Peptide drugs for treatment of inner ear or mastoid diseases

Abstract

Lipidated cyclic peptides, cyclic peptides, lipidated linear peptides, and linear peptides associated with SorCS2 are useful in the treatment or prevention of ear or mastoid diseases or disorders.

Description

Technical Field

[0001] This invention relates to peptides for the treatment or prevention of ear or mastoid diseases or conditions.

[0002] background

[0003] The sortilin-associated Vps10p domain of receptor 2 (SorCS2), a member of the Vps10p domain receptor family, has become a hot research topic in neuroscience because it is closely related to neuronal survival and function (Glerup, 2014; Glerup, 2016; Leloup, 2018; Ma, 2017; Malik, 2019; Yang, 2021). SorCS2 receptors mediate the sorting and transport of various ligands and receptors, which are crucial for neurite formation, synaptic plasticity, and axonal growth. Large cohort studies have highlighted the clinical relevance of SorCS2, linking it to a variety of neurodegenerative diseases and mental 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; Olila, 2009; Christoforou, 2011; Alemany, 2015; Reitz, 2015). Furthermore, SorCS2 has been functionally associated with serious neurodegenerative protein diseases such as amyotrophic lateral sclerosis (ALS) and HD (Mori, 2015; Ma, 2017; Sala). SorCS2 (2021) is also associated with pain-related diseases such as neuropathic pain (Richner, 2012; Ma, 2017; Miki, 2018). In these proteopathies, SorCS2 has been shown to mislocalize to disease-associated aggregates, leading to their dysfunction and accelerating disease progression.

[0004] Studies have shown that SorCS2 plays a crucial role in mediating brain-derived neurotrophic factor (BDNF) signaling. BDNF, through activation of its receptor TrkB, plays a central role in neuronal survival, differentiation, and synaptic plasticity. BDNF / TrkB signaling dysregulation has been shown to be associated with a variety of pathological processes, including several neurodegenerative diseases (Glerup, 2016; Qui, 2020). BDNF promotes the activation of cAMP response element-binding protein (CREB) (Glerup, 2016), and CREB has been shown to improve neuronal survival, synapse formation, and growth. BDNF self-generation via CREB is a key mediator in this process (Tao, 1998), thus establishing a positive feedback loop. Furthermore, CREB activation has been shown to induce mitochondrial biosynthesis by upregulating PGC1a (Wu, 2006; Kang, 2017). PGC1a is a major regulator of mitochondrial biosynthesis and function, including oxidative phosphorylation and ROS detoxification (Rius-Perez, 2020; Valle, 2005).

[0005] A recent study found that the absence of SorCS2 is a contributing factor to hearing loss in spontaneously deaf mouse strains, suggesting that SorCS2 may be crucial for maintaining cochlear morphology and function (Forge et al., 2017).

[0006] The auditory process begins with sound waves entering the outer ear and traveling along the ear canal to the tympanic membrane. The tympanic membrane vibrates, transmitting these vibrations to the bones of the middle ear—the malleus, incus, and stapes. These bones amplify the sound vibrations and transmit them to the cochlea in the inner ear. The cochlea is a fluid-filled structure with a basilar membrane. Upon receiving a sound signal, the cochlea generates a traveling wave. This traveling wave is first amplified by the outer hair cells (OHCs), which act as biological amplifiers / compressors and modulate the signal. The basilar membrane of the cochlea is highly frequency-specific and tonotopically organized. The base of the basilar membrane responds to high-frequency sounds, while the top responds to low-frequency sounds. The inner hair cells (IHCs) are responsible for transmitting most of the auditory signals from the cochlea to the brain for processing. The IHCs convert the mechanical vibrations caused by the sound waves into electrical signals. These electrical signals are then transmitted via neurotransmitter release to the spiral ganglion neurons (SGNs), which then transmit the auditory information to the brain for perception and interpretation.

[0007] The most common type of hearing loss is sensorineural hearing loss, which refers to any hearing loss caused by lesions in the cochlea, auditory nerve, or central nervous system. This differs from conductive hearing loss, which is caused by sound waves failing to reach the inner ear. More than 320 million people worldwide suffer from sensorineural hearing loss.

[0008] For many years, research on hearing loss has focused on OHC and IHC loss, but recent studies have 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 is called implicit hearing loss (HHL) because this dysfunction cannot be detected by standard hearing threshold tests.

