially G, K, Q or V. In some embodiments a variant comprises a substitution of X2 at position 1 . X2 may be a replacement for P, such as H, L, (Q), R or S, especially H, L, (Q) or R. Alternatively, X2 may be a replacement for D such as A, E, (G), H, N, V or Y. X2 may be a replacement for Q, such as E, H, (K), L, (P) or R. X2 may be a replacement for K, such as E, M, N, (Q), R, T. X2 may be a replacement for G, such as A, C, (D), E or R. X2 may be replaced by A, C, E, H, L, M, N, R, S, T, V or Y, especially A, E, H, L, M, N, R, T, V or Y.

[0524] In some embodiments a variant comprises a substitution of X3 at position 2. X3 may be a replacement for I, such as F, (L), M, N or (V). Alternatively, X3 may be a replacement for L such as F, H, (I), M, P, Q, R, (V) or W. X3 may be a replacement for A, such as D, E, G, S or T, especially D, E, G or T. X3 may be a replacement for T, such as (A), K, M, N, R or S, especially (A), K, M, N or R. X3 may be a replacement for V, such as D, E, (I), (L) or M. X3 may be replaced by D, E, F, G, H, K, M, N, P, Q, S or W, especially D, E, F, G, H, K, M, N, P, Q or W.

[0525] In some embodiments a variant comprises a substitution of E at position 3, such as replacement by A, D, G, K, Q or V, especially G, K, Q or V.

[0526] In some embodiments a variant comprises a substitution of H at position 4, such as replacement by D, L, N, P, Q, R or Y.

[0527] In some embodiments a variant comprises a substitution of X4 at position 5. X4 may be a replacement for E, such (A), D, G, K, Q or V. Alternatively, X4 may be a replacement for D such as H, N, or Y. X4 may be a replacement for A, such as D, (E), G, S or T, especially D, E, G or T. X4 may be replaced by G, K, Q, S, T or V, especially G, K, Q, T or V.

[0528] In some embodiments a variant comprises a substitution of E at position 6, such as replacement by A, D, G, K, Q or V.

[0529] In some embodiments a variant comprises a substitution of D at position 7, such as replacement by A, E, G, H, N, V or Y.

[0530] In some embodiments a variant comprises a substitution of V at position 8, such as replacement by D, E, I, L or M.

[0531] Suitably the peptide comprises an amino acid sequence selected from any one of SEQ ID No. 1 to 11 , 16 to 42 or 49. Such peptides may be in the form of a pharmaceutically acceptable salt.

[0532] Suitably the peptide consists of any one of CLP1 to CLP11 , LLP1 to LLP12, CP1 to CP15 or CP22 (as described in Tables 2 and 3). Such peptides may be in the form of a pharmaceutically acceptable salt. More suitably, the peptide consists of CLP1 or a pharmaceutically acceptable salt thereof.

[0533] Table 2 - Lipidated peptide overview

[0534]

[0535]

[0536] In CLP1 , the C18DA-YGIU-OEG-OEG- may be C18DA-L-YGIU-OEG-OEG. Alternatively, in CLP1 , the C18DA-YGIU-OEG-OEG- may be C18DA-D-YGIU-OEG-OEG. Alternatively, in CLP1 , the C18DA-YGIU-OEG-OEG- may be a mixture of C18DA-L-YGIU-OEG-OEG and C18DA- D-YGIU-OEG-OEG.

[0537] Table 3 - Non-lipidated peptide overview described in WO2022029281

[0538] Desirably, peptides and their conservatively substituted variants demonstrate improved functional capability, for example, the functional capability ability to increase BDNF, PGC1a, TFEB and / or phospho-CREB (Ser133) and / or ti / 2, AUG or Cmax (especially all of BDNF, PGC1a, TFEB, phospho-CREB (Ser133), t-1 / 2, AUC and Cmax) compared to CPX. Most suitably, peptides and their conservatively substituted variants demonstrate functional capability, for example, the functional capability ability to increase BDNF, PGC1a, TFEB and / or phospho-CREB (Ser133) and / or t-1 / 2, AUG and / or Cmax (especially all of BDNF, PGC1a, TFEB, phospho-CREB (Ser133), ti / 2, AUG and Cmax) compared at least equivalent to CLP1.

[0539] Desirably, peptides of use in the invention demonstrate one or more (such as all) of the following properties:

[0540] - in vitro stability - an absence of fibrillation at pH 6.5 and 7.5, suitably at pH 4.5, pH 6.5 and pH 7.5 (such as by the method of Example 5);

[0541] - in vivo stability - a t-1 / 2 of at least 1 hr, suitably at least 4 hours, especially at least 8 hours (such as by the method of Example 9). t-1 / 2 is desirably determined in the brain.

[0542] Lipidation

[0543] As described above, certain peptides of use in the invention are lipidated. Approaches to lipidation have been reviewed in the literature, including: Ostergaard, 1993; Bech, 2018; van Witteloostuijn, 2016. Kurtzhals, 2023 provides further information on lipidation. Ostergaard, 1993; Bech, 2018; van Witteloostuijn, 2016 and Kurtzhals, 2023 are incorporated herein by reference in their entirety for the purposes of defining lipid groups which may be of use in the present invention.

[0544] Although a number of residues can be used for lipidation, including Cys and Tyr, lipidation is conveniently performed at the side chain of a Lys residue. Lipidation is desirably located towards the N-terminus of the peptide. In the present invention a lipidated Lys residue is suitably positioned at Xi (position -2) or X2 (position 1). Li pidation may involve the replacement of a native amino residue with a residue more amenable to lipidation.

[0545] A linking group is generally used to space the lipid chain from the peptide.

[0546] A linker may comprise a yGlu residue, in particular an L-yGlu. Alternatively, a linker may comprise (i) L-Asp, L-Glu or D-Glu, especially L-Glu or D-Glu (ii) butanoyl-sulfonamide. A linker may comprise a plurality of residues (e.g. 2, 3, or 4), such as a plurality of L-yGlu (e.g. 2, 3, or 4), but may conveniently comprise one residue, such as one yGlu residue (e.g. one L-yGlu).

[0547] A linking group may also contain a spacer, such as OEG units, such as 1 to 4 OEG units, for example 2 OEG units. A linking group may contain b-Ala instead of OEG units.

[0548] Common lipid chains include carboxylic acids, such as C16, C18, C20 acids, and dicarboxylic acids, such as C18DA, C20DA diacids. However, other chain lengths and types may also be used in some cases, such as carboxylic acid isosteres like sulphonic acid or tetrazoles and the like. Suitably the lipid chain is C16DA, C18DA or C20DA, especially, C18DA or C20DA and in particular C18DA.

[0549] Suitably the peptide is lipidated by C18DA-yGlu-OEG-OEG-, such as C18DA-L-yGlu- OEG-OEG or such as C18DA-D-yGlu-OEG-OEG.

[0550] Typically the peptide has a single lipidation.

[0551] The optimal choice of lipidation type and location may depend on the structure of the specific peptide.

[0552] Methods for preparation of peptides

[0553] The peptides of use according to the present invention may be prepared by any methods known in the art. Thus, the peptides of may be prepared by standard peptide-preparation techniques, such as solution synthesis or Merrifield-type solid phase synthesis (as illustrated in Examples 1 and 2).

[0554] In one embodiment, the peptide of use according to the invention is synthetically made or produced. The methods for synthetic production of peptides are well known in the art. Detailed descriptions as well as practical advice for producing synthetic peptides may be found in Synthetic Peptides: A User's Guide (Advances in Molecular Biology), Grant G. A. ed., Oxford University Press, 2002, or in: Pharmaceutical Formulation: Development of Peptides and Proteins, Frokjaer and Hovgaard eds., Taylor and Francis, 1999. In one embodiment, the peptides of use in the invention are produced synthetically, in particular, by the sequence assisted peptide synthesis (SAPS) method, by solution synthesis, by solid-phase peptide synthesis (SPPS) such as Merrifield-type solid phase synthesis.

[0555] After purification of linear peptides, such as by reversed phase HPLC, the linear peptides may be further processed to cyclic peptides. Techniques for cyclizing a peptide and for obtaining a cyclic peptide, for example by using a solid support, are known (as illustrated in Example 2). An appropriate amino acid sequence is one which when cyclised provides the intended cyclic peptide (e.g. CLP1 to CLP11 , CP1 to CP15 or CP22). A side chain cyclised, head to side chain or tail to side chain cyclised peptide requires a linear sequence in normal N- to C-terminal residue order. However, a backbone cyclised peptide, for example consisting of CP1 may be formed from a linear peptide MTEPIEHEEDV, VMTEPI EHEED or the like.

[0556] A linear peptide will typically be joined exclusively by peptide bonds. A cyclised peptide will typically be joined exclusively by peptide bonds. A cyclised peptide may be backbone cyclised.

[0557] Synthetic preparation of a linear peptide may require or benefit from the presence of side chain protecting groups on some or all residues containing side chains which may be reactive, and side chain protecting groups may or may not be removed, or may be removed and reintroduced, depending on the particular sequence, prior to generation of a cyclised peptide, such as a backbone cyclised peptide. If some side chain protection is present during generation of a cyclised peptide, such as a backbone cyclised peptide, this may subsequently be removed to form a deprotected cyclised peptide. In preparation of a non-backbone cyclised peptide, protecting groups may be present at the N- or C- termini as required.

[0558] The linear peptide and / or the cyclised peptide (or protected versions thereof as appropriate) may be in the form of a salt, in particular a pharmaceutically acceptable salt.

[0559] The present invention provides a linear peptide, or a protected version thereof, which when cyclised provides a cyclic peptide as described herein, or a protected version thereof. The present invention provides a linear peptide, or a side chain protected version thereof, which when cyclised provides a cyclic peptide as described herein, or a side chain protected version thereof.

[0560] The present invention provides a lipidated linear peptide, or a protected version thereof, which when cyclised provides a lipidated cyclic peptide as described herein, ora protected version thereof. The present invention provides a lipidated linear peptide, ora side chain protected version thereof, which when cyclised provides a lipidated cyclic peptide as described herein, or a side chain protected version thereof.

[0561] Protected cyclic peptides and protected lipidated cyclic peptides also form part of the invention.

[0562] Amino acid protecting groups are known to the skilled person and are discussed, for example, in Isidro-Llobet et al, Chem Rev 2009 109 2455-2504 and Chandrudu et al, Molecules 2013 18(4):4373-4388. Common side chain protections include: Arg(Pbf), Asn(Trt), Asp(OtBu), Cys(Trt), Gln(Trt), Glu(OtBu), His(Trt), Lys(Boc), Ser(tBu), Thr(tBu) and Tyr(tBu).

[0563] Intermediates of use in the preparation of peptides (i.e the lipidated cyclic, cyclic, lipidated linear or linear and variants of any thereof) include such peptides, or a protected version thereof, covalently bound to a solid support. Covalent binding to a solid support may be direct with or through a spacing group.

[0564] Medical uses

[0565] As demonstrated in the examples herein, the peptides of the present invention can promote clearance of disease-causing aggregates, neuronal survival and improve mitochondrial as well as lysosomal function.

[0566] Suitably peptides (lipidated cyclic, cyclic, lipidated linear or linear and variants of any thereof) of use in the invention or pharmaceutically acceptable salts thereof, are capable of increasing BDNF levels. More suitably, BDNF levels are increased by at least 30% between 0 and 24 hours following administration in the assay of Example 10.

[0567] Suitably peptides (lipidated cyclic, cyclic, lipidated linear or linear and variants of any thereof) of use in the invention or pharmaceutically acceptable salts thereof, are capable of increasing phospho-CREB (Ser133) levels. More suitably, phospho-CREB (Ser133) levels are increased by at least 30% between 0 and 24 hours following administration in the assay of Example 10.

[0568] Suitably peptides (lipidated cyclic, cyclic, lipidated linear or linear and variants of any thereof) of use in the invention or pharmaceutically acceptable salts thereof, are capable of increasing PGC1a levels. More suitably, PGC1a levels are increased by at least 30% between 0 and 24 hours following administration in the assay of Example 10.

[0569] Suitably peptides (lipidated cyclic, cyclic, lipidated linear or linear and variants of any thereof) of use in the invention or pharmaceutically acceptable salts thereof, are capable of increasing TFEB levels. More suitably, TFEB levels are increased by at least 30% between 0 and 24 hours following administration in the assay of Example 10.

[0570] Suitably peptides (lipidated cyclic, cyclic, lipidated linear or linear and variants of any thereof) of use in the invention or pharmaceutically acceptable salts thereof, are capable of decreasing NfL levels. More suitably, NfL levels are decreased by at least 10%, especially at least 20%, in the assay of Example 31 .

[0571] Particularly, it has been demonstrated that the peptides of the present invention can mimic the neurotrophic effects elicited by the intracellular domain of SorCS2. Loss of SorCS2 has been identified as the causative factor for hearing loss in a spontaneous deaf mouse line, illustrating that SorCS2 might be critical for maintenance of cochlear morphology and function. More importantly, the neurotrophic effects of the peptides of the present invention are expected to translate to the IHC-SGN in hearing loss system and thus be able to restore synaptic connections, dendritic morphology and cell numbers to restore cochlear function after a trauma causing hearing loss. This is further supported by the clear beneficial effects of the peptides of the present invention on mitochondrial function, a key part of IHC-SGN pathology in hearing loss (Wong, 2019). This data supports the hypothesis that modulation of the SorCS2 pathway could have a therapeutic benefit in patients suffering from diseases or disorders of the ear or mastoid process.

[0572] The disease or disorder of the ear or mastoid process is desirably a disease or disorder of the ear or mastoid process which is susceptible to treatment or prophylaxis according to the invention. The disease or disorder of the ear or mastoid process is desirably a disease or disorder of the ear or mastoid process which is susceptible to modulation of SorCS2 pathways.

[0573] Diseases and disorders of the ear or mastoid process may be classified as set out in the 11threvision of the International Statistical Classification of Diseases and Related Health Problems (ICD), which is incorporated by reference herein for the purpose of defining particular diseases and disorders of the ear or mastoid process.

[0574] In one embodiment, the disease or disorder of the ear or mastoid process is a disease of the inner ear.

[0575] In one embodiment, the disease or disorder of the inner ear is an acute, episodic or chronic vestibular syndrome. Vestibular syndromes are characterised by vertigo, dizziness, or unsteadiness. Examples of such vestibular syndromes include vestibular neuritis, labyrinthitis, Meniere disease, vestibular migraine, benign positional paroxysmal vertigo, superior canal dehiscence syndrome, disembarkment syndrome, autoimmune inner ear disease, vestibular paroxysmia and persistent postural-perceptual dizziness. In one embodiment, the disease or disorder of the inner ear is Meniere disease. In one embodiment, the disease or disorder of the inner ear is a vertiginous syndrome.

[0576] In one embodiment, the disease or disorder of the ear or mastoid process is a disorder with hearing loss or impairment.

[0577] In one embodiment, the hearing loss is sensorineural hearing loss, wherein the cause of the hearing loss lies in the vestibulocochlear nerve, the inner ear, or central processing centers of the brain.

[0578] In one embodiment, the hearing loss is acquired, for example as a consequence of noise, disease, trauma, or as a side-effect of a medicine (ototoxic hearing loss). In an alternative embodiment, the hearing loss is congenital hearing loss, present at birth.

[0579] In one embodiment, the hearing loss is genetic hearing loss. Genetic hearing loss may be categorised as syndromic or non-syndromic. Examples of syndromes related to syndromic hearing loss include, but are not limited to Stickler Syndrome, Waardenburg Syndrome, Branchio- Oto-Renal Syndrome, CHARGE Syndrome, Treacher-Collins Syndrome, Usher Syndrome, Pendred Syndrome, Jervell and Lange-Nielsen Syndrome, Alport Syndrome, and X-Linked Congenital Stapes Fixation with Perilymph Gusher. Examples of genes related to non-syndromic hearing loss include, but are not limited to, GJB2, GJB6, STRC, KCNQ4, TECTA, and POU3F4, and changes in mitochondrial DNA (mtDNA). In one embodiment, the genetic hearing loss is a result of a mitochondrial condition. Mitochondrial conditions related to hearing loss include Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS), Maternally Inherited Diabetes and Deafness (MIDD), Kearns-Sayre Syndrome (KSS), and Myoclonic Epilepsy and Ragged Red Fibers (MERRF).

[0580] In one embodiment, the hearing loss is auditory synaptopathy or neuropathy, wherein the subject has normal outer hair cell function but lacking is synchrony of neural transmission of auditory information due to damage of the inner hair cells or their synapses or of the spiral ganglion cells or of the auditory nerve.

[0581] In one embodiment, the hearing loss is hidden hearing loss, wherein the hearing loss is not detectable by standard audiometry tests of auditory thresholds.

[0582] In one embodiment the disease or disorder of the ear or mastoid process is cochlear synaptopathy. In some embodiments cochlear synaptopathy may be associated with age, sensorineural hearing loss, noise-induced hearing loss. In some embodiments cochlear synaptopathy may be associated with inflammatory or neurodegenerative disorders, including Huntingdon’s Disease Parkinson’s Disease or Alzheimer’s Disease.

[0583] In one embodiment the disease or disorder of the ear or mastoid process is age-related hearing loss.

[0584] The impact of administration of peptides of the invention on vestibular function may be measured for example using balance tests such as Romberg's test and Unterberger's test or Video-Nystagmography. Quality of life tests may also be used to measure improvement in the number of days affected by vertigo symptoms.

[0585] The impact of administration of peptides of the invention on hearing loss may be quantified in various ways. For example, improvement in hearing may be measured using Pure Tone Audiometry (PTA), Auditory Brainstem Response (ABR; also known as auditory evoked potential (AEP)) and / or Otoacoustic emissions (OAEs). Improvement in hearing may also be measured using Speech detection threshold (SDT), Speech recognition threshold (SRT), Word recognition score (WR), the Hearing in Noise test (HINT), American English Matrix test (AEMT), Digits in Noise test (DIN), Words in Noise test (WIN), Speech Recognition in Noise test (SPRINT) or similar tests.

[0586] The impact of administration of peptides of the invention is suitably quantified by a speech in noise (SIN) test, which may be improved relative to untreated subjects. In particular, impact of administration of peptides of the invention may be quantified by words in noise (WIN) test, which may be improved relative to untreated subjects.

[0587] Absolute OAE amplitude may be increased relative to untreated subjects. The number of cochlear ribbon synapses, spiral ganglion neuron fibres and / or cells, inner hair cells and / or outer hair cells may be increased, particularly in the high-frequency regions of the cochlea.

[0588] In some embodiments the peptide is for prophylactic use. For example, treatment with the peptides for use of the invention may be given before a course of treatment with an ototoxic drug to prevent or reduce ototoxicity.

[0589] In other embodiments the peptide is for use in treatment, such as treatment of hearing loss.

[0590] The term "treatment" or "treating" as used herein includes the control, mitigation, reduction, or modulation of the disease or disorder or its symptoms.

[0591] The term "prophylaxis" is used herein to mean preventing symptoms of a disease or disorder in a subject or preventing recurrence of symptoms of a disease or disorder in an afflicted subject and is not limited to complete prevention of an affliction.

[0592] Suitably the subject is a human.

[0593] The human subject may be an infant, such as less than 2 years of age. Alternatively, the subject may be less than 18 years of age, such as 2 to 17 years old. The human subject may be an adult, such as aged 18 to 65. Alternatively, a human subject may be 66 years old or older.

[0594] The subject may be male. Alternatively, the subject is female.

[0595] A "treatment effect" or "therapeutic effect" is manifested if there is a change in the condition being treated, as measured by the criteria constituting the definition of the terms "treating" and "treatment." There is a "change" in the condition being treated if there is at least 5% improvement, preferably 10% improvement, more preferably at least 25%, even more preferably at least 50%, such as at least 75%, and most preferably at least 100% improvement in one of more parameters. The change can be based on improvement(s) in the severity of the treated condition in an individual, or on a difference in the frequency of improved conditions in populations of individuals with and without treatment with lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, variant of any thereof and / or a pharmaceutically acceptable salt of any thereof.

[0596] Suitably the lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, variant of any thereof and / or a pharmaceutically acceptable salt of any thereof, is administered to a subject in need thereof. Suitably the peptide of the invention, or a pharmaceutically acceptable salt thereof, is administered in a safe and effective amount i.e. an amount providing an acceptable balance of desired benefits and undesired side effects. A “safe and effective amount" is intended to include an amount that is effective to achieve a desirable effect in therapy and / or prophylaxis. A desirable effect is typically clinically significant and / or measurable, for instance in the context of (a) preventing a condition, disease or disorder occurring, in particular, when a subject is predisposed or at risk but has not yet been diagnosed; (b) inhibiting a condition, disease or disorder, i.e., slowing or arresting its development; and / or (c) relieving a condition, disease or disorder, i.e., causing regression of the condition, disease or disorder or a reduction in associated symptoms. The safe and effective amount may be one that is sufficient to achieve the desirable effect either when the peptide of the invention, or a pharmaceutically acceptable salt thereof, is administered alone or alternatively when it is administered in combination with one or more further active pharmaceutical ingredients, which either are further peptides of the invention, or a pharmaceutically acceptable salts thereof, or are different from the peptides of the invention.

[0597] In one embodiment of the present invention, the lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, variant of any thereof and / or a pharmaceutically acceptable salt of any thereof is administered in doses of from 1 pg / day to 200 mg / day.

[0598] In one embodiment of the present invention, one single dose of peptide is administered and may comprise of from 1 pg / kg body weight to 100 mg / kg body weight, such as 1 pg / kg body weight to 10 mg / kg body weight. A preferred dose is about 0.1 mg / kg to about 10 mg / kg and an especially preferred dose is about 0.1 mg / kg to about 5 mg / kg. A dose according to the present invention may be administered one or several times per day. A dose may also be administered in intermittent intervals, or intervals, whereby a dose is not administered every day. Rather one or more doses may be administered every second day, every third day, every fourth day, every fifth day, every sixth day, every week, every second week, every third week, every fourth week, every fifth week, every sixth week, or intervals within those ranges (such as every 2 to 4 weeks, or 4 to 6 weeks).

[0599] It will be appreciated that the preferred route of administration will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated, the location of the tissue to be treated in the body and the peptide of the invention chosen.

[0600] In one embodiment of the present invention, the route of administration allows for the lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, variant of any thereof and / or a pharmaceutically acceptable salt of any thereof to cross the blood-brain barrier.

[0601] For systemic treatment according to the present invention the route of administration is capable of introducing the lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, variant of any thereof and / or a pharmaceutically acceptable salt of any thereof into the blood stream to ultimately target the sites of desired action. Such routes of administration are any suitable routes, such as a parenteral route (including subcutaneous, intramuscular, intrathecal, intracerebral, intravenous and intradermal administration). Parenteral administration is any administration route not being the oral / enteral route whereby the medicament avoids first-pass degradation in the liver. Accordingly, parenteral administration includes any injections and infusions, for example bolus injection or continuous infusion, such as intravenous administration, intramuscular administration or subcutaneous administration. In one embodiment administration is subcutaneously, such as by injection. In one embodiment administration is intramuscularly, such as by injection. In one embodiment administration is administered intradermally, such as by injection. In one embodiment administration is intravenously, such as by injection.

[0602] Pharmaceutical compositions

[0603] Whilst it is possible for the lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, variant of any thereof and / or a pharmaceutically acceptable salt of any thereof of the present invention to be administered as the ‘raw’ peptide, it is desirable to present them in the form of a pharmaceutical composition. Accordingly, the present invention further provides a pharmaceutical formulation, which comprises a lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, variant of any thereof and / or a pharmaceutically acceptable salt of any thereof of the present invention, and a pharmaceutically acceptable carrier. The pharmaceutical compositions may be prepared by conventional techniques, e.g. as described in Remington: The Science and Practice of Pharmacy 2005, Lippincott, Williams & Wilkins.

[0604] Pharmaceutically acceptable carriers include water. For better stability, pharmaceutical compositions may be dry and extemporaneously reconstituted with water (or e.g. saline).

[0605] A pharmaceutically acceptable composition for parenteral administration should have a physiologically acceptable pH and should have a physiologically acceptable osmolality.

[0606] The pH of an aqueous composition may be adjusted in view of the components of the composition and necessary suitability for administration. The pH is generally at least 4, especially at least 5, in particular at least 5.5 such as at least 6. The pH is generally 9 or less, especially 8.5 or less, in particular 8 or less, such as 7.5 or less. The pH of may be 4 to 9, especially 5 to 8.5, in particular 5.5 to 8, such as 6.5 to 7.4 (e.g. 6.5 to 7.1).

[0607] For parenteral administration a physiologically acceptable osmolality is desirable to avoid excessive cell distortion or lysis. A physiologically acceptable osmolality will generally mean that solutions will have an osmolality which is approximately isotonic or mildly hypertonic. Suitably compositions for administration will have an osmolality of 250 to 750 mOsm / kg, especially 250 to 550 mOsm / kg, in particular 270 to 500 mOsm / kg, such as 270 to 400 mOsm / kg.

[0608] Other components, such as buffers or stabilizing agents, may also be present.

[0609] The phrase "pharmaceutically acceptable" is used herein to refer to those materials, compositions, dosage forms and the like which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals, for example human beings, without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0610] It will be appreciated that for use in medicine the salts of the peptides should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include those Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p.1418. Such pharmaceutically acceptable salts include acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid and organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid. Pharmaceutically acceptable salts may also be formed with organic bases such as basic amines e.g. with ammonia, meglumine, tromethamine, piperazine, arginine, choline, diethylamine, benzathine or lysine. Salts which are not considered to be pharmaceutically acceptable may still be of use, for example in the preparation of peptides and there pharmaceutically acceptable salts.

[0611] Certain of peptides may form salts with one or more equivalents of acid or base. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.

[0612] When the peptides contain a basic group as well as the free acid they may be zwitterionic. Pharmaceutical compositions of the present invention may be co-administered with one or more other therapeutic agents. Combined administration of two or more agents may be achieved in a number of different ways. Both may be administered together in a single composition, or they may be administered in separate compositions as part of a combined therapy. For example, one may be administered before or separately, after or sequentially, or concurrently or simultaneously with the other.

[0613] The invention is further illustrated by reference to the following clauses:

[0614] Clauses of the Invention

[0615] The invention is further illustrated by reference to the following clauses:

[0616] Clause 1 . A method for the treatment or prophylaxis of a disease or disorder of the ear or mastoid process in a subject, the method comprising the administration of a peptide or a pharmaceutically acceptable salt thereof, wherein the peptide is:

[0617] (i) a lipidated cyclic peptide comprising the sequence:

[0618] X2- X3- E - H - X4- E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0619] X2represents P, D, Q, K, G X3represents I, L, A, T, V X4represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 ;

[0620] (ii) a cyclic peptide comprising the sequence:

[0621] X2- X3- E - H - X4- E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein: X2 represents P, D, Q, K, G

[0622] X3 represents I, L, A, T, V

[0623] X4 represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 , wherein when X2 represents P then X3 is other than V;

[0624] (iii) a cyclic peptide comprising 10 or fewer amino acid residues within the cycle and comprising the sequence:

[0625] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0626] X2 represents P, D, Q, K, G

[0627] X3 represents I, L, A, T, V

[0628] X4 represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 ;

[0629] (iv) a lipidated linear peptide comprising the sequence:

[0630] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0631] X2 represents P, D, Q, K, G

[0632] X3 represents I, L, A, T, V

[0633] X4 represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 ;

[0634] (v) a linear peptide comprising the sequence:

[0635] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0636] X2 represents P, D, Q, K, G

[0637] X3 represents I, L, A, T, V

[0638] X4 represents E, A or comprising a conservatively substituted variant of said peptide, wherein when X2 represents P then X3 is other than V; or

[0639] (vi) a linear peptide comprising 10 or fewer amino acid residues within the backbone and comprising the sequence:

[0640] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0641] X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51.

[0642] Clause 2. A peptide or a pharmaceutically acceptable salt thereof for use in the treatment or prophylaxis of a disease or disorder of the ear or mastoid process, wherein the peptide is:

[0643] (i) a lipidated cyclic peptide comprising the sequence:

[0644] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0645] X2represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 ;

[0646] (ii) a cyclic peptide comprising the sequence:

[0647] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0648] X2represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 , wherein when X2represents P then X3 is other than V;

[0649] (iii) a cyclic peptide comprising 10 or fewer amino acid residues within the cycle and comprising the sequence:

[0650] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0651] X2represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 ;

[0652] (iv) a lipidated linear peptide comprising the sequence:

[0653] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0654] X2represents P, D, Q, K, G

[0655] A3 represents I, L, A, T, V X4represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 ;

[0656] (v) a linear peptide comprising the sequence:

[0657] X2- X3- E - H - X4- E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0658] X2represents P, D, Q, K, G

[0659] X3represents I, L, A, T, V X4represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 , wherein when X2represents P then X3 is other than V; or

[0660] (vi) a linear peptide comprising 10 or fewer amino acid residues within the backbone and comprising the sequence:

[0661] X2- X3- E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0662] X2represents P, D, Q, K, G

[0663] X3 represents I, L, A, T, V X4represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51. Clause 3. A pharmaceutical composition for the treatment or prophylaxis of a disease or disorder of the ear or mastoid process, said pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof, wherein the peptide is:

[0664] (i) a lipidated cyclic peptide comprising the sequence:

[0665] X2- X3- E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0666] X2represents P, D, Q, K, G

[0667] X3 represents I, L, A, T, V X4represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 ;

[0668] (ii) a cyclic peptide comprising the sequence:

[0669] X2- X3- E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0670] X2represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 , wherein when X2represents P then X3 is other than V;

[0671] (iii) a cyclic peptide comprising 10 or fewer amino acid residues within the cycle and comprising the sequence:

[0672] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0673] X2represents P, D, Q, K, G

[0674] X3 represents I, L, A, T, V

[0675] X4 represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 ;

[0676] (iv) a lipidated linear peptide comprising the sequence:

[0677] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0678] X2represents P, D, Q, K, G

[0679] X3 represents I, L, A, T, V

[0680] X4 represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 ;

[0681] (v) a linear peptide comprising the sequence:

[0682] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0683] X2represents P, D, Q, K, G

[0684] X3 represents I, L, A, T, V

[0685] X4 represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 , wherein when X2represents P then X3 is other than V; or

[0686] (vi) a linear peptide comprising 10 or fewer amino acid residues within the backbone and comprising the sequence:

[0687] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0688] X2represents P, D, Q, K, G

[0689] X3 represents I, L, A, T, V

[0690] X4 represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51.

[0691] Clause 4. Use of a peptide or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis of a disease or disorder of the ear or mastoid process, wherein the peptide is:

[0692] (i) a lipidated cyclic peptide comprising the sequence:

[0693] X2- X3- E - H - X4- E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0694] X2represents P, D, Q, K, G

[0695] X3represents I, L, A, T, V

[0696] X4represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 ;

[0697] (ii) a cyclic peptide comprising the sequence:

[0698] X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0699] X2represents P, D, Q, K, G

[0700] X3 represents I, L, A, T, V

[0701] X4represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 , wherein when X2represents P then X3 is other than V;

[0702] (iii) a cyclic peptide comprising 10 or fewer amino acid residues within the cycle and comprising the sequence:

[0703] X2- X3- E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0704] X2represents P, D, Q, K, G

[0705] X3 represents I, L, A, T, V

[0706] X4represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 ;

[0707] (iv) a lipidated linear peptide comprising the sequence:

[0708] X2- X3- E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0709] X2represents P, D, Q, K, G

[0710] X3 represents I, L, A, T, V

[0711] X4represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 ;

[0712] (v) a linear peptide comprising the sequence:

[0713] X2- X3- E - H - X4- E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0714] X2represents P, D, Q, K, G X3represents I, L, A, T, V X4represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 , wherein when X2represents P then X3 is other than V; or

[0715] (vi) a linear peptide comprising 10 or fewer amino acid residues within the backbone and comprising the sequence:

[0716] X2- X3- E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0717] X2represents P, D, Q, K, G

[0718] X3 represents I, L, A, T, V

[0719] X4represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51.

[0720] Clause A1. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses 1 to 4, wherein the peptide is a lipidated cyclic peptide comprising the sequence:

[0721] X2- X3- E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0722] X2represents P, D, Q, K, G

[0723] X3 represents I, L, A, T, V

[0724] X4represents E, A or a salt thereof, or comprising a conservatively substituted variant of SEQ ID No. 51 or a salt thereof.

[0725] Clause A2. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause A1, wherein the peptide is backbone cyclised.

[0726] Clause A3. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause A2, wherein the peptide is backbone cyclised and all residues of the peptide backbone are joined exclusively by peptide bonds. Clause A4. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A1 to A3, wherein the lipidated cyclic peptide, variant or salt comprises 25 or fewer amino acid residues within the cycle.

[0727] Clause A5. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause A4, wherein the lipidated cyclic peptide, variant or salt comprises 20 or fewer amino acid residues within the cycle, such as comprising 20 amino acid residues within the cycle.

[0728] Clause A6. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause A5, wherein the lipidated cyclic peptide, variant or salt comprises 15 or fewer amino acid residues within the cycle, such as comprising 15 amino acid residues within the cycle,

[0729] Clause A7. method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause A6, wherein the lipidated cyclic peptide, variant or salt comprises 12 or fewer amino acid residues within the cycle, such as comprising 12 amino acid residues within the cycle.

[0730] Clause A8. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause A7, wherein the lipidated cyclic peptide, variant or salt comprises 11 or fewer amino acid residues within the cycle.

[0731] Clause A9. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A1 to A8, wherein the lipidated cyclic peptide, variant or salt comprises at least 7 amino acid residues within the cycle, such as comprising 7 amino acid residues within the cycle.

[0732] Clause A10. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause A9, wherein the lipidated cyclic peptide, variant or salt comprises at least 8 amino acid residues within the cycle, such as comprising 8 amino acid residues within the cycle.

[0733] Clause A11. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause A10, wherein the lipidated cyclic peptide, variant or salt comprises at least 9 amino acid residues within the cycle, such as comprising 9 amino acid residues within the cycle.

[0734] Clause A12. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause A11, wherein the lipidated cyclic peptide, variant or salt comprises at least 10 amino acid residues within the cycle, such as comprising 10 amino acid residues within the cycle. Clause A13. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause A12, wherein the lipidated cyclic peptide, variant or salt comprises at least 11 amino acid residues within the cycle.

[0735] Clause A14. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause A1, wherein the lipidated cyclic peptide, variant or salt comprises 11 amino acid residues within the cycle.

[0736] Clause A15. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A9 to A14, wherein the lipidated cyclic peptide, variant or salt comprises the sequence:

[0737] E - X2- X3- E - H - X4- E position 0 1 2 3 4 5 6 (SEQ ID No.

[0738] 52) wherein:

[0739] X2represents P, D, Q, K, G

[0740] X3represents I, L, A, T, V

[0741] X4represents E, A or a salt thereof, or comprising a conservatively substituted variant of SEQ ID No.

[0742] 52 or a salt thereof.

[0743] Clause A16. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A9 to A14, wherein the lipidated cyclic peptide, variant or salt comprises the sequence:

[0744] X2- X3 - E - H - X4 - E - D position 1 2 3 4 5 6 7 (SEQ ID No.

[0745] 53) wherein:

[0746] X2represents P, D, Q, K, G

[0747] X3 represents I, L, A, T, V

[0748] X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[0749] 53 or a salt thereof.

[0750] Clause A17. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A10 to A14, wherein the lipidated cyclic peptide, variant or salt comprises the sequence:

[0751] T- E- X2- X3- E- H- X4- E position -1 0 1 2 3 4 5 6 (SEQ

[0752] ID No.54) wherein:

[0753] X2represents P, D, Q, K, G X3represents I, L, A, T, V X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[0754] 54 or a salt thereof.

[0755] Clause A18. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A10 to A14, wherein the lipidated cyclic peptide, variant or salt comprises the sequence:

[0756] E- X2- X3- E- H- X4- E- D position 0 1 2 3 4 5 6 7 (SEQ ID No.55) wherein:

[0757] X2represents P, D, Q, K, G

[0758] X3 represents I, L, A, T, V

[0759] X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[0760] 55 or a salt thereof.

[0761] Clause A19. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A10 to A14, wherein the lipidated cyclic peptide, variant or salt comprises the sequence:

[0762] X2- X3- E- H- X4- E- D- V position 1 2 3 4 5 6 7 8 (SEQ ID No.56) wherein:

[0763] X2represents P, D, Q, K, G

[0764] X3 represents I, L, A, T, V

[0765] X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[0766] 56 or a salt thereof. Clause A20. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A11 to A14, wherein the lipidated cyclic peptide, variant or salt comprises the sequence:

[0767] Xi - T - E - X2- X3- E - H - X4- E position -2 -1 0 1 2 3 4 5 6

[0768] (SEQ ID No.57) wherein:

[0769] Xi represents M, K

[0770] X2represents P, D, Q, K, G

[0771] X3 represents I, L, A, T, V

[0772] X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No. 57 or a salt thereof.

[0773] Clause A21. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A11 to A14, wherein the lipidated cyclic peptide, variant or salt comprises the sequence:

[0774] T- E- X2- X3- E- H- X4- E- D position -1 0 1 2 3 4 5 6 7

[0775] (SEQ ID No.58) wherein:

[0776] X2represents P, D, Q, K, G X3represents I, L, A, T, V X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No. 58 or a salt thereof.

[0777] Clause A22. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A11 to A14, wherein the lipidated cyclic peptide, variant or salt comprises the sequence:

[0778] E- X2- X3- E- H- X4- E- D- V position 0 1 2 3 4 5 6 7 8 (SEQ ID No.59) wherein:

[0779] X2represents P, D, Q, K, G X3 represents I, L, A, T, V X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[0780] 59 or a salt thereof.

[0781] Clause A23. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A12 to A14, wherein the lipidated cyclic peptide, variant or salt comprises the sequence:

[0782] Xi - T - E - X2- X3- E - H - X4- E - D position -2 -1 0 1 2 3 4 5 6 7

[0783] (SEQ ID No. 60) wherein:

[0784] Xi represents M, K

[0785] X2represents P, D, Q, K, G X3represents I, L, A, T, V X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[0786] 60 or a salt thereof.

[0787] Clause A24. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A12 to A14, wherein the lipidated cyclic peptide, variant or salt comprises the sequence:

[0788] T - E - X2- X3 - E - H - X4 - E - D - V position -1 0 1 2 3 4 5 6 7 8

[0789] (SEQ ID No. 61) wherein:

[0790] X2represents P, D, Q, K, G X3 represents I, L, A, T, V X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[0791] 61 or a salt thereof.

[0792] Clause A25. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A13 to A14, wherein the lipidated cyclic peptide, variant or salt comprises the sequence: Xi - T - E - X2- X3- E - H - X4- E - D - V position -2 -1 0 1 2 3 4 5 6 7 8

[0793] (SEQ ID No. 62) wherein:

[0794] Xi represents M, K

[0795] X2 represents P, D, Q, K, G

[0796] X3 represents I, L, A, T, V

[0797] X4 represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No. 62 or a salt thereof.

[0798] Clause A26. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A1 to A25, wherein Xi represents M.

[0799] Clause A27. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A1 to A25, wherein Xi represents K.

[0800] Clause A28. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A1 to A27, wherein X2 represents P.

[0801] Clause A29. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A1 to A27, wherein X2 represents D.

[0802] Clause A30. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A1 to A27, wherein X2 represents Q.

[0803] Clause A31. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A1 to A27, wherein X2 represents K.

[0804] Clause A32. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A1 to A27, wherein X2 represents G.

[0805] Clause A33. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A1 to A32, wherein X3 represents I.

[0806] Clause A34. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A1 to A32, wherein X3 represents L.

[0807] Clause A35. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A1 to A32, wherein X3 represents A. Clause A36. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A1 to A32, wherein X3 represents T.

[0808] Clause A37. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A1 to A32, wherein X3 represents V.

[0809] Clause A38. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A1 to A37, wherein X4 represents E.

[0810] Clause A39. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A1 to A37, wherein X4 represents A.

[0811] Clause A40. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A13 to A14, wherein the lipidated cyclic peptide, variant or salt comprises the sequence of any one of SEQ ID No. 1 to 11 or a salt thereof, or comprises a conservatively substituted variant of any one of SEQ ID No. 1 to 11 or a salt thereof, such as consisting of the sequence of any one of SEQ ID No. 1 to 11 or a salt thereof, or a consisting of a conservatively substituted variant of any one of SEQ ID No. 1 to 11 or a salt thereof.

[0812] Clause A41. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A13 to A14, wherein the lipidated cyclic peptide, variant or salt comprises the sequence of SEQ ID No. 1 or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No. 1 or a salt thereof, such as consisting of the sequence of SEQ ID No. 1 or a salt thereof, or consisting of a conservatively substituted variant of SEQ ID No. 1 or a salt thereof.

[0813] Clause A42. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A1 to A41, wherein the variant or salt thereof comprises two conservative substitutions.

[0814] Clause A43. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A1 to A42, wherein the variant or salt thereof comprises a substitution of Xi at position -2, such as replacement by E, N, Q, R, T I, L or V.

[0815] Clause A44. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A1 to A42, wherein the variant or salt thereof comprises a substitution of T at position -1 , such as replacement by A, K, M, N, R or S, especially A, K, M, N or R.

[0816] Clause A45. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A1 to A42, wherein the variant or salt thereof comprises a substitution of E at position 0, such as replacement by A, D, G, K, Q or V, especially G, K, Q or V.

[0817] Clause A46. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A1 to A42, wherein the variant or salt thereof comprises a substitution of X2 at position 1 , such as replacement by A, C, E, H, L, M, N, R, S, T, V or Y, especially A, E, H, L, M, N, R, T, V or Y.

[0818] Clause A47. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A1 to A42, wherein the variant or salt thereof comprises a substitution of X3 at position 2, such as replacement by D, E, F, G, H, K, M, N, P, Q, S or W, especially D, E, F, G, H, K, M, N, P, Q or W.

[0819] Clause A48. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A1 to A42, wherein the variant or salt thereof comprises a substitution of E at position 3, such as replacement by A, D, G, K, Q or V, especially G, K, Q or V.