[0009] One of the most well-defined mechanisms of HHL is the degeneration of the cochlear band synapse connecting the IHC and SGN, without the loss of hair cells or the SGN itself (cochlear synaptic lesions). In mice, excessive auditory exposure can keep cochlear sensory cells intact but leads to acute and irreversible synaptic band loss (Kujawa and Liberman, 2009), and these findings have since been validated in a variety of mammals. Latent hearing loss can be caused by a variety of environmental factors, most commonly noise exposure, but can also be caused by drug damage following treatment with ototoxic drugs such as cisplatin, salicylates, and various antibiotics. For example, certain doses of gentamicin, while not damaging hair cells, can lead to the loss of IHC synapses (Kohrman et al., 2020).

[0010] The SorCS2 signaling pathway is closely related to various hearing loss studies. Extensive evidence suggests that the neurotrophic factor BDNF is closely associated with the development and maintenance of the zonal synapse, a property confirmed both in vitro and in vivo. BDNF released by the IHC acts on TrkB on the SGN, and damage to the gene encoding this receptor leads to cochlear dysfunction (Fritzsch et al., 2004). Interestingly, there is evidence that salicylate treatment leads to BDNF downregulation, resulting in synaptic lesions and IHC loss (Singer et al., 2008). Consistent with this, exogenous administration of BDNF or TrkB-activating monoclonal antibodies has produced beneficial effects in isolated cochlear models; and beneficial effects have also been observed in rodent hearing loss models (Foster et al., 2022). The main challenge of such therapeutic interventions lies in drug delivery to the cochlea, but a specific recombinant BDNF formulation (OTO-413 developed by Otonomy) has shown preliminary evidence of efficacy in rodents and humans via intratympanic administration. Furthermore, noise exposure has been shown to reduce the expression and activity of PGC-1a, thereby affecting ROS detoxification and further exacerbating oxidative stress in animal models of noise-induced latent hearing loss (Liu et al., 2022). PGC1a has been shown to promote lysosomal biosynthesis by regulating TFEB (a major regulator of lysosomal biosynthesis) (Ghosh, 2015; Lynch, 2020). TFEB is also associated with sensorineural hearing loss; in kanamycin- and furosemide-induced degenerative SGNs, the nucleoplasmic TFEB ratio was reduced, and the late stage of autophagic flux was impaired. After partially improving autophagy dysfunction with mTOR inhibitors, TFEB translocation from the cytoplasm to the nucleus was promoted, resulting in a significant reduction in lysosomal defects, decreased oxidative stress levels, and increased density of surviving SGNs and auditory nerve fibers (Ye et al., 2019).

[0011] These data support the hypothesis that modulating the SorCS2 pathway may have therapeutic benefits for patients with inner ear disorders.

[0012] SorCS2 pathway modulators have been described and demonstrated to have practical medicinal value. WO2017101956 relates to linear peptides and methods for regulating phosphorylation of receptors SorCS1, SorCS2, or SorCS3 containing the Vps10 domain. WO2022029281 describes cyclic peptides and methods for regulating SorCS1, SorCS2, or SorCS3. International patent application PCT / EP2023 / 053211 (publication number WO2023152229) describes peptides and methods for regulating SorCS2.

[0013] There is still a need for medications to treat or prevent ear or mastoid diseases or conditions. Such medications may offer advantages over existing methods, for example, in one or more of the following ways: (i) Internal efficacy (iii) Pharmacokinetic characteristics; (iv) Physiological and chemical properties; and / or (vii) Safety or Therapeutic Index (TI). Summary of the Invention

[0014] This invention provides a method for treating or preventing ear or mastoid diseases or conditions in a subject, the method comprising administering a peptide or a pharmaceutically acceptable salt thereof, wherein the peptide is: (i) A lipid-cyclic peptide comprising the following sequence:

[0015] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conserved substitution variant of the peptide; (ii) A cyclic peptide comprising the following sequence:

[0016] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conserved substitution variant of the peptide, wherein X2 represents P and X3 is a term other than V; (iii) A cyclic peptide comprising 10 or fewer amino acid residues within a ring, and comprising the following sequence:

[0017] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conserved substitution variant of the peptide; (iv) A lipidated linear peptide comprising the following sequence:

[0018] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conserved substitution variant of the peptide; (v) A linear peptide comprising the following sequence:

[0019] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conserved substitution variant of the peptide, wherein X2 represents P and X3 is a term other than V; or (vi) A linear peptide comprising 10 or fewer amino acid residues in a main chain and containing the following sequence:

[0020] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conserved substitution variant of the peptide.

[0021] The present invention also provides a peptide or a pharmaceutically acceptable salt thereof for the treatment or prevention of diseases or conditions of the ear or mastoid process, wherein the peptide is: (i) A lipid-cyclic peptide comprising the following sequence:

[0022] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conserved substitution variant of the peptide; (ii) A cyclic peptide comprising the following sequence:

[0023] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conserved substitution variant of the peptide, wherein X2 represents P and X3 is a term other than V; (iii) A cyclic peptide comprising 10 or fewer amino acid residues within a ring, and comprising the following sequence:

[0024] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conserved substitution variant of the peptide; (iv) A lipidated linear peptide comprising the following sequence:

[0025] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conserved substitution variant of the peptide; (v) A linear peptide comprising the following sequence:

[0026] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conserved substitution variant of the peptide, wherein X2 represents P and X3 is a term other than V; or (vi) A linear peptide comprising 10 or fewer amino acid residues in a main chain and containing the following sequence:

[0027] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conserved substitution variant of the peptide.

[0028] The present invention also provides a pharmaceutical composition for treating or preventing ear or mastoid diseases or conditions, said pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof, wherein said peptide is: (i) A lipid-cyclic peptide comprising the following sequence:

[0029] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conserved substitution variant of the peptide; (ii) A cyclic peptide comprising the following sequence:

[0030] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conserved substitution variant of the peptide, wherein X2 represents P and X3 is a term other than V; (iii) A cyclic peptide comprising 10 or fewer amino acid residues within a ring, and comprising the following sequence:

[0031] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conserved substitution variant of the peptide; (iv) A lipidated linear peptide comprising the following sequence:

[0032] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conserved substitution variant of the peptide; (v) A linear peptide comprising the following sequence:

[0033] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conserved substitution variant of the peptide, wherein X2 represents P and X3 is a term other than V; or (vi) A linear peptide comprising 10 or fewer amino acid residues in a main chain and containing the following sequence:

[0034] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conserved substitution variant of the peptide.

[0035] The present invention further provides the use of a peptide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing diseases or conditions of the ear or mastoid process, wherein said peptide is: (i) A lipid-cyclic peptide comprising the following sequence:

[0036] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conserved substitution variant of the peptide; (ii) A cyclic peptide comprising the following sequence:

[0037] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conserved substitution variant of the peptide, wherein X2 represents P and X3 is a term other than V; (iii) A cyclic peptide comprising 10 or fewer amino acid residues within a ring, and comprising the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conserved substitution variant of the peptide; (iv) A lipidated linear peptide comprising the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conserved substitution variant of the peptide; (v) A linear peptide comprising the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conserved substitution variant of the peptide, wherein X2 represents P and X3 is a term other than V; or (vi) A linear peptide comprising 10 or fewer amino acid residues in a main chain and containing the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conserved substitution variant of the peptide. Attached Figure Description

[0038] Figures 1A to 1C Purification and qualitative analysis of CLP1: HPLC chromatogram of CLP1 ( Figure 1A The ultraviolet detection wavelength was 220 nm; LCMS chromatogram ( Figure 1B Full scan acquisition of cation mode spectra ( Figure 1C ).

[0039] Figure 2A and Figure 2B CLP1 increases the level of CREB transcriptional targets. 1 μM peptide CLP1 significantly increased the levels of CREB downstream targets in primary mouse neurons at 16 and 24 hours: neurotrophic factor BDNF ( Figure 2A ) and mitochondrial major regulator PGC1a ( Figure 2B Peptide CPX showed no effect at the above time points. Mean ± SEM; Figure 3A and Figure 3B CLP1 clears soluble mutations in fibroblasts (GM04719) derived from Huntington's disease patients. Variant HTT: 24 hours after treatment, peptides CLP1 and CPX significantly reduced mutant huntingtin protein (mHTT) in fibroblasts (GM04719) derived from Huntington's disease patients by 50% and 25%, respectively. Figure 3A At the same time, a significant decrease in total HTT levels was also observed. Figure 3B ).