[0820] Clause A49. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A1 to A42, wherein the variant or salt thereof comprises a substitution of H at position 4, such as replacement by D, L, N, P, Q, R or Y.

[0821] Clause A50. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A1 to A42, wherein the variant or salt thereof comprises a substitution of X4 at position 5, such as replacement by G, K, Q, S, T or V, especially G, K, Q, T or V.

[0822] Clause A51. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A1 to A42, wherein the variant or salt thereof comprises a substitution of E at position 6, such as replacement by A, D, G, K, Q or V.

[0823] Clause A52. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A1 to A42, wherein the variant or salt thereof comprises a substitution of D at position 7, such as replacement by A, E, G, H, N, V or Y. Clause A53. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A1 to A42, wherein the variant or salt thereof comprises a substitution of V at position 8 such as replacement by D, E, I, L or M.

[0824] Clause A54. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A42 to A53, wherein the variant or salt thereof comprises a substitution of Xi at position -2, such as replacement by E, N, Q, R, T I, L or V.

[0825] Clause A55. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A42 to A53, wherein the variant or salt thereof comprises a substitution of T at position -1 , such as replacement by A, K, M, N, R or S, especially A, K, M, N or R.

[0826] Clause A56. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A42 to A53, wherein the variant or salt thereof comprises a substitution of E at position 0, such as replacement by A, D, G, K, Q or V, especially G, K, Q or V.

[0827] Clause A57. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A42 to A53, wherein the variant or salt thereof comprises a substitution of X2 at position 1 , such as replacement by A, C, E, H, L, M, N, R, S, T, V or Y, especially A, E, H, L, M, N, R, T, V or Y.

[0828] Clause A58. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A42 to A53, wherein the variant or salt thereof comprises a substitution of X3 at position 2, such as replacement by D, E, F, G, H, K, M, N, P, Q, S or W, especially D, E, F, G, H, K, M, N, P, Q or W.

[0829] Clause A59. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A42 to A53, wherein the variant or salt thereof comprises a substitution of E at position 3, such as replacement by A, D, G, K, Q or V, especially G, K, Q or V.

[0830] Clause A60. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A42 to A53, wherein the variant or salt thereof comprises a substitution of H at position 4, such as replacement by D, L, N, P, Q, R or Y.

[0831] Clause A61. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A42 to A53, wherein the variant or salt thereof comprises a substitution of X4 at position 5, such as replacement by G, K, Q, S, T or V, especially G, K, Q, T or V.

[0832] Clause A62. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A42 to A53, wherein the variant or salt thereof comprises a substitution of E at position 6, such as replacement by A, D, G, K, Q or V.

[0833] Clause A63. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A42 to A53, wherein the variant or salt thereof comprises a substitution of D at position 7, such as replacement by A, E, G, H, N, V or Y.

[0834] Clause A64. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A42 to A53, wherein the variant or salt thereof comprises a substitution of V at position 8 such as replacement by D, E, I, L or M.

[0835] Clause A65. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A43 to A53, wherein the variant or salt thereof comprises one conservative substitution.

[0836] Clause A66. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A1 to A41 , wherein the peptide is a lipidated cyclic peptide or salt thereof.

[0837] Clause A67. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A1 to A66, wherein the lipidated cyclic peptide, variant or salt comprises a lipidated K residue.

[0838] Clause A68. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause A67, wherein the lipidated K residue is X2 position 1.

[0839] Clause A69. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause A67, wherein the lipidated K residue is Xi position -2.

[0840] Clause A70. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A1 to A69, wherein the lipid chain is a C16DA, C18DA or C20DA group.

[0841] Clause A71. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause A70, wherein the lipid chain is a C18DA group. Clause A72. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A1 to A71 , wherein the lipid is linked to the K residue via a yGlu.

[0842] Clause A73. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause A72, wherein the lipid is linked to the K residue via a yGlu and one to four OEG groups.

[0843] Clause A74. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause A73, wherein the lipid is linked to the K residue via a yGlu and two OEG groups.

[0844] Clause A75. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A1 to A69, wherein the lipid is C18DA-yGlu-OEG-OEG-.

[0845] Clause A76. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A1 to A69, wherein the lipid is C18DA-yGlu-OEG-OEG-.

[0846] Clause A77. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause A75 or A76, wherein the lipid is C18DA-L-yGlu-OEG-OEG-.

[0847] Clause A78. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause A75 or A76, wherein the lipid is C18DA-D-yGlu-OEG-OEG-.

[0848] Clause A79. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause A1 consisting of CLP1 or a salt thereof.

[0849] Clause A80. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause A1 consisting of CLP1, wherein the lipid is C18DA-L-yGlu-OEG-OEG-, or a salt thereof.

[0850] Clause A81. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause A1 consisting of CLP1, wherein the lipid is C18DA-D-yGlu-OEG-OEG-, or a salt thereof.

[0851] Clause A82. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause A1 consisting of CLP2 or a salt thereof.

[0852] Clause A83. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause A1, wherein the lipidated cyclic peptide or sale thereof consists of CLP3 or a salt thereof. Clause A84. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause A1, wherein the lipidated cyclic peptide or sale thereof consists of CLP4 or a salt thereof.

[0853] Clause A85. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause A1, , wherein the lipidated cyclic peptide or sale thereof consists of CLP5 or a salt thereof.

[0854] Clause A86. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause A1, , wherein the lipidated cyclic peptide or sale thereof consists of CLP6 or a salt thereof.

[0855] Clause A87. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause A1, , wherein the lipidated cyclic peptide or sale thereof consists of CLP7 or a salt thereof.

[0856] Clause A88. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause A1, , wherein the lipidated cyclic peptide or sale thereof consists of CLP8 or a salt thereof.

[0857] Clause A89. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause A1, , wherein the lipidated cyclic peptide or sale thereof consists of CLP9 or a salt thereof.

[0858] Clause A90. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause A1, , wherein the lipidated cyclic peptide or sale thereof consists of CLP10 or a salt thereof.

[0859] Clause A91. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause A1, , wherein the lipidated cyclic peptide or sale thereof consists of CLP11 or a salt thereof.

[0860] Clause A92. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A1 to A91 , wherein the salt is a pharmaceutically acceptable salt.

[0861] Clause A93. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any preceding A clause, wherein the peptide is a lipidated cyclic peptide.

[0862] Clause A94. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any preceding A clause, wherein the peptide is a lipidated variant peptide.

[0863] Clause A95. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use, according to any preceding A clause, wherein the peptide is a pharmaceutically acceptable salt of a lipidated cyclic peptide. Clause A96. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any preceding A clause, wherein the peptide is a pharmaceutically acceptable salt of a lipidated variant peptide.

[0864] Clause A97. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A1 to A96, wherein the lipidated cyclic peptide is not side chain modified.

[0865] Clause A98. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses A1 to A96, wherein the lipidated cyclic peptide is not modified.

[0866] Clause B1. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use accordingly to any one of clauses 1 to 4, wherein the peptide is a cyclic peptide comprising the sequence:

[0867] X2- X3- E - H - X4- E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0868] X2represents P, D, Q, K, G

[0869] X3represents I, L, A, T, V

[0870] X4represents E, A or a salt thereof, or comprising a conservatively substituted variant of SEQ ID No. 51 or a salt thereof, wherein when X2represents P then X3 is other than V.

[0871] Clause B2. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause B1, wherein the peptide is backbone cyclised.

[0872] Clause B3. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause B2, wherein the peptide is backbone cyclised and all residues of the peptide backbone are joined exclusively by peptide bonds.

[0873] Clause B4. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B1 to B3, wherein the cyclic peptide, variant or salt comprises 25 or fewer amino acid residues within the cycle.

[0874] Clause B5. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause B4, wherein the cyclic peptide, variant or salt comprises 20 or fewer amino acid residues within the cycle, such as comprising 20 amino acid residues within the cycle. Clause B6. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause B5, wherein the cyclic peptide, variant or salt comprises 15 or fewer amino acid residues within the cycle, such as comprising 15 amino acid residues within the cycle.

[0875] Clause B7. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause B6, wherein the cyclic peptide, variant or salt comprises 12 or fewer amino acid residues within the cycle, such as comprising 12 amino acid residues within the cycle.

[0876] Clause B8. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause B7, wherein the cyclic peptide, variant or salt comprises 11 or fewer amino acid residues within the cycle.

[0877] Clause B9. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B1 to B8, wherein the cyclic peptide, variant or salt comprises at least 7 amino acid residues within the cycle, such as comprising 7 amino acid residues within the cycle.

[0878] Clause B10. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause B9, wherein the cyclic peptide, variant or salt comprises at least 8 amino acid residues within the cycle, such as comprising 8 amino acid residues within the cycle.

[0879] Clause B11. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause B10, wherein the cyclic peptide, variant or salt comprises at least 9 amino acid residues within the cycle, such as comprising 9 amino acid residues within the cycle.

[0880] Clause B12. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause B11, wherein the cyclic peptide, variant or salt comprises at least 10 amino acid residues within the cycle, such as comprising 10 amino acid residues within the cycle.

[0881] Clause B13. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause B12, wherein the cyclic peptide, variant or salt comprises at least 11 amino acid residues within the cycle.

[0882] Clause B14. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause B1, wherein the cyclic peptide, variant or salt comprises 11 amino acid residues within the cycle. Clause B15. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B9 to B14, wherein the cyclic peptide, variant or salt comprises the sequence: E - X2- X3- E - H - X4 - E position 0 1 2 3 4 5 6 (SEQ ID No.

[0883] 52) wherein:

[0884] X2represents P, D, Q, K, G X3 represents I, L, A, T, V X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No. 52 or a salt thereof.

[0885] Clause B16. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B9 to B14, cyclic peptide, variant or salt comprises the sequence: X2- X3- E - H - X4- E - D position 1 2 3 4 5 6 7 (SEQ ID No.

[0886] 53) wherein:

[0887] X2represents P, D, Q, K, G X3represents I, L, A, T, V X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[0888] 53 or a salt thereof.

[0889] Clause B17. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B10 to B14, cyclic peptide, variant or salt comprises the sequence:

[0890] T - E - X2- X3 - E - H - X4 - E position -1 0 1 2 3 4 5 6 (SEQ

[0891] ID No. 54) wherein:

[0892] X2represents P, D, Q, K, G X3 represents I, L, A, T, V X4represents E, A or a salt thereof, or comprising a conservatively substituted variant of SEQ ID No.

[0893] 54 or a salt thereof. Clause B18. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B10 to B14, cyclic peptide, variant or salt comprises the sequence:

[0894] E- X2- X3- E- H- X4- E- D position 0 1 2 3 4 5 6 7 (SEQ ID No.55) wherein:

[0895] X2represents P, D, Q, K, G X3represents I, L, A, T, V X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[0896] 55 or a salt thereof.

[0897] Clause B19. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B10 to B14, cyclic peptide, variant or salt comprises the sequence:

[0898] X2- X3- E- H- X4- E- D- V position 1 2 3 4 5 6 7 8 (SEQ ID No.56) wherein:

[0899] X2represents P, D, Q, K, G X3 represents I, L, A, T, V X4represents E, A or a salt thereof, or comprising a conservatively substituted variant of SEQ ID No.

[0900] 56 or a salt thereof.

[0901] Clause B20. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B11 to B14, cyclic peptide, variant or salt comprises the sequence:

[0902] Xi - T - E - X2- X3- E - H - X4- E position -2 -1 0 1 2 3 4 5 6

[0903] (SEQ ID No.57) wherein:

[0904] Xi represents M, K X2represents P, D, Q, K, G X3 represents I, L, A, T, V X4represents E, A or a salt thereof, or comprising a conservatively substituted variant of SEQ ID No.

[0905] 57 or a salt thereof. Clause B21. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B11 to B14, cyclic peptide, variant or salt comprises the sequence:

[0906] T- E- X2- X3- E- H- X4- E- D position -1 0 1 2 3 4 5 6 7

[0907] (SEQ ID No.58) wherein:

[0908] X2represents P, D, Q, K, G X3represents I, L, A, T, V X4represents E, A or a salt thereof, or comprising a conservatively substituted variant of SEQ ID No. 58 or a salt thereof.

[0909] Clause B22. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B11 to B14, cyclic peptide, variant or salt comprises the sequence:

[0910] E- X2- X3- E- H- X4- E- D- V position 0 1 2 3 4 5 6 7 8 (SEQ ID No.59) wherein:

[0911] X2represents P, D, Q, K, G

[0912] X3represents I, L, A, T, V

[0913] X4represents E, A or a salt thereof, or comprising a conservatively substituted variant of SEQ ID No.

[0914] 59 or a salt thereof.

[0915] Clause B23. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B12 to B14, cyclic peptide, variant or salt comprises the sequence:

[0916] Xi - T - E - X2- X3- E - H - X4- E - D position -2 -1 0 1 2 3 4 5 6 7

[0917] (SEQ ID No.60) wherein:

[0918] Xi represents M, K

[0919] X2represents P, D, Q, K, G

[0920] X3represents I, L, A, T, V

[0921] X4represents E, A or a salt thereof, or comprising a conservatively substituted variant of SEQ ID No.

[0922] 60 or a salt thereof. Clause B24. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B12 to B14, cyclic peptide, variant or salt comprises the sequence: T - E - X2- X3 - E - H - X4 - E - D - V position -1 0 1 2 3 4 5 6 7 8

[0923] (SEQ ID No. 61) wherein:

[0924] X2represents P, D, Q, K, G

[0925] X3 represents I, L, A, T, V

[0926] X4represents E, A or a salt thereof, or comprising a conservatively substituted variant of SEQ ID No. 61 or a salt thereof.

[0927] Clause B25. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B13 to B14, cyclic peptide, variant or salt comprises the sequence: Xi - T - E - X2- X3- E - H - X4- E - D - V position -2 -1 0 1 2 3 4 5 6 7 8

[0928] (SEQ ID No. 62) wherein:

[0929] Xi represents M, K

[0930] X2represents P, D, Q, K, G X3represents I, L, A, T, V X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No. 62 or a salt thereof.

[0931] Clause B26. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B1 to B25, wherein Xi represents M.

[0932] Clause B27. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B1 to B25, wherein Xi represents K.

[0933] Clause B28. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B1 to B27, wherein X2represents P.

[0934] Clause B29. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B1 to B27, wherein X2represents D. Clause B30. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B1 to B27, wherein X2 represents Q.

[0935] Clause B31. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B1 to B27, wherein X2 represents K.

[0936] Clause B32. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B1 to B27, wherein X2 represents G.

[0937] Clause B33. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B1 to B32, wherein X3 represents I.

[0938] Clause B34. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B1 to B32, wherein X3 represents L.

[0939] Clause B35. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B1 to B32, wherein X3 represents A.

[0940] Clause B36. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B1 to B32, wherein X3 represents T.

[0941] Clause B37. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B1 to B27 or B29 to B32, wherein X3 represents V.

[0942] Clause B38. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B1 to B37, wherein X4 represents E.

[0943] Clause B39. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B1 to B37, wherein X4 represents A.

[0944] Clause B40. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B13 to B14, wherein the cyclic peptide, variant or salt comprises the sequence of any one of SEQ ID No. 1 to 10 and 28 to 39, or a salt thereof, or comprises a conservatively substituted variant of any one of SEQ ID No. 1 to 10 and 28 to 39 or a salt thereof, such as consisting of the sequence of any one of SEQ ID No. 1 to 10 and 28 to 39, or a salt thereof, or consisting of a conservatively substituted variant of any one of SEQ ID No. 1 to 10 and 28 to 39 or a salt thereof.

[0945] Clause B41. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B13 to B14, wherein the cyclic peptide, variant or salt comprises the sequence of SEQ ID No. 1 , or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No. 1 or a salt thereof, such as consisting of the sequence of SEQ ID No. 1 , or a salt thereof, or consisting of a conservatively substituted variant of SEQ ID No. 1 or a salt thereof.

[0946] Clause B42. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B1 to B41, wherein the variant or salt thereof comprises two conservative substitutions.

[0947] Clause B43. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B1 to B42, wherein the variant or salt thereof comprises a substitution of Xi at position -2, such as replacement by E, N, Q, R, T I, L or V.

[0948] Clause B44. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B1 to B42, wherein the variant or salt thereof comprises a substitution of T at position -1 , such as replacement by A, K, M, N, R or S, especially A, K, M, N or R.

[0949] Clause B45. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B1 to B42, wherein the variant or salt thereof comprises a substitution of E at position 0, such as replacement by A, D, G, K, Q or V, especially G, K, Q or V.

[0950] Clause B46. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B1 to B42, wherein the variant or salt thereof comprises a substitution of X2 at position 1 , such as replacement by A, C, E, H, L, M, N, R, S, T, V or Y, especially A, E, H, L, M, N, R, T, V or Y.

[0951] Clause B47. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B1 to B42, wherein the variant or salt thereof comprises a substitution of X3 at position 2, such as replacement by D, E, F, G, H, K, M, N, P, Q, S or W, especially D, E, F, G, H, K, M, N, P, Q or W. Clause B48. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B1 to B42, wherein the variant or salt thereof comprises a substitution of E at position 3, such as replacement by A, D, G, K, Q or V, especially G, K, Q or V.

[0952] Clause B49. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B1 to B42, wherein the variant or salt thereof comprises a substitution of H at position 4, such as replacement by D, L, N, P, Q, R or Y.

[0953] Clause B50. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B1 to B42, wherein the variant or salt thereof comprises a substitution of X4 at position 5, such as replacement by G, K, Q, S, T or V, especially G, K, Q, T or V.

[0954] Clause B51. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B1 to B42, wherein the variant or salt thereof comprises a substitution of E at position 6, such as replacement by A, D, G, K, Q or V.

[0955] Clause B52. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B1 to B42, wherein the variant or salt thereof comprises a substitution of D at position 7, such as replacement by A, E, G, H, N, V or Y.

[0956] Clause B53. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B1 to B42, wherein the variant or salt thereof comprises a substitution of V at position 8, such as replacement by D, E, I, L or M.

[0957] Clause B54. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B42 to B53, wherein the variant or salt thereof comprises a substitution of Xi at position -2, such as replacement by E, N, Q, R, T I, L or V.

[0958] Clause B55. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B42 to B53, wherein the variant or salt thereof comprises a substitution of T at position -1 , such as replacement by A, K, M, N, R or S, especially A, K, M, N or R.

[0959] Clause B56. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B42 to B53, wherein the variant or salt thereof comprises a substitution of E at position 0, such as replacement by A, D, G, K, Q or V, especially G, K, Q or V. Clause B57. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B42 to B53, wherein the variant or salt thereof comprises a substitution of X2 at position 1 , such as replacement by A, C, E, H, L, M, N, R, S, T, V or Y, especially A, E, H, L, M, N, R, T, V or Y.

[0960] Clause B58. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B42 to B53, wherein the variant or salt thereof comprises a substitution of X3 at position 2, such as replacement by D, E, F, G, H, K, M, N, P, Q, S or W, especially D, E, F, G, H, K, M, N, P, Q or W.

[0961] Clause B59. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B42 to B53, wherein the variant or salt thereof comprises a substitution of E at position 3, such as replacement by A, D, G, K, Q or V, especially G, K, Q or V.

[0962] Clause B60. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B42 to B53, wherein the variant or salt thereof comprises a substitution of H at position 4, such as replacement by D, L, N, P, Q, R or Y.

[0963] Clause B61. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B42 to B53, wherein the variant or salt thereof comprises a substitution of X4 at position 5, such as replacement by G, K, Q, S, T or V, especially G, K, Q, T or V.

[0964] Clause B62. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B42 to B53, wherein the variant or salt thereof comprises a substitution of E at position 6, such as replacement by A, D, G, K, Q or V.

[0965] Clause B63. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B42 to B53, wherein the variant or salt thereof comprises a substitution of D at position 7, such as replacement by A, E, G, H, N, V or Y.

[0966] Clause B64. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B42 to B53, wherein the variant or salt thereof comprises a substitution of V at position 8, such as replacement by D, E, I, L or M.

[0967] Clause B65. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B43 to B53, wherein the variant or salt thereof comprises one conservative substitution.

[0968] Clause B66. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B1 to B41 , wherein the peptide is a cyclic peptide or salt thereof.

[0969] Clause B67. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause B1, wherein the cyclic peptide or salt consists of SEQ ID No. 1 or a salt thereof.

[0970] Clause B68. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause B1, wherein the cyclic peptide or salt consists of SEQ ID No. 2 or a salt thereof.

[0971] Clause B69. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause B1, wherein the cyclic peptide or salt consists of SEQ ID No. 3 or a salt thereof.

[0972] Clause B70. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause B1, wherein the cyclic peptide or salt consists of SEQ ID No. 4 or a salt thereof.

[0973] Clause B71. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause B1, wherein the cyclic peptide or salt consists of SEQ ID No. 5 or a salt thereof.

[0974] Clause B72. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause B1, wherein the cyclic peptide or salt consists of SEQ ID No. 6 or a salt thereof.

[0975] Clause B73. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause B1, wherein the cyclic peptide or salt consists of SEQ ID No. 7 or a salt thereof.