[0040] Figures 4A to 4G Chemical and physical stability of CLP1 in three buffer solutions: CLP1 at pH 4.5 ( Figure 4A pH 6.5 Figure 4B ) and pH 7.5 ( Figure 4C The stability of CLP1 in the buffer system after 14 days at 40°C was assessed using ThT assay. No fibrillation was observed in any of the buffers, indicating that CLP1 showed stability relative to the positive control group. Figure 4G ), at pH 4.5 ( Figure 4D pH 6.5 Figure 4E ) and pH 7.5 ( Figure 4F It exhibits good physical stability under all conditions.

[0041] Figures 5A to 5C CLP1 is stable in plasma and brain homogenate.CLP1 and CPX in human plasma ( Figure 5A ) and mouse plasma ( Figure 5B Both showed limited degradation. CLP1 exhibited higher stability than CPX in mouse brain homogenate. Figure 5C ).

[0042] Figures 6A to 6D Metabolic stability of CLP1 in liver S9 fraction: Stability of CLP1 in S9 fraction of liver from 5 different species - Intrinsic clearance of CLP1 Figure 6A ), inherent clearance of 7-ethoxycoumarin positive control ( Figure 6B ), the remaining percentage of CLP1 ( Figure 6C The remaining percentage of the 7-ethoxycoumarin positive control () and 7-ethoxycoumarin positive control () Figure 6D ).

[0043] Figure 7A and Figure 7B CLP1 brain free fractions: Mouse brain ( ) was measured by LCMS Figure 7A ) and the human brain ( Figure 7B The brain free fraction of CLP1 in ).

[0044] Figures 8A to 8C Pharmacokinetics of CLP1 in wild-type mice: CLP1 levels in plasma were measured by LCMS / MS within 1 to 24 hours post-injection. Figure 8A ), whole brain ( Figure 8B ) and cerebrospinal fluid ( Figure 8C The concentration in ).

[0045] Figures 9A to 9C A single injection of CLP1 into wild-type mice: Four hours later, CLP1 showed a strong trend toward increasing BDNF. Figure 9A Post-hoc analysis showed that the effect of CLP1 on BDNF levels was significantly time-dependent (p=0.0438), but this was not observed in two-way ANOVA. CLP1 significantly increased PGC1a levels 2–4 hours after injection. Figure 9B ), and significantly increased transcription factor EB (TFEB) 2-8 hours after injection. Figure 8C Mean ± SEM; Figure 10A and Figure 10B Wild-type mice were treated with daily CLP1 for 7 days. CLP1 and CPX significantly increased PGC1a expression at daily doses of CLP1 of 0.2 mg / kg and 2 mg / kg, respectively, and at a daily dose of CPX of 13 mg / kg. Figure 10A Furthermore, CLP1 daily doses of 0.2 mg / kg and 2 mg / kg, and CPX daily doses of 13 mg / kg, significantly increased GRN expression. Figure 10C Following daily subcutaneous injections of CLP1 (0.2 mg / kg) and CPX (13 mg / kg), BDNF levels significantly increased. Figure 10B ).

[0046] Figures 11A to 11F CLP1 improves behavior in a Huntington's disease R6 / 2 mouse model. Schematic diagram of the PoC study in Example 11 ( Figure 11A Neither CLP1 nor CPX changed body weight. Figure 11B CLP1 significantly improved grasping behavior in R6 / 2-treated mice at weeks 9 and 14, while CPX only improved grasping behavior at week 9. Figure 11C No significant effect was observed in the rotator test. Figure 11D The Kaplan-Meier curve shows the cumulative survival rate (). Figure 11E In this severe Huntington's disease model, CLP1 increased the mean survival of treated R6 / 2 mice by 7 days and the median survival by 13 days. Figure 11F ).

[0047] Figures 12A to 12D : CLP1 improves behavior in a mouse model of Parkinson's disease (MPTP model). Schematic diagram of the experimental design in Example 12 ( Figure 12A Behavioral and biochemical analyses were performed on day 10. CLP1 treatment significantly increased the distance traveled in the open field test, particularly in the 2 mg / kg dose group. Figure 12B CLP1 completely restored grip strength in mice at both 0.2 mg / kg and 2 mg / kg doses. Figure 12C Following MPTP injection, animal body weight initially decreased, then gradually increased during the experiment. Compared to untreated mice (sham-operated group), MPTP significantly altered the body weight of the treated mice at the experimental endpoint; while the body weight of the CLP1-treated mice showed no significant change compared to the sham-operated group at the experimental endpoint. Figure 12D ).

[0048] Figure 13A and Figure 13B CLP1 can improve neuronal survival in a mouse model of Parkinson's disease (MPTP model). Tyrosine hydroxylase (TH)+ neurons in the substantia nigra pars compacta (SNpc) of six mice were immunostained and counted to measure the viability of dopaminergic neurons. The number of positive cells is expressed as the average of three brain slices. Figure 13A Representative images from each group are shown. Quantitative analysis of TH staining showed that CLP1 (0.2 mg / kg) had a significant effect on the survival of TH+ neurons. Figure 13B ).

[0049] Figures 14A to 14F CLP1 clears and reduces the spread of human α-synuclein PFF in the body. A schematic diagram of the experimental design for Example 13 is shown. Figure 14A The injection site was the amygdala. Thirty-two days after treatment, the ipsilateral and contralateral spread of PFF in the substantia nigra pars compacta and amygdala was assessed. Figure 14B It shows the black matter (). Figure 14C ) and amygdala ( Figure 14DRepresentative images of CLP1. CLP1 significantly reduced the number of PFF inclusions in the ipsilateral substantia nigra and contralateral amygdala, and also showed a clear trend of reducing ipsilateral amygdala inclusions. Figure 14E Immunostaining and imaging of TH+ neurons were performed on one of the brain cells. Figure 14F TH staining clearly showed the loss of striatal dopaminergic nerve endings in solvent-treated rats, with almost complete loss of signal at the injection site. CLP1 treatment significantly protected dopaminergic nerve endings.

[0050] Figure 15 FSL data Eight-week-old FSL rats were treated daily for eight days with 0.2 mg / kg or 2 mg / kg CLP1 or 13 mg / kg CPX dissolved in 4.38 mM L-His, 140 mM NaCl, 0.2% Tween-20, and 1500 IU hyaluronidase (pH 6.15). Following treatment, BDNF levels in the hippocampus were measured using Western blot and normalized to β-actin. The figure shows the density quantification results of the Western blot bands. BDNF levels were normalized to those of the control (FRL) rats.

[0051] Figures 16A to 16F CLP1 increases the duration of wakefulness in Wistar Kyoto rats.

[0052] Within 0-3 hours after injection, ketamine and CLP1 have an effect on the conscious state ( Figure 16A ), NREM ( Figure 16B ) and REM ( Figure 16C The effects of ketamine and CLP1 on sleep; and 11-12 hours after injection, the effects of ketamine and CLP1 on wakefulness ( Figure 16D ), NREM ( Figure 16E ) and REM ( Figure 16F The effects of sleep.

[0053] Figures 17A to 17D Brain and plasma stability of CLP1 to CLP10 and LLP1 to LLP10: Peptides CLP1 and LLP1 to LLP10 in plasma ( Figure 17A ) and mouse brain homogenate ( Figure 17C The stability of peptides CLP1 to CLP10 in plasma ( Figure 17B ) and mouse brain homogenate ( Figure 17D Stability in ).

[0054] Figures 18A to 18D Effects of CLP1 to CLP10 and LLP1 to LLP10 on CREB target genes: In primary cortical neurons, after stimulation with the corresponding peptides for 8-24 hours, CLP1 to CLP10 ( Figure 18A ) and CLP1 and LLP1 to LLP10 ( Figure 18B The impact of ) on BDNF levels, and CLP1 to CLP10 ( Figure 18C) and CLP1 and LLP1 to LLP10 ( Figure 18D The effect of PGC1a on PGC1a levels.

[0055] Figure 19A and Figure 19B CLP1 and CLP10 clear fibroblasts (GM04719) derived from Huntington's disease patients. Soluble mutant HTT: Peptides CLP1 and CLP10 significantly reduced the level of mutant huntingtin protein (mHTT) by 50% in fibroblasts (GM04719) derived from Huntington's disease patients 24 hours after treatment (measured using an MW1 antibody that specifically recognizes polyglutamine stretches). Figure 19A ), and the overall HTT level also decreased ( Figure 19B ).

[0056] Figures 20A to 20D Pharmacokinetics of the selected peptide in wild-type mice: The plasma concentrations of cyclic peptides were determined by LCMS / MS within 1 to 48 hours. Figure 20A ) and whole brain ( Figure 20C ) concentration. Calculate plasma ( Figure 20B ) and brain ( Figure 20D The PK metric of ).