[0976] Clause B74. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause B1, wherein the cyclic peptide or salt consists of SEQ ID No. 8 or a salt thereof.

[0977] Clause B75. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause B1, wherein the cyclic peptide or salt consists of SEQ ID No. 9 or a salt thereof.

[0978] Clause B76. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause B1, wherein the cyclic peptide or salt consists of SEQ ID No. 10 or a salt thereof. Clause B77. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause B1, wherein the cyclic peptide or salt consists of CP1 or a salt thereof.

[0979] Clause B78. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause B1, wherein the cyclic peptide or salt consists of CP2 or a salt thereof.

[0980] Clause B79. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause B1, wherein the cyclic peptide or salt consists of CP3 or a salt thereof.

[0981] Clause B80. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause B1, wherein the cyclic peptide or salt consists of CP4 or a salt thereof.

[0982] Clause B81. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause B1, wherein the cyclic peptide or salt consists of CP5 or a salt thereof.

[0983] Clause B82. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause B1, wherein the cyclic peptide or salt consists of CP6 or a salt thereof.

[0984] Clause B83. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause B1, wherein the cyclic peptide or salt consists of CP7 or a salt thereof.

[0985] Clause B84. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause B1, wherein the cyclic peptide or salt consists of CP8 or a salt thereof.

[0986] Clause B85. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause B1, wherein the cyclic peptide or salt consists of CP9 or a salt thereof.

[0987] Clause B86. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause B1, wherein the cyclic peptide or salt consists of CP10 or a salt thereof.

[0988] Clause B87. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause B1, wherein the cyclic peptide or salt consists of CP11 or a salt thereof.

[0989] Clause B88. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause B1, wherein the cyclic peptide or salt consists of CP12 or a salt thereof. Clause B89. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B1 to B98, wherein the salt is a pharmaceutically acceptable salt.

[0990] Clause B90. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any preceding B clause, wherein the peptide is a cyclic peptide.

[0991] Clause B91. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any preceding B clause, wherein the peptide is a variant peptide.

[0992] Clause B92. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any preceding B clause, wherein the peptide is a pharmaceutically acceptable salt of a cyclic peptide.

[0993] Clause B93. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any preceding B clause, wherein the peptide is a pharmaceutically acceptable salt of the variant peptide.

[0994] Clause B94. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B1 to B93, wherein the cyclic peptide is not side chain modified.

[0995] Clause B95. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses B1 to B93, wherein the cyclic peptide is not modified.

[0996] Clause C1. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one clauses 1 to 28, wherein the peptide is a cyclic peptide comprising 10 or fewer amino acid residues within the cycle and comprising the sequence:

[0997] X2- X3- E - H - X4- E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[0998] X2represents P, D, Q, K, G

[0999] X3represents I, L, A, T, V

[1000] X4represents E, A or a salt thereof, or comprising a conservatively substituted variant of SEQ ID No. 51 or a salt thereof.

[1001] Clause C2. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause C1, wherein the peptide is backbone cyclised. Clause C3. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause C2, wherein the peptide is backbone cyclised and all residues of the peptide backbone are joined exclusively by peptide bonds.

[1002] Clause C4. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C1 to C3, wherein the cyclic peptide, variant or salt comprises 6 amino acid residues within the cycle.

[1003] Clause C5. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C1 to C3 wherein the cyclic peptide, variant or salt comprises 7 amino acid residues within the cycle.

[1004] Clause C6. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C1 to C3, wherein the cyclic peptide, variant or salt comprises 8 amino acid residues within the cycle.

[1005] Clause C7. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C1 to C3, wherein the cyclic peptide, variant or salt comprises 9 amino acid residues within the cycle.

[1006] Clause C8. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C1 to C3, wherein the cyclic peptide, variant or salt comprises 10 amino acid residues within the cycle.

[1007] Clause C9. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C1 to C3 or C5 to C8, wherein the cyclic peptide, variant or salt comprises the sequence:

[1008] E - X2- X3- E - H - X4- E position 0 1 2 3 4 5 6 (SEQ ID No.

[1009] 52) wherein:

[1010] X2represents P, D, Q, K, G

[1011] X3represents I, L, A, T, V

[1012] X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No. 52 or a salt thereof. Clause C10. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C1 to C3 or C5 to C8, wherein the cyclic peptide, variant or salt comprises the sequence:

[1013] X2- X3- E- H- X4- E- D position 1 2 3 4 5 6 7 (SEQ ID No.

[1014] 53) wherein:

[1015] X2represents P, D, Q, K, G X3represents I, L, A, T, V X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[1016] 53 or a salt thereof.

[1017] Clause C11. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C1 to C3 or C6 to C8, wherein the cyclic peptide, variant or salt comprises the sequence:

[1018] T- E- X2- X3- E- H- X4- E position -1 0 1 2 3 4 5 6 (SEQ

[1019] ID No.54) wherein:

[1020] X2represents P, D, Q, K, G

[1021] X3 represents I, L, A, T, V

[1022] X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[1023] 54 or a salt thereof.

[1024] Clause C12. The cyclic peptide, variant or salt according to any one of clauses C1 to C3 or C6 to C8, wherein the cyclic peptide, variant or salt comprises the sequence:

[1025] E- X2- X3- E- H- X4- E- D position 0 1 2 3 4 5 6 7 (SEQ

[1026] ID No.55) wherein:

[1027] X2represents P, D, Q, K, G

[1028] X3 represents I, L, A, T, V

[1029] X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[1030] 55 or a salt thereof. Clause C13. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C1 to C3 or C6 to C8, wherein the cyclic peptide, variant or salt comprisesthe sequence:

[1031] X2- X3- E- H- X4- E- D- V position 1 2 3 4 5 6 7 8 (SEQ

[1032] ID No.56) wherein:

[1033] X2represents P, D, Q, K, G

[1034] X3 represents I, L, A, T, V

[1035] X4 represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[1036] 56 or a salt thereof.

[1037] Clause C14. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C1 to C3 or C7 to C8, wherein the cyclic peptide, variant or salt comprises the sequence:

[1038] Xi - T - E - X2- X3- E - H - X4- E position -2 -1 0 1 2 3 4 5 6

[1039] (SEQ ID No.57) wherein:

[1040] Xi represents M, K

[1041] X2represents P, D, Q, K, G

[1042] X3 represents I, L, A, T, V

[1043] X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[1044] 57 or a salt thereof.

[1045] Clause C15. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C1 to C3 or C7 to C8, wherein the cyclic peptide, variant or salt comprises the sequence:

[1046] T- E- X2- X3- E- H- X4- E- D position -1 0 1 2 3 4 5 6 7

[1047] (SEQ ID No.58) wherein:

[1048] X2represents P, D, Q, K, G

[1049] X3 represents I, L, A, T, V X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[1050] 58 or a salt thereof.

[1051] Clause C16. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C1 to C3 or C7 to C8, wherein the cyclic peptide, variant or salt comprises the sequence: E- X2- X3- E- H- X4- E- D- V position 0 1 2 3 4 5 6 7 8 (SEQ ID No.59) wherein:

[1052] X2represents P, D, Q, K, G X3represents I, L, A, T, V X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[1053] 59 or a salt thereof.

[1054] Clause C17. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C1 to C3 or C8, wherein the cyclic peptide, variant or salt comprises the sequence: Xi - T - E - X2- X3- E - H - X4- E - D position -2 -1 0 1 2 3 4 5 6 7

[1055] (SEQ ID No.60) wherein:

[1056] Xi represents M, K

[1057] X2represents P, D, Q, K, G X3represents I, L, A, T, V X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[1058] 60 or a salt thereof.

[1059] Clause C18. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C1 to C3 or C8, wherein the cyclic peptide, variant or salt comprises the sequence: T- E- X2- X3- E- H- X4- E- D- V position -1 0 1 2 3 4 5 6 7 8

[1060] (SEQ ID No.61) wherein:

[1061] X2represents P, D, Q, K, G X3 represents I, L, A, T, V

[1062] X4 represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No. 61 or a salt thereof.

[1063] Clause C19. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C1 to C18, wherein Xi represents M.

[1064] Clause C20. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C1 to C18, wherein Xi represents K.

[1065] Clause C21. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C1 to C20, wherein X2 represents P.

[1066] Clause C22. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C1 to C20, wherein X2 represents D.

[1067] Clause C23. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C1 to C20, wherein X2 represents Q.

[1068] Clause C24. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C1 to C20, wherein X2 represents K.

[1069] Clause C25. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C1 to C20, wherein X2 represents G.

[1070] Clause C26. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses 01 to C25, wherein X3 represents I.

[1071] Clause C27. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C1 to 025, wherein X3 represents L.

[1072] Clause C28. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses 01 to 025, wherein X3 represents A.

[1073] Clause C29. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses 01 to 025, wherein X3 represents T. Clause C30. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C1 to C25, wherein X3 represents V.

[1074] Clause C31. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C1 to C30, wherein X4 represents E.

[1075] Clause C32. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C1 to C30, wherein X4 represents A.

[1076] Clause C33. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C1 to C32, wherein the sequence of the cyclic peptide is (i) a portion of any one of SEQ ID No. 1 to 10 and 28 to 39, or a salt thereof, or (ii) a conservatively substituted variant of any one of SEQ ID No. 1 to 10 and 28 to 39 or a salt thereof.

[1077] Clause C34. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause C33, wherein the sequence of the cyclic peptide is (i) a portion of SEQ ID No. 1, or a salt thereof, or (ii) a conservatively substituted variant of SEQ ID No. 1 or a salt thereof.

[1078] Clause C35. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C1 to C32, wherein the cyclic peptide, variant or salt comprises the sequence of any one of SEQ ID No. 40 to 42, or a salt thereof, or comprises a conservatively substituted variant of any one of SEQ ID No. 40 to 42 or a salt thereof, such as consisting of the sequence of any one of SEQ ID No. 40 to 42, or a salt thereof, or consisting of a conservatively substituted variant of any one of SEQ ID No. 40 to 42 or a salt thereof.

[1079] Clause C36. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C1 to C35, wherein the variant or salt thereof comprises two conservative substitutions.

[1080] Clause C37. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C1 to C36, wherein the variant or salt thereof comprises a substitution of Xi at position -2, such as replacement by E, N, Q, R, T I, L or V.

[1081] Clause C38. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C1 to C36, wherein the variant or salt thereof comprises a substitution of T at position -1 , such as replacement by A, K, M, N, R or S, especially A, K, M, N or R.

[1082] Clause C39. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C1 to C36, wherein the variant or salt thereof comprises a substitution of E at position 0, such as replacement by A, D, G, K, Q or V, especially G, K, Q or V.

[1083] Clause C40. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses 01 to C36, wherein the variant or salt thereof comprises a substitution of X2 at position 1 , such as replacement by A, C, E, H, L, M, N, R, S, T, V or Y, especially A, E, H, L, M, N, R, T, V or Y.

[1084] Clause C41. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C1 to 036, wherein the variant or salt thereof comprises a substitution of X3 at position 2, such as replacement by D, E, F, G, H, K, M, N, P, Q, S or W, especially D, E, F, G, H, K, M, N, P, Q or W.

[1085] Clause C42. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses 01 to 036, wherein the variant or salt thereof comprises a substitution of E at position 3, such as replacement by A, D, G, K, Q or V, especially G, K, Q or V.

[1086] Clause C43. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses 01 to 036, wherein the variant or salt thereof comprises a substitution of H at position 4, such as replacement by D, L, N, P, Q, R or Y.

[1087] Clause C44. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses 01 to 036, wherein the variant or salt thereof comprises a substitution of X4 at position 5, such as replacement by G, K, Q, S, T or V, especially G, K, Q, T or V.

[1088] Clause C45. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses 01 to 036, wherein the variant or salt thereof comprises a substitution of E at position 6, such as replacement by A, D, G, K, Q or V.

[1089] Clause C46. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses 01 to 036, wherein the variant or salt thereof comprises a substitution of D at position 7, such as replacement by A, E, G, H, N, V or Y. Clause C47. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C1 to C36, wherein the variant or salt thereof comprises a substitution of V at position 8, such as replacement by D, E, I, L or M.

[1090] Clause C48. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C36 to C47, wherein the variant or salt thereof comprises a substitution of Xi at position -2, such as replacement by E, N, Q, R, T I, L or V.

[1091] Clause C49. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C36 to C47, wherein the variant or salt thereof comprises a substitution of T at position -1 , such as replacement by A, K, M, N, R or S, especially A, K, M, N or R.

[1092] Clause C50. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C36 to C47, wherein the variant or salt thereof comprises a substitution of E at position 0, such as replacement by A, D, G, K, Q or V, especially G, K, Q or V.

[1093] Clause C51. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C36 to C47, wherein the variant or salt thereof comprises a substitution of X2 at position 1 , such as replacement by A, C, E, H, L, M, N, R, S, T, V or Y, especially A, E, H, L, M, N, R, T, V or Y.

[1094] Clause C52. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C36 to C47, wherein the variant or salt thereof comprises a substitution of X3 at position 2, such as replacement by D, E, F, G, H, K, M, N, P, Q, S or W, especially D, E, F, G, H, K, M, N, P, Q or W.

[1095] Clause C53. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C36 to C47, wherein the variant or salt thereof comprises a substitution of E at position 3, such as replacement by A, D, G, K, Q or V, especially G, K, Q or V.

[1096] Clause C54. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C36 to C47, wherein the variant or salt thereof comprises a substitution of H at position 4, such as replacement by D, L, N, P, Q, R or Y.

[1097] Clause C55. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C36 to C47, wherein the variant or salt thereof comprises a substitution of X4 at position 5, such as replacement by G, K, Q, S, T or V, especially G, K, Q, T or V.

[1098] Clause C56. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C36 to C47, wherein the variant or salt thereof comprises a substitution of E at position 6, such as replacement by A, D, G, K, Q or V.

[1099] Clause C57. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use to any one of clauses C36 to C47, wherein the variant or salt thereof comprises a substitution of D at position 7, such as replacement by A, E, G, H, N, V orY.

[1100] Clause C58. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C36 to C47, wherein the variant or salt thereof comprises a substitution of V at position 8, such as replacement by D, E, I, L or M.

[1101] Clause C59. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C37 to C47, wherein the variant or salt thereof comprises one conservative substitution.

[1102] Clause C60. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C1 to 035, wherein the peptide is a cyclic peptide or salt thereof.

[1103] Clause C61. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause 01, wherein the cyclic peptide or salt consists of CP13 or a salt thereof.

[1104] Clause C62. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause 01, wherein the cyclic peptide or salt consists of CP14 or a salt thereof.

[1105] Clause C63. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause 01, wherein the cyclic peptide or salt consists of CP15 or a salt thereof.

[1106] Clause C64. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses 01 to 063, wherein the salt is a pharmaceutically acceptable salt.

[1107] Clause C65. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any preceding 0 clause, wherein the peptide is a cyclic peptide. Clause C66. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any preceding C clause, wherein the peptide is a variant peptide.

[1108] Clause C67. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any preceding C clause, wherein the peptide is a pharmaceutically acceptable salt of a cyclic peptide.

[1109] Clause C68. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any preceding C clause, wherein the peptide is a pharmaceutically acceptable salt of the variant peptide.

[1110] Clause C69. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C1 to C68, wherein the cyclic peptide is not side chain modified.

[1111] Clause C70. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses C1 to C68, wherein the cyclic peptide is not modified.

[1112] Clause D1. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses 1 to 4, wherein the peptide is a lipidated linear peptide comprising the sequence:

[1113] X2- X3- E - H - X4- E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[1114] X2represents P, D, Q, K, G

[1115] X3represents I, L, A, T, V

[1116] X4represents E, A or a salt thereof, or comprising a conservatively substituted variant of SEQ ID No. 51 or a salt thereof.

[1117] Clause D2. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause D1, wherein all residues of the peptide backbone are joined exclusively by peptide bonds.

[1118] Clause D3. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause D1 or D2, wherein the lipidated linear peptide, variant or salt comprises 25 or fewer amino acid residues within the backbone.

[1119] Clause D4. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause D3, wherein the lipidated linear peptide, variant or salt comprises 20 or fewer amino acid residues within the backbone, such as comprising 20 amino acid residues within the backbone.

[1120] Clause D5. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause D4, wherein the lipidated linear peptide, variant or salt comprises 15 or fewer amino acid residues within the backbone, such as comprising 15 amino acid residues within the backbone.

[1121] Clause D6. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause D5, wherein the lipidated linear peptide, variant or salt comprises 12 or fewer amino acid residues within the backbone, such as comprising 12 amino acid residues within the backbone.

[1122] Clause D7. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause D6, wherein the lipidated linear peptide, variant or salt comprises 11 or fewer amino acid residues within the backbone.

[1123] Clause D8. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D1 to D7, wherein the lipidated linear peptide, variant or salt comprises at least 7 amino acid residues within the backbone, such as comprising 7 amino acid residues within the backbone.

[1124] Clause D9. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause D8, wherein the lipidated linear peptide, variant or salt comprises at least 8 amino acid residues within the backbone, such as comprising 8 amino acid residues within the backbone.

[1125] Clause D10. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause D9, wherein the lipidated linear peptide, variant or salt comprises at least 9 amino acid residues within the backbone, such as comprising 9 amino acid residues within the backbone.

[1126] Clause D11. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause D10, wherein the lipidated linear peptide, variant or salt comprises at least 10 amino acid residues within the backbone, such as comprising 10 amino acid residues within the backbone. Clause D12. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause D11, wherein the lipidated linear peptide, variant or salt comprises at least 11 amino acid residues within the backbone

[1127] Clause D13. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause D12, wherein the lipidated linear peptide, variant or salt comprises 11 amino acid residues within the backbone.

[1128] Clause D14. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D8 to D13, wherein the lipidated linear peptide, variant or salt comprises the sequence:

[1129] E - X2- X3- E - H - X4- E position 0 1 2 3 4 5 6 (SEQ ID No.

[1130] 52) wherein:

[1131] X2represents P, D, Q, K, G X3represents I, L, A, T, V X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[1132] 52 or a salt thereof.

[1133] Clause D15. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D8 to D13, wherein the lipidated linear peptide, variant or salt comprises the sequence:

[1134] X2- X3 - E - H - X4 - E - D position 1 2 3 4 5 6 7 (SEQ ID No.

[1135] 53) wherein:

[1136] X2represents P, D, Q, K, G

[1137] X3 represents I, L, A, T, V

[1138] X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[1139] 53 or a salt thereof.

[1140] Clause D16. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D9 to D13, wherein the lipidated linear peptide, variant or salt comprises the sequence:

[1141] T- E- X2- X3- E- H- X4- E position -1 0 1 2 3 4 5 6 (SEQ

[1142] ID No.54) wherein:

[1143] X2represents P, D, Q, K, G X3represents I, L, A, T, V X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[1144] 54 or a salt thereof.

[1145] Clause D17. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D9 to D13, wherein the lipidated linear peptide, variant or salt comprises the sequence:

[1146] E- X2- X3- E- H- X4- E- D position 0 1 2 3 4 5 6 7 (SEQ ID No.55) wherein:

[1147] X2represents P, D, Q, K, G

[1148] X3 represents I, L, A, T, V

[1149] X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[1150] 55 or a salt thereof.

[1151] Clause D18. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D9 to D13, wherein the lipidated linear peptide, variant or salt comprises the sequence:

[1152] X2- X3- E- H- X4- E- D- V position 1 2 3 4 5 6 7 8 (SEQ ID No.56) wherein:

[1153] X2represents P, D, Q, K, G

[1154] X3 represents I, L, A, T, V

[1155] X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[1156] 56 or a salt thereof. Clause D19. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D10 to D13, wherein the lipidated linear peptide, variant or salt comprises the sequence:

[1157] Xi - T - E - X2- X3- E - H - X4- E position -2 -1 0 1 2 3 4 5 6

[1158] (SEQ ID No.57) wherein:

[1159] Xi represents M, K

[1160] X2represents P, D, Q, K, G

[1161] X3 represents I, L, A, T, V

[1162] X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No. 57 or a salt.

[1163] Clause D20. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D10 to D13, wherein the lipidated linear peptide, variant or salt comprises the sequence:

[1164] T- E- X2- X3- E- H- X4- E- D position -1 0 1 2 3 4 5 6 7

[1165] (SEQ ID No.58) wherein:

[1166] X2represents P, D, Q, K, G X3represents I, L, A, T, V X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No. 58 or a salt thereof.

[1167] Clause D21. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D10 to D13, wherein the lipidated linear peptide, variant or salt comprises the sequence:

[1168] E- X2- X3- E- H- X4- E- D- V position 0 1 2 3 4 5 6 7 8 (SEQ ID No.59) wherein:

[1169] X2represents P, D, Q, K, G X3 represents I, L, A, T, V X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[1170] 59 or a salt thereof.

[1171] Clause D22. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D11 to D23, wherein the lipidated linear peptide, variant or salt comprises the sequence:

[1172] Xi - T - E - X2- X3- E - H - X4- E - D position -2 -1 0 1 2 3 4 5 6 7

[1173] (SEQ ID No. 60) wherein:

[1174] Xi represents M, K

[1175] X2represents P, D, Q, K, G X3represents I, L, A, T, V X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[1176] 60 or a salt thereof.

[1177] Clause D23. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D11 to D13, wherein the lipidated linear peptide, variant or salt comprises the sequence:

[1178] T - E - X2- X3 - E - H - X4 - E - D - V position -1 0 1 2 3 4 5 6 7 8

[1179] (SEQ ID No. 61) wherein:

[1180] X2represents P, D, Q, K, G

[1181] X3 represents I, L, A, T, V

[1182] X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[1183] 61 or a salt thereof.

[1184] Clause D24. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D12 to D13, wherein the lipidated linear peptide, variant or salt comprises the sequence: Xi - T - E - X2- X3- E - H - X4- E - D - V position -2 -1 0 1 2 3 4 5 6 7 8

[1185] (SEQ ID No. 62) wherein:

[1186] Xi represents M, K

[1187] X2 represents P, D, Q, K, G

[1188] X3 represents I, L, A, T, V

[1189] X4 represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No. 62 or a salt thereof.

[1190] Clause D25. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D1 to D24, wherein Xi represents M.

[1191] Clause D26. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D1 to D24, wherein Xi represents K.

[1192] Clause D27. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D1 to D26, wherein X2 represents P.

[1193] Clause D28. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D1 to D26, wherein X2 represents D.

[1194] Clause D29. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D1 to D26, wherein X2 represents Q.

[1195] Clause D30. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D1 to D26, wherein X2 represents K.

[1196] Clause D31. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D1 to D26, wherein X2 represents G.

[1197] Clause D32. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D1 to D31, wherein X3 represents I.

[1198] Clause D33. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D1 to D31, wherein X3 represents L.

[1199] Clause D34. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D1 to D31, wherein X3 represents A. Clause D35. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D1 to D31, wherein X3 represents T.

[1200] Clause D36. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D1 to D31, wherein X3 represents V.

[1201] Clause D37. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D1 to D36, wherein X4 represents E.

[1202] Clause D38. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D1 to D36, wherein X4 represents A.

[1203] Clause D39. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D13 to D14, wherein the lipidated linear peptide, variant or salt comprises the sequence of any one of SEQ ID No. 1 to 11 or a salt thereof, or comprises a conservatively substituted variant of any one of SEQ ID No. 1 to 11 or a salt thereof, such as consisting of the sequence of any one of SEQ ID No. 1 to 11 or a salt thereof, or consisting of a conservatively substituted variant of any one of SEQ ID No. 1 to 11 or a salt thereof.

[1204] Clause D40. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D13 to D14, wherein the lipidated linear peptide, variant or salt comprises the sequence of SEQ ID No. 1 or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No. 1 or a salt thereof, such as consisting of the sequence of SEQ ID No. 1 or a salt thereof, or consisting of a conservatively substituted variant of SEQ ID No. 1 or a salt thereof.

[1205] Clause D41. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D13 to D14, wherein the lipidated linear peptide, variant or salt comprises the sequence of any one of LLP1 to LLP12 or a salt thereof, or comprises a conservatively substituted variant of any one of LLP1 to LLP12 or a salt thereof, such as consisting of the sequence of any one of LLP1 to LLP12 or a salt thereof, or consisting of a conservatively substituted variant of any one of LLP1 to LLP 12 or a salt thereof.

[1206] Clause D42. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D1 to D41, wherein the variant or salt thereof comprises two conservative substitutions.

[1207] Clause D43. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D1 to D42, wherein the variant or salt thereof comprises a substitution of Xi at position -2, such as replacement by E, N, Q, R, T I, L or V.

[1208] Clause D44. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D1 to D42, wherein the variant or salt thereof comprises a substitution of T at position -1 , such as replacement by A, K, M, N, R or S, especially A, K, M, N or R.

[1209] Clause D45. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D1 to D42, wherein the variant or salt thereof comprises a substitution of E at position 0, such as replacement by A, D, G, K, Q or V, especially G, K, Q or V.

[1210] Clause D46. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D1 to D42, wherein the variant or salt thereof comprises a substitution of X2 at position 1 , such as replacement by A, C, E, H, L, M, N, R, S, T, V or Y, especially A, E, H, L, M, N, R, T, V or Y.

[1211] Clause D47. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D1 to D42, wherein the variant or salt thereof comprises a substitution of X3 at position 2, such as replacement by D, E, F, G, H, K, M, N, P, Q, S or W, especially D, E, F, G, H, K, M, N, P, Q or W.

[1212] Clause D48. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D1 to D42, wherein the variant or salt thereof comprises a substitution of E at position 3, such as replacement by A, D, G, K, Q or V, especially G, K, Q or V.

[1213] Clause D49. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D1 to D42, wherein the variant or salt thereof comprises a substitution of H at position 4, such as replacement by D, L, N, P, Q, R or Y.

[1214] Clause D50. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D1 to D42, wherein the variant or salt thereof comprises a substitution of X4 at position 5, such as replacement by G, K, Q, S, T or V, especially G, K, Q, T or V. Clause D51. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D1 to D42, wherein the variant or salt thereof comprises a substitution of E at position 6, such as replacement by A, D, G, K, Q or V.

[1215] Clause D52. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D1 to D42, wherein the variant or salt thereof comprises a substitution of D at position 7, such as replacement by A, E, G, H, N, V or Y.

[1216] Clause D53. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D1 to D42, wherein the variant or salt thereof comprises a substitution of V at position 8, such as replacement by D, E, I, L or M.

[1217] Clause D54. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D42 to D53, wherein the variant or salt thereof comprises a substitution of Xi at position -2, such as replacement by E, N, Q, R, T I, L or V.

[1218] Clause D55. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D42 to D53, wherein the variant or salt thereof comprises a substitution of T at position -1 , such as replacement by A, K, M, N, R or S, especially A, K, M, N or R.

[1219] Clause D56. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D42 to D53, wherein the variant or salt thereof comprises a substitution of E at position 0, such as replacement by A, D, G, K, Q or V, especially G, K, Q or V.

[1220] Clause D57. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D42 to D53, wherein the variant or salt thereof comprises a substitution of X2 at position 1 , such as replacement by A, C, E, H, L, M, N, R, S, T, V or Y, especially A, E, H, L, M, N, R, T, V or Y.

[1221] Clause D58. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D42 to D53, wherein the variant or salt thereof comprises a substitution of X3 at position 2, such as replacement by D, E, F, G, H, K, M, N, P, Q, S or W, especially D, E, F, G, H, K, M, N, P, Q or W.

[1222] Clause D59. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D42 to D53, wherein the variant or salt thereof comprises a substitution of E at position 3, such as replacement by A, D, G, K, Q or V, especially G, K, Q or V.

[1223] Clause D60. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D42 to D53, wherein the variant or salt thereof comprises a substitution of H at position 4, such as replacement by D, L, N, P, Q, R or Y.

[1224] Clause D61. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D42 to D53, wherein the variant or salt thereof comprises a substitution of X4 at position 5, such as replacement by G, K, Q, S, T or V, especially G, K, Q, T or V.

[1225] Clause D62. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D42 to D53, wherein the variant or salt thereof comprises a substitution of E at position 6, such as replacement by A, D, G, K, Q or V.

[1226] Clause D63. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D42 to D53, wherein the variant or salt thereof comprises a substitution of D at position 7, such as replacement by A, E, G, H, N, V or Y.

[1227] Clause D64. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D42 to D53, wherein the variant or salt thereof comprises a substitution of V at position 8, such as replacement by D, E, I, L or M.

[1228] Clause D65. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D43 to D53, wherein the variant or salt thereof comprises one conservative substitution.

[1229] Clause D66. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D1 to D41 , wherein the peptide is a lipidated linear peptide or salt thereof.

[1230] Clause D67. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D1 to D66, wherein the lipidated linear peptide, variant or salt comprises a lipidated K residue.

[1231] Clause D68. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause D67, wherein the lipidated K residue is X2 position 1. Clause D69. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause D67, wherein the lipidated K residue is Xi position -2.

[1232] Clause D70. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D1 to D69, wherein the lipid chain is a C16DA, C18DA or C20DA group.

[1233] Clause D71. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause D70, wherein the lipid chain is a C18DA group.

[1234] Clause D72. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D1 to D71, wherein the lipid is linked to the K residue via a yGlu.

[1235] Clause D73. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause D72, wherein the lipid is linked to the K residue via a yGlu and one to four OEG groups.

[1236] Clause D74. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause D73, wherein the lipid is linked to the K residue via a yGlu and two OEG groups.

[1237] Clause D75. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D1 to D69, wherein the lipid is C18DA-yGlu-OEG-OEG-.

[1238] Clause D76. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D1 to D69, wherein the lipid is C18DA-yGlu-OEG-OEG-.

[1239] Clause D77. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to either clause D75 or D76, wherein the lipid is C18DA-L-yGlu-OEG-OEG-.

[1240] Clause D78. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to either clause D75 or D76, wherein the lipid is C18DA-D-yGlu-OEG-OEG-.

[1241] Clause D79. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D1 to D78, wherein the lipidated linear peptide, variant or salt is N-terminally acetylated.

[1242] Clause D80. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D1 to D78, wherein the lipidated linear peptide, variant or salt is not N-terminally modified.

[1243] Clause D81. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D1 to D80, wherein the lipidated linear peptide, variant or salt is C-terminally amidated.

[1244] Clause D82. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D1 to D80, wherein the lipidated linear peptide, variant or salt is not C-terminally modified.

[1245] Clause D83. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause D1 , wherein the lipidated linear peptide or salt consists of LLP1 or a salt thereof.

[1246] Clause D84. The lipidated linear peptide or salt according to clause D1 wherein the lipidated linear peptide or salt consists of LLP2 or a salt thereof.

[1247] Clause D85. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause D1 wherein the lipidated linear peptide or salt consists of LLP3 or a salt thereof.

[1248] Clause D86. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause D1 wherein the lipidated linear peptide or salt consists of LLP4 or a salt thereof.

[1249] Clause D87. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause D1, wherein the lipidated linear peptide or salt consists of LLP5 or a salt thereof.

[1250] Clause D88. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause D1, wherein the lipidated linear peptide or salt consists of LLP6 or a salt thereof.

[1251] Clause D89. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause D1, wherein the lipidated linear peptide or salt consists of LLP7 or a salt thereof.

[1252] Clause D90. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause D1, wherein the lipidated linear peptide or salt consists of LLP8 or a salt thereof.

[1253] Clause D91. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause D1, wherein the lipidated linear peptide or salt consists of LLP9 or a salt thereof. Clause D92. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause D1, wherein the lipidated linear peptide or salt consists of LLP10 or a salt thereof.

[1254] Clause D93. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause D1, wherein the lipidated linear peptide or salt consists of LLP11 or a salt thereof.

[1255] Clause D94. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause D1, wherein the lipidated linear peptide or salt consists of LLP12 or a salt thereof.

[1256] Clause D95. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D1 to D95, wherein the salt is a pharmaceutically acceptable salt.

[1257] Clause D96. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any preceding D clause, wherein the peptide is a lipidated linear peptide.

[1258] Clause D97. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any preceding D clause, wherein the peptide is a lipidated variant peptide.

[1259] Clause D98. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any preceding D clause, wherein the peptide is a pharmaceutically acceptable salt of a lipidated linear peptide.

[1260] Clause D99. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any preceding D clause, wherein the peptide is a pharmaceutically acceptable salt of the lipidated variant peptide.

[1261] Clause D100. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D1 to D99, wherein the lipidated linear peptide is not side chain modified.

[1262] Clause D101. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses D1 to D99, wherein the lipidated linear peptide is not modified.

[1263] Clause E1. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses 1 to 4, wherein the peptide is a linear peptide comprising the sequence:

[1264] X2- X3- E - H - X4- E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[1265] X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E, A or a salt thereof, or comprising a conservatively substituted variant of SEQ ID No. 51 or a salt thereof, wherein when X2 represents P then X3 is other than V.

[1266] Clause E2. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E1 , wherein all residues of the peptide backbone are joined exclusively by peptide bonds.

[1267] Clause E3. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E1 or E2, wherein the linear peptide, variant or salt comprises 25 or fewer amino acid residues within the backbone.

[1268] Clause E4. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E3, wherein the linear peptide, variant or salt comprises 20 or fewer amino acid residues within the backbone, such as comprising 20 amino acid residues within the backbone.

[1269] Clause E5. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E4, wherein the linear peptide, variant or salt comprises 15 or fewer amino acid residues within the backbone, such as comprising 15 amino acid residues within the backbone.

[1270] Clause E6. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E5, wherein the linear peptide, variant or salt comprises 12 or fewer amino acid residues within the backbone, such as comprising 12 amino acid residues within the backbone.

[1271] Clause E7. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E6, wherein the linear peptide, variant or salt comprises 11 or fewer amino acid residues within the backbone.

[1272] Clause E8. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E1 to E7, wherein the linear peptide, variant or salt comprises at least 7 amino acid residues within the backbone, such as comprising 7 amino acid residues within the backbone.

[1273] Clause E9. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E8, wherein the linear peptide, variant or salt comprises at least 8 amino acid residues within the backbone, such as comprising 8 amino acid residues within the backbone.

[1274] Clause E10. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E9, wherein the linear peptide, variant or salt comprises at least 9 amino acid residues within the backbone, such as comprising 9 amino acid residues within the backbone.

[1275] Clause E11. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E10, wherein the linear peptide, variant or salt comprises at least 10 amino acid residues within the backbone, such as comprising 10 amino acid residues within the backbone.

[1276] Clause E12. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E11, wherein the linear peptide, variant or salt comprises at least 11 amino acid residues within the backbone

[1277] Clause E13. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E12, wherein the linear peptide, variant or salt comprises 11 amino acid residues within the backbone.

[1278] Clause E14. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E8 to E13, wherein the linear peptide, variant or salt comprises the sequence: E - X2- X3- E - H - X4- E position 0 1 2 3 4 5 6 (SEQ ID No.

[1279] 52) wherein:

[1280] X2represents P, D, Q, K, G X3represents I, L, A, T, V X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No. 52 or a salt thereof.

[1281] Clause E15. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E8 to E13, wherein the linear peptide, variant or salt comprises the sequence: X2- X3- E - H - X4- E - D position 1 2 3 4 5 6 7 (SEQ ID No.

[1282] 53) wherein: X2represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[1283] 53 or a salt thereof.

[1284] Clause E16. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E9 to E13, wherein the linear peptide, variant or salt comprises the sequence:

[1285] T- E- X2- X3- E- H- X4- E position -1 0 1 2 3 4 5 6 (SEQ

[1286] ID No.54) wherein:

[1287] X2represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[1288] 54 or a salt thereof.

[1289] Clause E17. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E9 to E13, wherein the linear peptide, variant or salt comprises the sequence:

[1290] E- X2- X3- E- H- X4- E- D position 0 1 2 3 4 5 6 7 (SEQ ID No.55) wherein:

[1291] X2represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[1292] 55 or a salt thereof.

[1293] Clause E18. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E9 to E13, wherein the linear peptide, variant or salt comprises the sequence:

[1294] X2- X3- E- H- X4- E- D- V position 1 2 3 4 5 6 7 8 (SEQ ID No.56) wherein:

[1295] X2represents P, D, Q, K, G X3represents I, L, A, T, V X4 represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[1296] 56 or a salt thereof.

[1297] Clause E19. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E10 to E13, wherein the linear peptide, variant or salt comprises the sequence:

[1298] Xi - T - E - X2- X3- E - H - X4- E position -2 -1 0 1 2 3 4 5 6

[1299] (SEQ ID No.57) wherein:

[1300] Xi represents M, K X2represents P, D, Q, K, G X3represents I, L, A, T, V X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[1301] 57 or a salt thereof.

[1302] Clause E20. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E10 to E13, wherein the linear peptide, variant or salt comprises the sequence:

[1303] T- E- X2- X3- E- H- X4- E- D position -1 0 1 2 3 4 5 6 7

[1304] (SEQ ID No.58) wherein:

[1305] X2represents P, D, Q, K, G X3 represents I, L, A, T, V X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[1306] 58 or a salt thereof.

[1307] Clause E21. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E10 to E13, wherein the linear peptide, variant or salt comprises the sequence:

[1308] E- X2- X3- E- H- X4- E- D- V position 0 1 2 3 4 5 6 7 8 (SEQ ID No.59) wherein:

[1309] X2represents P, D, Q, K, G X3represents I, L, A, T, V X4 represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[1310] 59 or a salt thereof.

[1311] Clause E22. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E11 to E13, wherein the linear peptide, variant or salt comprises the sequence: Xi - T - E - X2- X3- E - H - X4- E - D position -2 -1 0 1 2 3 4 5 6 7

[1312] (SEQ ID No. 60) wherein:

[1313] Xi represents M, K

[1314] X2represents P, D, Q, K, G X3represents I, L, A, T, V X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[1315] 60 or a salt thereof.

[1316] Clause E23. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E11 to E13, wherein the linear peptide, variant or salt comprises the sequence: T - E - X2- X3- E - H - X4 - E - D - V position -1 0 1 2 3 4 5 6 7 8

[1317] (SEQ ID No. 61) wherein:

[1318] X2represents P, D, Q, K, G X3 represents I, L, A, T, V X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[1319] 61 or a salt thereof.

[1320] Clause E24. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E12 to E13, wherein the linear peptide, variant or salt comprises the sequence: Xi - T - E - X2- X3- E - H - X4- E - D - V position -2 -1 0 1 2 3 4 5 6 7 8

[1321] (SEQ ID No. 62) wherein:

[1322] Xi represents M, K X2 represents P, D, Q, K, G

[1323] X3 represents I, L, A, T, V

[1324] X4 represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No. 62 or a salt thereof.

[1325] Clause E25. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E1 to E24, wherein Xi represents M.

[1326] Clause E26. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E1 to E24, wherein Xi represents K.

[1327] Clause E27. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E1 to E25, wherein X2 represents P.

[1328] Clause E28. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E1 to E25, wherein X2 represents D.

[1329] Clause E29. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E1 to E25, wherein X2 represents Q.

[1330] Clause E30. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E1 to E25, wherein X2 represents K.

[1331] Clause E31. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E1 to E25, wherein X2 represents G.

[1332] Clause E32. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E1 to E31 , wherein X3 represents I.

[1333] Clause E33. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E1 to E31 , wherein X3 represents L.

[1334] Clause E34. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E1 to E31 , wherein X3 represents A. Clause E35. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E1 to E31 , wherein X3 represents T.

[1335] Clause E36. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E1 to E26 or E28 to E31 , wherein X3 represents V.

[1336] Clause E37. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E1 to E36, wherein X4 represents E.

[1337] Clause E38. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E1 to E36, wherein X4 represents A.

[1338] Clause E39. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E12 to E13, wherein the linear peptide, variant or salt comprises the sequence of any one of SEQ ID No. 1 to 10 and 16 to 39, or a salt thereof, or comprises a conservatively substituted variant of any one of SEQ ID No. 1 to 10 and 16 to 39 or a salt thereof, such as consisting of the sequence of any one of SEQ ID No. 1 to 10 and 16 to 39, or a salt thereof, or consisting of a conservatively substituted variant of any one of SEQ ID No. 1 to 10 and 16 to 39 or a salt thereof.

[1339] Clause E40. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E12 to E13, wherein the linear peptide, variant or salt comprises the sequence of SEQ ID No. 1 , or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No. 1 or a salt thereof, such as consisting of the sequence of SEQ ID No. 1 , or a salt thereof, or consisting of a conservatively substituted variant of SEQ ID No. 1 or a salt thereof.

[1340] Clause E41. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E1 to E40, wherein the variant or salt thereof comprises two conservative substitutions.

[1341] Clause E42. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E1 to E41, wherein the variant or salt thereof comprises a substitution of Xi at position -2, such as replacement by E, N, Q, R, T I, L or V.

[1342] Clause E43. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E1 to E41 , wherein the variant or salt thereof comprises a substitution of T at position -1 , such as replacement by A, K, M, N, R or S, especially A, K, M, N or R.

[1343] Clause E44. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E1 to E41, wherein the variant or salt thereof comprises a substitution of E at position 0, such as replacement by A, D, G, K, Q or V, especially G, K, Q or V.

[1344] Clause E45. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E1 to E41, wherein the variant or salt thereof comprises a substitution of X2 at position 1 , such as replacement by A, C, E, H, L, M, N, R, S, T, V or Y, especially A, E, H, L, M, N, R, T, V or Y.

[1345] Clause E46. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E1 to E41, wherein the variant or salt thereof comprises a substitution of X3 at position 2, such as replacement by D, E, F, G, H, K, M, N, P, Q, S or W, especially D, E, F, G, H, K, M, N, P, Q or W.

[1346] Clause E47. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E1 to E41, wherein the variant or salt thereof comprises a substitution of E at position 3, such as replacement by A, D, G, K, Q or V, especially G, K, Q or V.

[1347] Clause E48. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E1 to E41, wherein the variant or salt thereof comprises a substitution of H at position 4, such as replacement by D, L, N, P, Q, R or Y.

[1348] Clause E49. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E1 to E41, wherein the variant or salt thereof comprises a substitution of X4 at position 5, such as replacement by G, K, Q, S, T or V, especially G, K, Q, T or V.

[1349] Clause E50. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E1 to E41, wherein the variant or salt thereof comprises a substitution of E at position 6, such as replacement by A, D, G, K, Q or V.

[1350] Clause E51. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E1 to E41, wherein the variant or salt thereof comprises a substitution of D at position 7, such as replacement by A, E, G, H, N, V or Y. Clause E52. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E1 to E41, wherein the variant or salt thereof comprises a substitution of V at position 8, such as replacement by D, E, I, L or M.

[1351] Clause E53. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E41 to E52, wherein the variant or salt thereof comprises a substitution of Xi at position -2, such as replacement by E, N, Q, R, T I, L or V.

[1352] Clause E54. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E41 to E52, wherein the variant or salt thereof comprises a substitution of T at position -1 , such as replacement by A, K, M, N, R or S, especially A, K, M, N or R.

[1353] Clause E55. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E41 to E52, wherein the variant or salt thereof comprises a substitution of E at position 0, such as replacement by A, D, G, K, Q or V, especially G, K, Q or V.

[1354] Clause E56. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E41 to E52, wherein the variant or salt thereof comprises a substitution of X2 at position 1 , such as replacement by A, C, E, H, L, M, N, R, S, T, V or Y, especially A, E, H, L, M, N, R, T, V or Y.

[1355] Clause E57. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E41 to E52, wherein the variant or salt thereof comprises a substitution of X3 at position 2, such as replacement by D, E, F, G, H, K, M, N, P, Q, S or W, especially D, E, F, G, H, K, M, N, P, Q or W.

[1356] Clause E58. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E41 to E52, wherein the variant or salt thereof comprises a substitution of E at position 3, such as replacement by A, D, G, K, Q or V, especially G, K, Q or V.

[1357] Clause E59. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E41 to E52, wherein the variant or salt thereof comprises a substitution of H at position 4, such as replacement by D, L, N, P, Q, R or Y.

[1358] Clause E60. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E41 to E52, wherein the variant or salt thereof comprises a substitution of X4 at position 5, such as replacement by G, K, Q, S, T or V, especially G, K, Q, T or V.

[1359] Clause E61. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E41 to E52, wherein the variant or salt thereof comprises a substitution of E at position 6, such as replacement by A, D, G, K, Q or V.

[1360] Clause E62. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E41 to E52, wherein the variant or salt thereof comprises a substitution of D at position 7, such as replacement by A, E, G, H, N, V or Y.

[1361] Clause E63. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E41 to E52, wherein the variant or salt thereof comprises a substitution of V at position 8, such as replacement by D, E, I, L or M.

[1362] Clause E64. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E42 to E52, wherein the variant or salt thereof comprises one conservative substitution.

[1363] Clause E65. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E1 to E40, wherein the peptide is a linear peptide or salt thereof.

[1364] Clause E66. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E1 to E65, wherein the linear peptide, variant or salt is N-terminally acetylated.

[1365] Clause E67. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E1 to E65, wherein the linear peptide, variant or salt is not N-terminally modified.

[1366] Clause E68. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E1 to E67, wherein the linear peptide, variant or salt is C-terminally amidated.

[1367] Clause E69. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E1 to E67, wherein the linear peptide, variant or salt is not C-terminally modified.

[1368] Clause E70. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E1, wherein the linear peptide or salt consists of SEQ ID No. 1 or a salt thereof. Clause E71. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E1, wherein the linear peptide or salt consists of SEQ ID No. 2 or a salt thereof.

[1369] Clause E72. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E1, wherein the linear peptide or salt consists of SEQ ID No. 3 or a salt thereof.

[1370] Clause E73. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E1, wherein the linear peptide or salt consists of SEQ ID No. 4 or a salt thereof.

[1371] Clause E74. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E1, wherein the linear peptide or salt consists of SEQ ID No. 5 or a salt thereof.

[1372] Clause E75. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E1, wherein the linear peptide or salt consists of SEQ ID No. 6 or a salt thereof.

[1373] Clause E76. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E1, wherein the linear peptide or salt consists of SEQ ID No. 7 or a salt thereof.

[1374] Clause E77. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E1, wherein the linear peptide or salt consists of SEQ ID No. 8 or a salt thereof.

[1375] Clause E78. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E1, wherein the linear peptide or salt consists of SEQ ID No. 9 or a salt thereof.

[1376] Clause E79. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E1, wherein the linear peptide or salt consists of SEQ ID No. 10 or a salt thereof.

[1377] Clause E80. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E1, wherein the linear peptide or salt consists of SEQ ID No. 16 or a salt thereof.

[1378] Clause E81. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E1, wherein the linear peptide or salt consists of SEQ ID No. 17 or a salt thereof.

[1379] Clause E82. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E1, wherein the linear peptide or salt consists of SEQ ID No. 18 or a salt thereof. Clause E83. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E1, wherein the linear peptide or salt consists of SEQ ID No. 19 or a salt thereof.

[1380] Clause E84. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E1, wherein the linear peptide or salt consists of SEQ ID No. 20 or a salt thereof.

[1381] Clause E85. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E1, wherein the linear peptide or salt consists of SEQ ID No. 21 or a salt thereof.

[1382] Clause E86. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E1, wherein the linear peptide or salt consists of SEQ ID No. 22 or a salt thereof.

[1383] Clause E87. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E1 , wherein the linear peptide or salt consists of SEQ ID No. 23 or a salt thereof.

[1384] Clause E88. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E1, wherein the linear peptide or salt consists of SEQ ID No. 24 or a salt thereof.

[1385] Clause E89. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E1, wherein the linear peptide or salt consists of SEQ ID No. 25 or a salt thereof.

[1386] Clause E90. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E1, wherein the linear peptide or salt consists of SEQ ID No. 26 or a salt thereof.

[1387] Clause E91. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E1, wherein the linear peptide or salt consists of SEQ ID No. 27 or a salt thereof.

[1388] Clause E92. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E1, wherein the linear peptide or salt consists of SEQ ID No. 28 or a salt thereof.

[1389] Clause E93. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E1, wherein the linear peptide or salt consists of SEQ ID No. 29 or a salt thereof.

[1390] Clause E94. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E1 , wherein the linear peptide or salt consists of SEQ ID No. 30 or a salt thereof. Clause E95. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E1, wherein the linear peptide or salt consists of SEQ ID No. 31 or a salt thereof.

[1391] Clause E96. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E1 , wherein the linear peptide or salt consists of SEQ ID No. 32 or a salt thereof.

[1392] Clause E97. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E1, wherein the linear peptide or salt consists of SEQ ID No. 33 or a salt thereof.

[1393] Clause E98. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E1, wherein the linear peptide or salt consists of SEQ ID No. 34 or a salt thereof.

[1394] Clause E99. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E1, wherein the linear peptide or salt consists of SEQ ID No. 35 or a salt thereof.

[1395] Clause E100. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E1, wherein the linear peptide or salt consists of SEQ ID No. 36 or a salt thereof.

[1396] Clause E101. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E1, wherein the linear peptide or salt consists of SEQ ID No. 37 or a salt thereof.

[1397] Clause E102. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause E1, wherein the linear peptide or salt consists of SEQ ID No. 38 or a salt thereof.

[1398] Clause E103. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E1 to E102, wherein the salt is a pharmaceutically acceptable salt.

[1399] Clause E104. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any preceding E clause, wherein the peptide is a linear peptide.

[1400] Clause E105. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any preceding E clause, wherein the peptide is a variant peptide.

[1401] Clause E106. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or useaccording to any preceding E clause, wherein the peptide is a pharmaceutically acceptable salt of a linear peptide. Clause E107. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any preceding E clause, wherein the peptide is a pharmaceutically acceptable salt of the variant peptide.

[1402] Clause E108. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E1 to E107, wherein the linear peptide is not side chain modified.

[1403] Clause E109. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses E1 to E107, wherein the linear peptide is not modified.

[1404] Clause F1. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses 1 to 28, wherein the peptide is a linear peptide comprising 10 or fewer amino acid residues within the backbone and comprising the sequence:

[1405] X2- X3- E - H - X4- E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:

[1406] X2represents P, D, Q, K, G

[1407] X3represents I, L, A, T, V

[1408] X4represents E, A or a salt thereof, or comprising a conservatively substituted variant of SEQ ID No. 51 or a salt thereof.

[1409] Clause F2. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause F1, wherein all residues of the peptide backbone are joined exclusively by peptide bonds.

[1410] Clause F3. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause F1 or F2, wherein the linear peptide, variant or salt comprises 6 amino acid residues within the backbone.

[1411] Clause F4. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause F1 or F2, wherein the linear peptide, variant or salt comprises 7 amino acid residues within the backbone.

[1412] Clause F5. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause F1 or F2, wherein the linear peptide, variant or salt comprises 8 amino acid residues within the backbone. Clause F6. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause F1 or F2, wherein the linear peptide, variant or salt comprises 9 amino acid residues within the backbone.

[1413] Clause F7. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause F1 or F2, wherein the linear peptide, variant or salt comprises 10 amino acid residues within the backbone.

[1414] Clause F8. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1, F2 or F4 to F7, wherein the linear peptide, variant or salt comprises the sequence:

[1415] E - X2- X3- E - H - X4- E position 0 1 2 3 4 5 6 (SEQ ID No.

[1416] 52) wherein:

[1417] X2represents P, D, Q, K, G X3represents I, L, A, T, V X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[1418] 52 or a salt thereof.

[1419] Clause F9. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1, F2 or F4 to F7, wherein the linear peptide, variant or salt comprises the sequence:

[1420] X2- X3 - E - H - X4 - E - D position 1 2 3 4 5 6 7 (SEQ ID No.

[1421] 53) wherein:

[1422] X2represents P, D, Q, K, G

[1423] X3 represents I, L, A, T, V

[1424] X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[1425] 53 or a salt thereof.

[1426] Clause F10. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1, F2 or F5 to F7, wherein the linear peptide, variant or salt comprises the sequence:

[1427] T- E- X2- X3- E- H- X4- E position -1 0 1 2 3 4 5 6 (SEQ

[1428] ID No.54) wherein:

[1429] X2represents P, D, Q, K, G X3represents I, L, A, T, V X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[1430] 54 or a salt thereof.

[1431] Clause F11. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1, F2 or F5 to F7, wherein the linear peptide, variant or salt comprises the sequence:

[1432] E- X2- X3- E- H- X4- E- D position 0 1 2 3 4 5 6 7 (SEQ ID No.55) wherein:

[1433] X2represents P, D, Q, K, G

[1434] X3 represents I, L, A, T, V

[1435] X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[1436] 55 or a salt thereof.

[1437] Clause F12. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1, F2 or F6 to F7, wherein the linear peptide, variant or salt comprises the sequence:

[1438] X2- X3- E- H- X4- E- D- V position 1 2 3 4 5 6 7 8 (SEQ ID No.56) wherein:

[1439] X2represents P, D, Q, K, G

[1440] X3 represents I, L, A, T, V

[1441] X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[1442] 56 or a salt thereof. Clause F13. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1, F2, F6 or F7, wherein the linear peptide, variant or salt comprises the sequence: Xi - T - E - X2- X3- E - H - X4- E position -2 -1 0 1 2 3 4 5 6

[1443] (SEQ ID No.57) wherein:

[1444] Xi represents M, K

[1445] X2represents P, D, Q, K, G X3represents I, L, A, T, V X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[1446] 57 or a salt thereof.

[1447] Clause F14. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1, F2, F6 or F7, wherein the linear peptide, variant or salt comprises the sequence: T- E- X2- X3- E- H- X4- E- D position -1 0 1 2 3 4 5 6 7

[1448] (SEQ ID No.58) wherein:

[1449] X2represents P, D, Q, K, G X3 represents I, L, A, T, V X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[1450] 58 or a salt thereof.

[1451] Clause F15. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1, F2, F6 or F7, wherein the linear peptide, variant or salt comprises the sequence: E- X2- X3- E- H- X4- E- D- V position 0 1 2 3 4 5 6 7 8 (SEQ ID No.59) wherein:

[1452] X2represents P, D, Q, K, G X3 represents I, L, A, T, V X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No.

[1453] 59 or a salt thereof. Clause F16. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1, F2 or F7, wherein the linear peptide, variant or salt comprises the sequence: Xi - T - E - X2- X3- E - H - X4- E - D position -2 -1 0 1 2 3 4 5 6 7

[1454] (SEQ ID No. 60) wherein:

[1455] Xi represents M, K

[1456] X2 represents P, D, Q, K, G X3represents I, L, A, T, V X4represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No. 60 or a salt thereof.

[1457] Clause F17. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1,

[1458] F2 or F7, wherein the linear peptide, variant or salt comprises the sequence:

[1459] T - E - X2- X3 - E - H - X4 - E - D - V position -1 0 1 2 3 4 5 6 7 8

[1460] (SEQ ID No. 61) wherein:

[1461] X2 represents P, D, Q, K, G

[1462] X3 represents I, L, A, T, V

[1463] X4 represents E, A or a salt thereof, or comprises a conservatively substituted variant of SEQ ID No. 61 or a salt thereof.

[1464] Clause F18. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1 to F17, wherein Xi represents M.

[1465] Clause F19. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1 to F17, wherein Xi represents K.

[1466] Clause F20. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1 to F19, wherein X2 represents P.

[1467] Clause F21. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1 to F19, wherein X2 represents D. Clause F22. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1 to F19, wherein X2 represents Q.

[1468] Clause F23. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1 to F19, wherein X2 represents K.

[1469] Clause F24. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1 to F19, wherein X2 represents G.

[1470] Clause F25. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1 to F24, wherein X3 represents I.

[1471] Clause F26. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1 to F24, wherein X3 represents L.

[1472] Clause F27. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1 to F24, wherein X3 represents A.

[1473] Clause F26. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1 to F24, wherein X3 represents T.

[1474] Clause F29. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1 to F24, wherein X3 represents V.

[1475] Clause F30. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1 to F29, wherein X4 represents E.

[1476] Clause F31. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1 to F29, wherein X4 represents A.

[1477] Clause F32. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1 to F31 , wherein the linear peptide, variant or salt comprises the sequence of any one of SEQ ID No. 40 to 42, or a salt thereof, or comprises a conservatively substituted variant of any one of SEQ ID No. 40 to 42 or a salt thereof.

[1478] Clause F33. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause F32, wherein the linear peptide, variant or salt consists of the sequence of any one of SEQ ID No. 40 to 42, or a salt thereof, or consists of a conservatively substituted variant of any one of SEQ ID No. 40 to 42 or a salt thereof.

[1479] Clause F34. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1 to F33, wherein the variant or salt thereof comprises two conservative substitutions.

[1480] Clause F35. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1 to F34, wherein the variant or salt thereof comprises a substitution of Xi at position -2, such as replacement by E, N, Q, R, T I, L or V.

[1481] Clause F36. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1 to F34, wherein the variant or salt thereof comprises a substitution of T at position - 1 , such as replacement by A, K, M, N, R or S, especially A, K, M, N or R.

[1482] Clause F37. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1 to F34, wherein the variant or salt thereof comprises a substitution of E at position 0, such as replacement by A, D, G, K, Q or V, especially G, K, Q or V.

[1483] Clause F38. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1 to F34, wherein the variant or salt thereof comprises a substitution of X2 at position

[1484] 1 , such as replacement by A, C, E, H, L, M, N, R, S, T, V or Y, especially A, E, H, L, M, N, R, T, V or Y.

[1485] Clause F39. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1 to F34, wherein the variant or salt thereof comprises a substitution of X3 at position

[1486] 2, such as replacement by D, E, F, G, H, K, M, N, P, Q, S or W, especially D, E, F, G, H, K, M, N, P, Q or W.

[1487] Clause F40. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1 to F34, wherein the variant or salt thereof comprises a substitution of E at position

[1488] 3, such as replacement by A, D, G, K, Q or V, especially G, K, Q or V.

[1489] Clause F41. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1 to F34, wherein the variant or salt thereof comprises a substitution of H at position

[1490] 4, such as replacement by D, L, N, P, Q, R or Y. Clause F42. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1 to F34, wherein the variant or salt thereof comprises a substitution of X4 at position

[1491] 5, such as replacement by G, K, Q, S, T or V, especially G, K, Q, T or V.

[1492] Clause F43. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1 to F34, wherein the variant or salt thereof comprises a substitution of E at position

[1493] 6, such as replacement by A, D, G, K, Q or V.

[1494] Clause F44. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1 to F34, wherein the variant or salt thereof comprises a substitution of D at position

[1495] 7, such as replacement by A, E, G, H, N, V or Y.

[1496] Clause F45. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1 to F34, wherein the variant or salt thereof comprises a substitution of V at position

[1497] 8, such as replacement by D, E, I, L or M.

[1498] Clause F46. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F34 to F45, wherein the variant or salt thereof comprises a substitution of Xi at position -2, such as replacement by E, N, Q, R, T I, L or V.

[1499] Clause F47. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F34 to F45, wherein the variant or salt thereof comprises a substitution of T at position -1 , such as replacement by A, K, M, N, R or S, especially A, K, M, N or R.

[1500] Clause F48. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F34 to F45, wherein the variant or salt thereof comprises a substitution of E at position 0, such as replacement by A, D, G, K, Q or V, especially G, K, Q or V.

[1501] Clause F49. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F34 to F45, wherein the variant or salt thereof comprises a substitution of X2 at position 1 , such as replacement by A, C, E, H, L, M, N, R, S, T, V or Y, especially A, E, H, L, M, N, R, T, V or Y.

[1502] Clause F50. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F34 to F45, wherein the variant or salt thereof comprises a substitution of X3 at position 2, such as replacement by D, E, F, G, H, K, M, N, P, Q, S or W, especially D, E, F, G, H, K, M, N, P, Q or W.

[1503] Clause F51. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F34 to F45, wherein the variant or salt thereof comprises a substitution of E at position 3, such as replacement by A, D, G, K, Q or V, especially G, K, Q or V.

[1504] Clause F52. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F34 to F45, wherein the variant or salt thereof comprise a substitution of H at position 4, such as replacement by D, L, N, P, Q, R or Y.

[1505] Clause F53. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F34 to F45, wherein the variant or salt thereof comprises a substitution of X4 at position 5, such as replacement by G, K, Q, S, T or V, especially G, K, Q, T or V.

[1506] Clause F54. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F34 to F45, wherein the variant or salt thereof comprises a substitution of E at position 6, such as replacement by A, D, G, K, Q or V.

[1507] Clause F55. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F34 to F45, wherein the variant or salt thereof comprises a substitution of D at position 7, such as replacement by A, E, G, H, N, V or Y.

[1508] Clause F56. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F34 to F45, wherein the variant or salt thereof comprises a substitution of V at position 8, such as replacement by D, E, I, L or M.

[1509] Clause F57. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F35 to F45, wherein the variant or salt thereof comprises one conservative substitution.

[1510] Clause F58. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1 to F57, wherein the linear peptide, variant or salt is N-terminally acetylated.

[1511] Clause F59. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1 to F57, wherein the linear peptide, variant or salt is not N-terminally modified. Clause F60. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1 to F59, wherein the linear peptide, variant or salt is C-terminally amidated.

[1512] Clause F61. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1 to F59, wherein the linear peptide, variant or salt is not C-terminally modified.

[1513] Clause F62. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1 to F33, wherein the peptide is a linear peptide.

[1514] Clause F63. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause F1, wherein the linear peptide or salt consists of SEQ ID No. 40 or a salt thereof.

[1515] Clause F64. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause F1, wherein the linear peptide or salt consists of SEQ ID No. 41 or a salt thereof.

[1516] Clause F65. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause F1, wherein the linear peptide or salt consists of SEQ ID No. 42 or a salt thereof.

[1517] Clause F66. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1 to F65, wherein the salt is a pharmaceutically acceptable salt.

[1518] Clause F67. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any preceding F clause, wherein the peptide is a linear peptide.

[1519] Clause F68. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any preceding F clause, wherein the peptide is a variant peptide.

[1520] Clause F69. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any preceding F clause, wherein the peptide is a pharmaceutically acceptable salt of a linear peptide.

[1521] Clause F70. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any preceding F clause, wherein the peptide is a pharmaceutically acceptable salt of the variant peptide.

[1522] Clause F71. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1 to F70, wherein the linear peptide is not side chain modified. Clause F72. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses F1 to F70, wherein the linear peptide is not modified.

[1523] Clause G1. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses 1 to 4, A1 to A98, B1 to B99, C1 to C70, D1 to D101, E1 to E109 or F1 to F72, wherein the lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, variant of any thereof and / or salt of any thereof is capable of increasing BDNF levels.

[1524] Clause G2. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause G1 , wherein the lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, variant of any thereof and / or salt of any thereof is capable of increasing BDNF levels by at least 20% between 0 and 24 hours following administration in the assay of Example 10.

[1525] Clause H1. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses 1 to 4, A1 to A98, B1 to B95, C1 to C70, D1 to D101, E1 to E109 or F1 to F72, wherein the lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, variant of any thereof and / or salt of any thereof is capable of increasing phosphor-CREB (Ser133) levels.

[1526] Clause H2. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause H1 , wherein the lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, variant of any thereof and / or salt of any thereof is capable of increasing CREB levels by at least 30% between 0 and 24 hours following administration in the assay of Example 10.

[1527] Clause 11. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses 1 to 4,A1 to A99, B1 to B95, C1 to C70, D1 to D101 , E1 to E109 or F1 to F72, wherein the lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, variant of any thereof and / or salt of any thereof is capable of increasing PGC1a levels.

[1528] Clause I2. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause 11 , wherein the lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, variant of any thereof and / or salt of any thereof is capable of increasing PGC1a levels by at least 30% between 0 and 24 hours following administration in the assay of Example 10.

[1529] Clause J1. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses 1 to 4, A1 to A99, B1 to B95, C1 to C70, D1 to D101, E1 to E109 or F1 to F72, wherein the lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, variant of any thereof and / or salt of any thereof is capable of increasing TFEB levels.

[1530] Clause J2. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause J1 , wherein the lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, variant of any thereof and / or salt of any thereof is capable of increasing TFEB levels by at least 30% between 0 and 24 hours following administration in the assay of Example 10.

[1531] Clause K1. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses 1 to 4, A1 to A99, B1 to B95, C1 to C70, D1 to D101, E1 to E109 or F1 to F72, wherein the lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, variant of any thereof and / or salt of any thereof is capable of decreasing NfL levels.

[1532] Clause K2. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause K1 , wherein the lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, variant of any thereof and / or salt of any thereof is capable of decreasing NfL levels by at least 10% between in the assay of Example 31.

[1533] Clause L1. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any preceding clause, wherein the lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, variant of any thereof and / or salt of any thereof has improved ability to increase BDNF, PGC1a, TFEB and / or phospho-CREB (Ser133) as compared to CPX.

[1534] Clause L2. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any preceding clause, wherein the lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, variant of any thereof and / or salt of any thereof has improved ti / 2, AUC or Cmax, particularly in the brain, as compared to CPX. Clause L3. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any preceding clause, wherein the lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, variant of any thereof and / or salt of any thereof has improved ti / 2 in the brain, as compared to CPX.

[1535] Clause L4. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any preceding clause, wherein the lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, variant of any thereof and / or salt of any thereof has ability to increase BDNF, PGC1a, TFEB and / or phospho-CREB (Ser133) at least equivalent to CLP1.

[1536] Clause L5. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any preceding clause, wherein the lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, variant of any thereof and / or salt of any thereof has ti / 2, AUC or Cmax, particularly in the brain, at least equivalent to CLP1.

[1537] Clause L6. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any preceding clause, wherein the lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, variant of any thereof and / or salt of any thereof has ti / 2 particularly in the brain, at least equivalent to CLP1.

[1538] Clause L7. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any preceding clause, wherein the lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, variant of any thereof and / or salt of any thereof demonstrates an absence of fibrillation at pH 6.5 and 7.5, suitably at pH 4.5, pH 6.5 and pH 7.5 (such as by the method of Example 5).

[1539] Clause L8. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any preceding clause, wherein the lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, variant of any thereof and / or salt of any thereof demonstrates a ti / 2 of at least 1 hr, suitably at least 4 hours, especially at least 8 hours (such as by the method of Example 9).

[1540] Clause L9. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause Q8, wherein the lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, variant of any thereof and / or salt of any thereof demonstrates a ti / 2 in the brain of at least 1 hr, suitably at least 4 hours, especially at least 8 hours (such as by the method of Example 9).

[1541] Clause M1. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses 1 to L9, wherein the disease or disorder of the ear or mastoid process is a disease or disorder with hearing loss or impairment.

[1542] Clause M2. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause M1 , wherein the hearing loss is sensorineural hearing loss.

[1543] Clause M3. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause M1 or M2, wherein the hearing loss is acquired hearing loss.

[1544] Clause M4. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause M1 or M2, wherein the hearing loss is congenital hearing loss.

[1545] Clause M5. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses M1 to M4, wherein the hearing loss is genetic hearing loss.

[1546] Clause M6. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause M5, wherein the genetic hearing loss is syndromic hearing loss.

[1547] Clause M7. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause M6, wherein the syndrome is selected from Stickler Syndrome, Waardenburg Syndrome, Branchio-Oto-Renal Syndrome, CHARGE Syndrome, Treacher-Collins Syndrome, Usher Syndrome, Pendred Syndrome, Jervell and Lange-Nielsen Syndrome, Alport Syndrome, and X-Linked Congenital Stapes Fixation with Perilymph Gusher.

[1548] Clause M8. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause M5, wherein the genetic hearing loss is non-syndromic hearing loss.

[1549] Clause M9. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause M8, wherein the non-syndromic hearing loss is relation to a mutation in one or more of the genes selected from GJB2, GJB6, STRC, KCNQ4, TECTA, and POU3F4. Clause M10. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses M1 to M5, wherein the hearing loss related to a mitochondrial condition.

[1550] Clause M11. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause M10, wherein the mitochondrial condition is selected from Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS), Maternally Inherited Diabetes and Deafness (MIDD), Kearns-Sayre Syndrome (KSS), and Myoclonic Epilepsy and Ragged Red Fibers (MERRF).

[1551] Clause M12. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses M1 to M11 , wherein the hearing loss is auditory synaptopathy or neuropathy.

[1552] Clause M13. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses M1 to M12, wherein the hearing loss is hidden hearing loss.

[1553] Clause M14. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause M1 , wherein the disease or disorder of the ear or mastoid process is a vestibular syndrome.

[1554] Clause M15. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause M14, wherein the vestibular syndrome is Meniere disease.

[1555] Clause M16. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause M14, wherein the vestibular syndrome is a vertiginous syndrome.

[1556] Clause M17. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses 1 to M16, wherein administration of the peptide results in hearing improvement.

[1557] Clause M18. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause M17, wherein the hearing improvement is measured using pure tone audiometry.

[1558] Clause M19. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause M17 or M18, wherein the hearing improvement is measured using auditory brainstem response.

[1559] Clause M20. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses M17 to M19, wherein the hearing improvement is measured using otoacoustic emissions.

[1560] Clause M21. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses M17 to M20, wherein the hearing improvement is an improvement in one or more of speech detection threshold, speech recognition threshold and / or word recognition score,

[1561] Clause M22. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses M17 to M21 , wherein the hearing improvement is measured using one or more of the Hearing in Noise test (HINT), American English Matrix test (AEMT), Digits in Noise test (DIN), Words in Noise test (WIN), Speech Recognition in Noise test (SPRINT).

[1562] Clause M23. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses 1 to M22, wherein administration of the peptide increases the number of cochlear ribbon synapses.

[1563] Clause M24. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses 1 to M23, wherein administration of the peptide increases the number of spiral ganglion neuron cells,

[1564] Clause M25. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses 1 to M24, wherein administration of the peptide increases the number of inner hair cells and / or outer hair cells.

[1565] Clause M26. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses 1 to M25, for use in treatment.

[1566] Clause M27. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses 1 to M25, for use in prophylaxis.

[1567] Clause M28. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses 1 to M27, for use in a human subject.

[1568] Clause M29. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses 1 to M28, wherein the human subject is less than 2 years of age. Clause M30. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses 1 to M28, wherein the subject is 2 to 17 years old.

[1569] Clause M31. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses 1 to M28, wherein the human subject is aged 18 to 65.

[1570] Clause M32. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of clauses 1 to M28, wherein the human subject is aged 66 years old or older.

[1571] Clause M33. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any preceding clause where the disease or disorder of the ear or mastoid process is cochlear synaptopathy.

[1572] Clause M34. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause M33 wherein the cochlear synaptopathy is associated with age, sensorineural hearing loss, noise- induced hearing loss.

[1573] Clause M35. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause M33 wherein the cochlear synaptopathy is associated with inflammatory or neurodegenerative disorders, isuch as Huntingdon’s Disease Parkinson’s Disease or Alzheimer’s Disease.

[1574] Clause M36. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any preceding clause where the disease or disorder of the ear or mastoid process is age-related hearing loss.

[1575] Clause M36. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any preceding clause where hearing loss is due to noise exposure.

[1576] Clause M37. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any preceding clause where hearing loss is due to ototoxic drug exposure.

[1577] Clause M38. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any preceding clause wherein speech in noise (SIN) test is improved relative to untreated subjects. Clause M39. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to clause M38 wherein words in noise (WIN) test is improved relative to untreated subjects.

[1578] Clause M40. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any preceding clause wherein absolute OAE amplitude is increased relative to untreated subjects.

[1579] Clause M41. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any preceding clause wherein the peptide is backbone cyclised and the backbone of the peptide is joined exclusively by peptide bonds.

[1580] Clause M42. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any preceding clause wherein all residues within a cyclic peptide are within the cycle.

[1581] The present invention is also described in more detail with reference to the Examples which follow, but is not limited thereto. The examples may be modified without departing from the scope of the invention.

[1582] In addition, as used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to “a peptide” includes two or more such peptides, and the like.

[1583] All publications, patents and patent applications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety.

[1584] Examples

[1585] Statistics

[1586] Unless otherwise indicated, two-tailed Student’s t-test was used to assess significance. Error bars indicate S.E.M. *p<0.05, **p<0.01 , ***p<0.001 , ****p<0.0001.

[1587] Example 1: Peptide synthesis

[1588] Linear peptides were synthesized using standard Fmoc (fluorenylmethyloxycarbonyl) chemistry.

[1589] Resin preparation:

[1590] Fmoc-Pro-OH (0.2 mmol, 1 eq) and N,N-diisopropylethylamine (DIPEA) (0.14 mL, 4 eq) were added to 2-CTC Resin (0.2 mmol, 1.00 eq, Sub 1.05 mmol / g) in dichloromethane (DCM) (10 mL). The mixture was agitated with N2 for 2 h at 20°C, then methanol (MeOH) (0.5 mL) added and agitated with N2 bubbling for another 30 min. The resin was washed three times with dimethylformamide (DMF) (15 mL).

[1591] Deprotection:

[1592] Fmoc removal was performed using 20% piperidine in DMF (15 mL) added and to the resin and agitated with N2 for 30 min. The resin was washed with DMF four times (15 mL) and filtered.

[1593] Coupling:

[1594] The consecutive amino acid couplings were performed using a solution of 2-(1 H- benzotriazole-1-yl)-1 ,1 ,3,3tetramethyluronium hexafluorophosphate (HBTU) (2.85 eq), DIPEA (6 eq) and Fmoc-protected amino acids (3 eq) in DMF (5 mL) added to the resin and agitated with N2 for 30 min at 20°C. The resin was then washed four times with DMF (15 mL). Fmoc deprotection and coupling steps were repeated for each of the subsequent amino acids until the desired peptide sequence was achieved. The resin was then washed four times with dimethylformamide (DMF) (15 mL). Fmoc removal and coupling steps were repeated until the desired peptide sequence was achieved. The resultant sidechain protected and resin bound linear peptide was used directly in the next step.

[1595] The Fmoc-protected amino acid building blocks used were: Fmoc-Ala-OH, Fmoc- Arg(Pbf)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Gln(Trt)-OH, FmocGlu(OtBu)-OH, Fmoc-Gly-OH, Fmoc-His(Trt)-OH, Fmoc-lle-OH, Fmoc-Leu-OH, Fmoc- Lys(Boc)OH, Fmoc-Met-OH, Fmoc-Phe-OH, Fmoc-Pro-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)- OH, Fmoc-Tyr(tBu)-OH, and Fmoc-L-Val-OH. If nothing else is specified, the natural L-form of the amino acids were used. Addition of lipids on lysine-residues was carried out using orthogonally protected Lys (Dde-Lys(Fmoc)-OH), in which the Dde is placed on alpha amine, while Fmoc is placed on sidechain amine. After coupling of the protected Lys, the Fmoc was first removed, then the lipid was coupled to the resulting exposed amine. Dde was subsequently removed and the peptide chain was elongated using Fmoc chemistry as usual.

[1596] Example 2: Peptide cleavage, cyclisation and purification

[1597] After final amino acid coupling and Fmoc removal, the resin from Example 1 was washed with DMF 5 times, with MeOH 3 times, and dried under vacuum. To develop cyclic peptides, the peptide resin was then treated with the cleavage cocktail (1% trifluoroacetic acid (TFA) / 99% DCM) (15 mL) for 15 min and the peptide containing TFA-DCM mixture was collected. The cleavage was repeated three times. In relation to linear peptides, these were cleaved and directly deprotected using strong acid (95%TFA). In relation to cyclic peptides, the peptide (in 1% TFA / 99% DCM) was diluted in DCM (200 mL) together with 2-(1 H-benzotriazole- 1-yl)-1 ,1,3,3-tetramethylaminium tetrafluoroborate (TBTU) (2 eq) and 1 -hydroxybenzotriazole hydrate (HOBT) (2 eq) and DI PEA (6 eq) to couple the head to tail of the peptide. The mixture was stirred at 20 °C for 1 h. Cyclisation was monitored by LC-MS.

[1598] After stirring, the mixture was washed with 1 M hydrochloric acid (HCI) (30 mL) twice and dried under reduced pressure. 5 mL of cleavage buffer (92.5% TFA 12.5% 3- mercaptopropionic acid 12.5% triisopropyl silane 12.5% H2O) was added to the flask containing the sidechain protected cyclic peptide and the mixture was stirred for 2 h at 20 °C. The peptide was precipitated with ice cold tert-butyl methyl ether (40 mL) and centrifuged (2 min at 3000 rpm) and washed two times with ice cold tert-butyl methyl ether (40 mL). The crude peptide was dried under vacuum for 2 hours and purified by prep-HPLC and the target peptide fraction freeze dried to give a white solid:

[1599] Prep-HPLC method: (system: Gilson GX-281; column: Gemini, C18, 110A, 5 pm or Luna, C18, 100A, 10 pm; gradient: gradient run-time 50 minutes; 0 to 50 min 7 to 37% B; flow rate: 20 mL / min; column temperature: 30°C; diode array: 220 / 254 nm; solvent A: 0.075% TFA in water; solvent B: acetonitrile.

[1600] A qualitative analysis of the peptides was conducted by HPLC and LCMS (see Fig. 1): HPLC: Column: Gemini C18, 110A, 5 pm, 150 x 4.6 mm; gradient: gradient run-time 20 minutes; 0.00-20.00 min 15-45% B, 20.10-23.00 min 95% B, 23.00-23.10 min 95-15% B, 23. IQ- 28.00 min 15% B; flow rate: 1.0 mL / min; diode array, 220 / 254 nm; column temperature: 30°C; solvent A: 0.1% TFA in water; solvent B: 0.075% TFA in acetonitrile).

[1601] LCMS method for final products: (system: Agilent Infinity II 1260 HPLC series; column: Xbridge C18, 130A, 3.5 pm, 2.1 x 30 mm; detector: Agilent LCMS (G6125C), single quadrupole TIC scan; scanning range: m / z min 100, m / z max. 2000, positive mode, electrospray; gradient: gradient run-time 1 minutes; 0.00-1.00 min 10-80% B; column cleaning and equilibration; 1.00- 1.01 80-95% B, 1.01-1.60 min 95% B, 1.60-1.61 min 95-10% B, 1.61-2.00 min 10% B; flow rate: 1.2 mL / min; diode array: 215 or 220 nm; column temperature: room temperature; solvent A: 0.1% TFA in water; solvent B: 0.075% TFA in acetonitrile

[1602] Results

[1603] A summary of data on LC-MS and HPLC purity is shown in the table below, with exemplary chromatograms and mass spectrum for CLP1 shown in Fig. 1A to Fig. 1C.

[1604] Table 4 - Summary of peptide HPLC purification and MS characterisation monoisotopic

[1605] Example 3: CLP1 treatment leads to increase in CREB-targeted genes

[1606] SorCS2 has recently been established to play a critical role in BDNF / TrkB signaling by being indispensable in the activation of downstream kinases (Glerup, 2016). A major mediator of the neurotrophin responses to BDNF results from the activation of transcription factor CREB (Finkbeiner, 1997; Walton, 2000; Benito, 2010; Sakamoto, 2011). Activation of CREB is well- known to improve survival, synaptic formation and growth in neurons. A critical mediator of this is the production of BDNF itself, by CREB (Tao, 1998), thereby establishing a positive feedback loop. Similarly has CREB activation been described to induce mitochondrial biogenesis through the upregulation of master regulator PGC1a (Wu, 2006; Kang, 2017). Indeed, the cyclized peptide-mimetic of the SorCS2 receptor fragment, CPX, increases BDNF levels after 4 hours of stimulation in wild-type neurons (WO2022029281). As CLP1 is a cyclised lipidated peptidemimetic of the SorCS2 receptor-fragment important for the BDNF-signal transduction, whether CLP1 treatment leads to increased BDNF and PGC1a production in wild-type neurons as a consequence of CREB activation was assessed. The effects of cyclised and stabilised lipidated peptide CLP1 were compared with those of cyclised peptide CPX.

[1607] Cortical neurons were isolated from pO wild-type mice and seeded in a density of 200,000 per well (24-well tray). After 7 days in vitro the neurons were stimulated with 1 uM CLP1 or CPX in neurobasal A 15 media and incubated at 37°C and 5% CO2 for 8, 16 or 24 hours. Hereafter, the neurons were lysed in RIPA lysis buffer containing complete cocktail protease inhibitor. BDNF and PGC1a levels were analysed by western blotting normalized to beta-actin.

[1608] As shown in Fig. 2A and Fig. 2B, CLP1 significantly upregulated both of the assessed CREB-downstream target genes of BDNF by 180% (p=0.0174) and PGC1a by 611% (p<0.0001) after 24 hours of stimulation. CPX did not increase the levels of either BDNF or PGC1a, possibly due to the fact that its effect is elicited prior to the assessed timepoints. This indicates prolonged signaling of CLP1 compared to CPX.

[1609] Example 4: CLP1 clears soluble mHTT in Huntington’s patient-derived fibroblasts

[1610] Autophagy is the process of clearing misfolded proteins, aggregates or damaged organelles. In addition to driving mitochondrial biogenesis, PGC1a, has been shown to promote lysosomal biogenesis through regulation of TFEB (master regulator of lysosomal biogenesis) (Ghosh, 2015; Lynch, 2020). CLP1-induced decrease of mHTT (mutated Huntingtin) protein expressed from the disease-causing gene in HD, as a cause of PGC1a upregulation and regulation of TFEB, was assessed. CPX, which has previously shown to reduce mutated HTT levels (WO2022029281), was included to compare efficacy. Patient-derived fibroblasts GM04476 (from Coriell Biobank) were seeded at 30,000-50,000 per well in a 96-well plate. The following day, the cells were treated with 1 uM of CLP1 or CPX and incubated at 37°C and 5% CO2 for 24 hours. Hereafter, the cells were lysed in RIPA lysis buffer containing complete cocktail protease inhibitor. Total Huntingtin levels were analysed by antibody mab2166 (Sigma- Aldrich) and mutated Huntingtin levels were measured by antibody (MW1 ab), which only detects the mutated-allele in western blotting. The levels were normalized to beta-actin. As shown in Fig. 3A and Fig. 3B, both CLP1 and CPX reduced levels of mutated Huntingtin to 50% (p=0.0048) and 75% (p=0.0209), respectively, while reducing total levels of Huntingtin (mutated and healthy allele) to -65% (p=0.0036) for CLP1 and 75% for CPX (p=0.0056). This demonstrates increased efficacy of CLP1 compared to CPX in addition to CLP1 eliciting degradation more specifically towards the mutated Huntingtin protein than healthy, thereby providing a valuable opportunity as a therapeutic drug for HD patients.

[1611] Example 5: Chemical and physical stability of CLP1

[1612] To better understand the chemical basis of CLP1 stability and degradation the chemical and physical stability of CLP1 in three buffer systems was evaluated. Solutions of CLP1 were prepared in three buffer systems with different pH-values and the samples were incubated at 40°C without agitation. Chemical stability was assessed by means of UPLC-UV on the day of preparation (tO) and after two weeks of incubation (t14) . The physical stability was assessed by means of a Thioflavin T (ThT) assay over the course of four days with agitation at 40 °C.

[1613] For each assay the samples were dissolved to a peptide concentration of 1 mg / mL either in 25 % acetonitrile (ACN) (for analytical standard solutions) or in one of the three buffer systems (50 mM sodium acetate buffer, pH 4.5 (22.5 mM sodium acetate + 27.5 mM glacial acetic acid); 50 mM L-Histidine buffer, pH 6.5; 50 mM sodium phosphate buffer, pH 7.5 (40.6 mM Na2HPC>4 + 9.4 mM NaHzPC i)). All buffers were prepared in ultrapure water (Milli-Q® Reference A+ System, Merck) with a resistivity of 18.2 MQ cm. The samples were centrifuged at 13300 rpm (17000g) for 10 min prior to UPLC-UV measurements. For the physical stability study, the samples were filtered through 0.22 urn cellulose filters (13 0, Frisenette) prior to setting up the ThT assay.

[1614] UPLC-UV method for chemical : column Kinetex 1.7 pm C18 100 A 150x2.1 mm from Phenomenex; mobile phase A: Ultrapure water + 0.1 % TFA; mobile phase B: Acetonitrile + 0.1 % TFA; injection volume: 2 pL of CLP1 ; flow rate: 0.3 mL / min detection wavelength: 220 Gradient:

[1615] Time %B Curve

[1616] 0.00 5 5

[1617] 17.0 80 5

[1618] 17.5 5 1

[1619] 23.0 5

[1620] Platereader settings for ThT : Excitation wavelength: 450 nm; dicroic filter: 465 nm; emission wavelength: 486 nm; focal height: 3.5 mm; gain: 1000; number of cycles: 1000; cycle time: 360 s; number of flashes per well: 20; shaking: 300 rpm, 5s on, 5s off between cycles; temperature: 40 °C. The results (Fig. 4A to Fig. 4C) show that the highest degradation was seen at pH 4.5 for CLP1 (9% decrease in AUC). CLP1 showed equally good chemical stability at pH 6.5 and 7.5 (1 % decrease in AUC). The physical stability was assessed by a ThT assay to evaluate the fibrillation behavior over the course of 96 hours. CLP1 did not show any fibrillation in any of the buffers, demonstrating good physical stability (Fig. 4D to Fig. 4G). Each line represents an individual replicate.

[1621] Example 6: CLP1 free fraction and stability

[1622] An important aspect of drug-development is pharmacokinetics, including absorption, distribution, metabolism and excretion (ADME). The stability of CLP1 was assessed in both human and mouse plasma and mouse brain homogenate samples. As CLP1 has been stabilized by substitution of two amino acids compared to CPX, CPX was included as a reference in these stability assays. The stability of CLP1 was likewise assessed in liver S9 fractions from mouse, dog, rat, human and monkey. Brain binding (free fraction) in both mouse and human brain homogenates was also evaluated.

[1623] Plasma stability

[1624] Frozen mouse or human plasma were thawed in a water bath at 37 °C prior to use. Plasma was centrifuged at 4000 rpm for 5 min and clots were removed (if any). Mouse or human plasma were incubated with 2 uM of CLP1 or CPX or 2 uM of propantheline bromide (positive control for degradation) and left at 37 °C in a water bath. At each time point, stop solution (200 ng / mL tolbutamide and 200 ng / mL labetalol in MeOH) was added to precipitate the protein and after mixing and centrifugation, supernatant was used for LCMS analysis. As demonstrated by Fig. 5A and Fig. 5B, CLP1 and CPX had a half-life (t1X) of more than 28.9 hours. This demonstrates high plasma stability. % Remaining= 100 x (PAR at appointed incubation time I PAR at TO time), where PAR is peak area ratio of analyte versus internal standard (IS) and half-life was calculated by ti / 2 =0.693k.

[1625] Mouse brain stability

[1626] Frozen mouse brain homogenate was thawed in a water bath at 37 °C prior to use. Mouse brain homogenate was incubated with 1 uM of CLP1 or CPX or 2 uM of 7- ethoxycoumarin (positive control of degradation) and left at 37 °C in a water bath. At each time point, stop solution (200 ng / mL tolbutamide and 200 ng / mL labetalol in MeOH) was added to precipitate the protein and after mixing and centrifugation, supernatant was used for LCMS analysis. As demonstrated by Fig. 5C, CLP1 had a half-life (t1X) of 40.7 hours, compared to 28.9 hours for CPX. This demonstrates high brain stability of CLP1 , which is improved when compared to CPX.

[1627] Example 7: CLP1 metabolic stability in liver fractions As the majority of drug metabolism occurs in the liver, liver in vitro preparations may serve as models to evaluate metabolic stability of drugs. To test metabolic stability, S9 fractions are often used, which contains a mixture of unfractionated microsomes and cytosol with a wide variety of drug-metabolizing enzymes. Liver S9 fractions are commonly used as a preferred test system for in vitro ADME.

[1628] Liver S9 stability

[1629] CLP1 was added to Human liver S9, CD-1 Mouse liver S9, Sprague Dawley Rat liver S9, Beagle Dog liver S9 and Cynomolgus Monkey liver S9 solutions (1 mg protein / mL) in 100 mM potassium phosphate buffer to a final concentration of 1 uM. 7-ethoxycoumarin (1 uM) was used as a positive control for clearance. A cofactor regenerating system was added to initiate reaction containing nicotinamide adenine dinucleotide phosphate (NADP) (1.3 mM), glucose 6- phosphate (G6P) (3.3 mM), glucose-6-phosphate dehydrogenase (G6PDH) (0.4 U / rnL), uridine diphosphate glucuronic acid (LIDPGA) (2.5 mM), 3'-Phosphoadenosine-5'-phosphosulfate (PAPS) (0.1 mM), glutathione (GSH) (5 mM), MgCh (3.3 mM) in 100 mM phosphate buffer. Reactions were carried out at different timepoints between 0 to 2 hours, before terminated using stop solution. After shaking and centrifugation of the plate supernatant was used for LCMS analysis. As demonstrated by Fig. 6A (intrinsic clearance rate) and Fig. 6C (% remaining), CLP1 shows very low clearance of <2.4 pL / min / mg in all species and a half-life ( / 2) of at least 289 min. T1Z> was calculated as: T1 = ...

Claims

Claims1. A method for the treatment or prophylaxis of a disease or disorder of the ear or mastoid process in a subject, the method comprising the administration of a peptide or a pharmaceutically acceptable salt thereof, wherein the peptide is:(i) a lipidated cyclic peptide comprising the sequence:X2- X3- E - H - X4- E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:X2represents P, D, Q, K, GX3represents I, L, A, T, VX4represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 ;(ii) a cyclic peptide comprising the sequence:X2- X3- E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:X2represents P, D, Q, K, GX3 represents I, L, A, T, VX4represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 , wherein when X2represents P then X3 is other than V;(iii) a cyclic peptide comprising 10 or fewer amino acid residues within the cycle and comprising the sequence:X2- X3- E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:X2represents P, D, Q, K, GX3 represents I, L, A, T, VX4represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 ;(iv) a lipidated linear peptide comprising the sequence:X2- X3- E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:X2represents P, D, Q, K, GX3 represents I, L, A, T, VX4represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 ;(v) a linear peptide comprising the sequence:X2- X3- E - H - X4- E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:X2represents P, D, Q, K, GX3represents I, L, A, T, V X4represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 , wherein when X2represents P then X3 is other than V; or(vi) a linear peptide comprising 10 or fewer amino acid residues within the backbone and comprising the sequence:X2- X3- E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:X2represents P, D, Q, K, GX3 represents I, L, A, T, V X4represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51.

2. A peptide or a pharmaceutically acceptable salt thereof for use in the treatment or prophylaxis of a disease or disorder of the ear or mastoid process, wherein the peptide is:(i) a lipidated cyclic peptide comprising the sequence:X2- X3- E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:X2represents P, D, Q, K, GX3 represents I, L, A, T, V X4represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 ;(ii) a cyclic peptide comprising the sequence:X2- X3- E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:X2represents P, D, Q, K, G X3 represents I, L, A, T, VX4 represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 , wherein when X2represents P then X3 is other than V;(iii) a cyclic peptide comprising 10 or fewer amino acid residues within the cycle and comprising the sequence:X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:X2represents P, D, Q, K, GX3 represents I, L, A, T, VX4 represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 ;(iv) a lipidated linear peptide comprising the sequence:X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:X2represents P, D, Q, K, GX3 represents I, L, A, T, VX4 represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 ;(v) a linear peptide comprising the sequence:X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:X2represents P, D, Q, K, GX3 represents I, L, A, T, VX4 represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 , wherein when X2represents P then X3 is other than V; or(vi) a linear peptide comprising 10 or fewer amino acid residues within the backbone and comprising the sequence:X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:X2represents P, D, Q, K, GX3 represents I, L, A, T, VX4 represents E, Aor comprising a conservatively substituted variant of SEQ ID No. 51.

3. A pharmaceutical composition for the treatment or prophylaxis of a disease or disorder of the ear or mastoid process, said pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof, wherein the peptide is:(i) a lipidated cyclic peptide comprising the sequence:X2- X3- E - H - X4- E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:X2represents P, D, Q, K, GX3represents I, L, A, T, VX4represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 ;(ii) a cyclic peptide comprising the sequence:X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:X2represents P, D, Q, K, GX3 represents I, L, A, T, VX4represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 , wherein when X2represents P then X3 is other than V;(iii) a cyclic peptide comprising 10 or fewer amino acid residues within the cycle and comprising the sequence:X2- X3- E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:X2represents P, D, Q, K, GX3 represents I, L, A, T, VX4represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 ;(iv) a lipidated linear peptide comprising the sequence:X2- X3- E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:X2represents P, D, Q, K, GX3 represents I, L, A, T, VX4represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 ;(v) a linear peptide comprising the sequence:X2- X3- E - H - X4- E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:X2represents P, D, Q, K, GX3represents I, L, A, T, V X4represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 , wherein when X2represents P then X3 is other than V; or(vi) a linear peptide comprising 10 or fewer amino acid residues within the backbone and comprising the sequence:X2- X3- E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:X2represents P, D, Q, K, GX3 represents I, L, A, T, V X4represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51.

4. Use of a peptide or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis of a disease or disorder of the ear or mastoid process, wherein the peptide is:(i) a lipidated cyclic peptide comprising the sequence:X2- X3- E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:X2represents P, D, Q, K, GX3 represents I, L, A, T, V X4represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 ;(ii) a cyclic peptide comprising the sequence:X2- X3- E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:X2represents P, D, Q, K, GXa represents I, L, A, T, VX4 represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 , wherein when X2represents P then X3 is other than V;(iii) a cyclic peptide comprising 10 or fewer amino acid residues within the cycle and comprising the sequence:X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:X2represents P, D, Q, K, GX3 represents I, L, A, T, VX4 represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 ;(iv) a lipidated linear peptide comprising the sequence:X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:X2represents P, D, Q, K, GX3 represents I, L, A, T, VX4 represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 ;(v) a linear peptide comprising the sequence:X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:X2represents P, D, Q, K, GX3 represents I, L, A, T, VX4 represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 , wherein when X2represents P then X3 is other than V; or(vi) a linear peptide comprising 10 or fewer amino acid residues within the backbone and comprising the sequence:X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:X2represents P, D, Q, K, GX3 represents I, L, A, T, VX4represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51.

5. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of claims 1 to 4, wherein the peptide is a lipidated cyclic peptide comprising the sequence:X2- X3- E - H - X4- E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:X2represents P, D, Q, K, GX3represents I, L, A, T, VX4represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51.

6. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to claim 5, wherein the lipidated cyclic peptide comprises the sequence:X2- X3 - E - H - X4 - E (SEQ ID No. 51) position 1 2 3 4 5 6 wherein:X2represents P, D, Q, K, GX3 represents I, L, A, T, VX4represents E, A wherein the peptide comprises 15 or fewer amino acid residues within the cycle, is backbone cyclised and all residues of the peptide backbone are joined exclusively by peptide bonds.

7. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to claim 6, wherein the lipidated cyclic peptide comprises the sequence:E - X2- X3- E - H - X4 - E (SEQ ID No. 52) position 0 1 2 3 4 5 6 wherein:X2represents P, D, Q, K, GX3 represents I, L, A, T, VX4represents E, Awherein the peptide comprises 15 or fewer amino acid residues within the cycle, is backbone cyclised and all residues of the peptide backbone are joined exclusively by peptide bonds.

8. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to claim 7, wherein the lipid of the lipidated cyclic peptide is C18DA-yGlu-0EG-0EG-.

9. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of claims 1 to 8, wherein the lipidated cyclic peptide is selected from:wherein the cyclic peptides are backbone cyclized and wherein all residues of the peptide backbones are joined exclusively by peptide bonds.

10. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to claim 9, wherein the cyclic lipidated peptide consists of peptide CLP1 :(K*TEQIEHEEDV) SEQ ID No. 1wherein *= C18DA-yGlu-OEG-OEG- and wherein the peptide is backbone cyclised and all residues of the peptide backbone are joined exclusively by peptide bonds.11 . The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to claim 10, wherein the cyclic lipidated peptide consists of peptide CLP1 :(K*TEQIEHEEDV) SEQ ID No. 1 , wherein *= C18DA-L-yGlu-OEG-OEG- and wherein the peptide is backbone cyclised and all residues of the peptide backbone are joined exclusively by peptide bonds.

12. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to claim 10, wherein the cyclic lipidated peptide consists of peptide CLP1 :(K*TEQIEHEEDV) SEQ ID No. 1 , wherein *= C18DA-D-yGlu-OEG-OEG- and wherein the peptide is backbone cyclised and all residues of the peptide backbone are joined exclusively by peptide bonds.

13. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to claim 9, wherein the cyclic lipidated peptide consists of peptide CLP4:(K*TEDVEHEEDV) SEQ ID No. 4, wherein *= C18DA-yGlu-OEG-OEG- and wherein the peptide is backbone cyclised and all residues of the peptide backbone are joined exclusively by peptide bonds.

14. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to claim 9, wherein the cyclic lipidated peptide consists of peptide CLP5:(K*TEDIEHEEDV) SEQ ID No. 5, wherein *= C18DA-yGlu-OEG-OEG- and wherein the peptide is backbone cyclised and all residues of the peptide backbone are joined exclusively by peptide bonds.

15. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to claim 9, wherein the cyclic lipidated peptide consists of peptide CLP9:(MTEK*VEHEEDV) SEQ ID No. 9, wherein *= C18DA-yGlu-OEG-OEG- and wherein the peptide is backbone cyclised and all residues of the peptide backbone are joined exclusively by peptide bonds.

16. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to claim 9, wherein the cyclic lipidated peptide consisting of peptide CLP10:(MTEK*IEHEEDV) SEQ ID No. 10, wherein *= C18DA-yGlu-OEG-OEG- and wherein the peptide is backbone cyclised and all residues of the peptide backbone are joined exclusively by peptide bonds.

17. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of claims 1 to 4, wherein the peptide is a cyclic peptide comprising the sequence:X2- X3- E - H - X4- E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:X2represents P, D, Q, K, GX3represents I, L, A, T, VX4represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 , wherein when X2represents P then X3 is other than V.

18. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to claim 17, wherein the cyclic peptide comprises the sequence:X2- X3- E - H - X4 - E (SEQ ID No. 51) position 1 2 3 4 5 6 wherein:X2represents P, D, Q, K, GX3 represents I, L, A, T, VX4represents E, A wherein when X2represents P then X3 is other than V, the peptide comprises 15 or fewer amino acid residues within the cycle, is backbone cyclised and all residues of the peptide backbone are joined exclusively by peptide bonds.

19. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to claim 18, wherein the cyclic peptide comprises the sequence:E - X2- X3- E - H - X4 - E (SEQ ID No. 52) position 0 1 2 3 4 5 6wherein:X2 represents P, D, Q, K, GX3 represents I, L, A, T, VX4 represents E, A wherein when X2 represents P then X3 is other than V, the peptide comprises 15 or fewer amino acid residues within the cycle, is backbone cyclised and all residues of the peptide backbone are joined exclusively by peptide bonds.

20. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of claims 17 to 19, selected from:wherein the peptides are backbone cyclised and all residues of the peptide backbones are joined exclusively by peptide bonds.

21. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to claim 20, wherein the cyclic peptide consists of peptide CP7:(MTEKVEHEEDV) SEQ ID No. 34, wherein the peptide is backbone cyclised and all residues of the peptide backbone are joined exclusively by peptide bonds.

22. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to claim 20, wherein the cyclic peptide consists of peptide CP9:(MTEQIEHEEDV) SEQ ID No. 36, wherein the peptide is backbone cyclised and all residues of the peptide backbone are joined exclusively by peptide bonds.

23. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to claim 19, wherein the cyclic peptide consists of peptide CP10:(MTEDIEHEEDV) SEQ ID No. 37, wherein the peptide is backbone cyclised and all residues of the peptide backbone are joined exclusively by peptide bonds.

24. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of claims 1 to 4, wherein the peptide is a cyclic peptide comprising 10 or fewer amino acid residues within the cycle and comprising the sequence:X2- X3- E - H - X4- E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:X2represents P, D, Q, K, GX3represents I, L, A, T, VX4represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51.

25. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to claim 24, wherein the cyclic peptide comprises the sequence:X2- X3- E - H - X4- E (SEQ ID No. 51) position 1 2 3 4 5 6 wherein:X2represents P, D, Q, K, GX3represents I, L, A, T, VX4represents E, A wherein the peptide is backbone cyclised and all residues of the peptide backbone are joined exclusively by peptide bonds.

26. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to claim 25, wherein the cyclic peptide comprises the sequence:E - X2- X3- E - H - X4- E (SEQ ID No. 52)position 0 1 2 3 4 5 6 wherein:X2represents P, D, Q, K, GX3 represents I, L, A, T, VX4 represents E, A wherein the peptide is backbone cyclised and all residues of the peptide backbone are joined exclusively by peptide bonds.

27. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of claims 24 to 26, wherein the cyclic peptide is selected from:wherein the peptides are backbone eye ised and all residues of the peptide backbones are joined exclusively by peptide bonds.

28. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any of claims 1 to 4, wherein the peptide is a lipidated linear peptide comprising the sequence:X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:X2represents P, D, Q, K, GX3 represents I, L, A, T, VX4 represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51.

29. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to claim 28, wherein the lipidated linear peptide comprises the sequence:X2- X3 - E - H - X4 - E (SEQ ID No. 51) position 1 2 3 4 5 6 wherein:X2represents P, D, Q, K, GX3 represents I, L, A, T, VX4 represents E, A wherein the peptide comprises 15 or fewer amino acid residues and all residues of the peptide backbone are joined exclusively by peptide bonds.

30. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to claim 29, wherein the lipidated linear peptide comprises the sequence:E - X2- X3 - E - H - X4 - E (SEQ ID No. 52) position 0 1 2 3 4 5 6 wherein:X2represents P, D, Q, K, GX3 represents I, L, A, T, VX4 represents E, A wherein the peptide comprises 15 or fewer amino acid residues and all residues of the peptide backbone are joined exclusively by peptide bonds.

31. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to claim 30, wherein the lipid of the lipidated cyclic peptide is C18DA-yGlu-OEG-OEG-.

32. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of claims 28 to 31 , wherein the lipidated linear peptide is selected from:wherein all residues of the peptide backbones are joined exclusively by peptide bonds.

33. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any of claims 1 to 4, wherein the peptide is a linear peptide comprising the sequence:X2- X3- E - H - X4- E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:X2represents P, D, Q, K, GX3represents I, L, A, T, VX4represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51 , wherein when X2represents P then X3 is other than V.

34. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to claim 33, wherein the linear peptide comprises the sequence:X2- X3- E - H - X4 - E (SEQ ID No. 51) position 1 2 3 4 5 6 wherein:X2represents P, D, Q, K, GX3 represents I, L, A, T, VX4represents E, A wherein when X2represents P then X3 is other than V, the peptide comprises 15 or fewer amino acid residues and all residues of the peptide backbone are joined exclusively by peptide bonds.

35. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to claim 34, wherein the linear peptide comprises the sequence:E - X2- X3- E - H - X4 - E (SEQ ID No. 52) position 0 1 2 3 4 5 6 wherein:X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E, A wherein when X2 represents P then X3 is other than V, the peptide comprises 15 or fewer amino acid residues and all residues of the peptide backbone are joined exclusively by peptide bonds.

36. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of claims 1 to 4, wherein the peptide is a linear peptide comprising 10 or fewer amino acid residues within the backbone and comprising the sequence:X2- X3 - E - H - X4 - E position 1 2 3 4 5 6 (SEQ ID No. 51) wherein:X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E, A or comprising a conservatively substituted variant of SEQ ID No. 51.

37. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to claim 36, wherein the linear peptide comprises the sequence:X2- X3 - E - H - X4 - E (SEQ ID No. 51) position 1 2 3 4 5 6 wherein:X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E, A wherein all residues of the peptide backbone are joined exclusively by peptide bonds.

38. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to claim 37, wherein the linear peptide comprises the sequence:E - X2- X3 - E - H - X4 - E (SEQ ID No. 52) position 0 1 2 3 4 5 6 wherein:X2 represents P, D, Q, K, GX3represents I, L, A, T, VX4 represents E, A wherein all residues of the peptide backbone are joined exclusively by peptide bonds.

39. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of claims 1 to 38, wherein the disease or disorder of the ear or mastoid process is a vestibular syndrome such as Meniere disease or a vertiginous syndrome.

40. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of claims 1 to 39, wherein the disease or disorder of the ear or mastoid process is a disease or disorder with hearing loss or impairment.

41. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to claim 40, wherein the hearing loss is sensorineural hearing loss.

42. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to claim 40 or claim 41 , wherein the hearing loss is a result of a mitochondrial condition.

43. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of claims 40 to 42, wherein the hearing loss is hidden hearing loss.

44. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of claims 40 to 43, wherein the hearing loss is hearing loss is auditory synaptopathy.

45. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of claims 1 to 44, wherein administration of the peptide results in hearing improvement.

46. The method, peptide or pharmaceutically acceptable salt thereof for use, pharmaceutical composition for use, or use according to any one of claims 1 to 45, wherein administration of the peptide results in an increased number of cochlear ribbon synapses, spiral ganglion neuron fibres, spiral ganglion neuron cells, inner hair cells and / or outer hair cells.

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