[0057] Figures 21A to 21C The in vivo efficacy of the selected peptides in wild-type mice: CLP1 significantly increased BDNF levels ( Figure 21A ), and together with CLP4, increased the level of tropomyosin receptor kinase B (TrkB). Figure 21C All variants significantly increased PGC1a levels ( ). Figure 21B ).

[0058] Figures 22A to 22D Physical stability of CLP10 in three buffer solutions: Using ThT assays, CLP10 exhibited fibrinolysis in a buffer solution at pH 4.5. Figure 22A ), while at pH 6.5 ( Figure 22B ) and pH 7.5 ( Figure 22C It remains stable in the buffer system. See positive control for details. Figure 22D .

[0059] Figure 23A and Figure 23B CLP1 and CLP10 brain free fractions: Mouse brain ( ) was measured by LCMS Figure 23A ) and the human brain ( Figure 23B The brain free fractions of CLP1 and CLP10 in ).

[0060] Figure 24A and Figure 24B Pharmacokinetics of CLP10: 24 hours after injection, plasma ( Figure 24A ) and brain ( Figure 24B The CLP10 levels in the samples remained stable.

[0061] Figure 25 Lipid peptides LLP11, LLP12, and CLP11 increase BDNF in vivo. BDNF levels in wild-type mice 4-8 hours after injection.

[0062] Figure 26 Identification of short, active sequences (CP13 to CP17): The activity of CLP1 and non-lipolated cyclic peptides (CP13 to CP17 and CPX).

[0063] Figure 27A and Figure 27B : Stability of cyclic non-lipidized peptides CP1 to CP12: peptides in mouse brain ( Figure 27A ) and plasma ( Figure 27B Stability in ).

[0064] Figures 28A to 28C In vivo effects of non-liposome peptides CP5 to CP12: CP6, CP7, and CP10 significantly increased TFEB ( Figure 28B CP5, CP7, and CP9 significantly increased BDNF (). Figure 28B CP5, CP6, CP7, CP8, and CP10 significantly increased PGC1a levels. Figure 28C ).

[0065] Figure 29 Effects of amino acid variants on activity (CP18 to CP22): The BDNF levels of primary cortical neurons were compared with those after CLP1 treatment following treatment with non-lipidated cyclic peptides (CP18 to CP22 and CPX).

[0066] Figure 30 Effects of different esterification processes on activity (CLP12 to CLP15): The BDNF levels of primary cortical neurons were compared with those after CLP1 treatment following treatment with lipotropic cyclic peptides (CLP12 to CP15).

[0067] Figures 31A to 31C CLP1 increases GRN and rescues lysosomal dysfunction in a GRN-hybrid mouse FTD model. Subcutaneous daily administration of CLP1 (0.2 mg / kg) to GRN heterozygous mice for 7 days increased GRN levels. Figure 31A ), and lysosomal protein LAMP1 ( Figure 31B ) and p62 ( Figure 31C It has returned to normal levels.

[0068] Figures 32A to 32I Behavioral phenotypes of the CLP1-rescued Huntington's disease model zQ175: Compared with wild-type littermates, zQ175 mice had reduced body weight, and the treatment had no effect on body weight. Figure 32A Throughout the study, the mice exhibited a high fall latency during the rotating rod behavior test. Figure 32B At 12 months of age, the fall latency in the treatment groups (CPX and CLP1) tended to be longer than that in the zQ175+ solvent group. The number of errors made by mice during the transverse balance beam test (…) Figure 32C CLP1 reduced the number of errors in 12-month-old mice, and the difference was significant compared with the CPX treatment group. Principal component analysis plot of in-cage data ( Figure 32D ) and hierarchical cluster analysis ( Figure 32E The results showed that CLP1 treatment could rescue the behavioral phenotype of the zQ175 HD mouse model, while CPX treatment also showed a significant rescue effect. Regarding individual behavioral parameters of CPX and CLP1 (…),… Figure 32F and Figure 32G Compared with WT mice, zQ175 mice had higher levels of CSF and NfL in their blood. Figure 32H and Figure 32I Both CLP1 and CPX treatments showed a trend of reducing NfL levels.

[0069] Figure 33A and Figure 33B CLP1 increases GBA in human iPSC-derived dopaminergic neurons. Levels of TFEB and GCase in hIPSC-derived dopaminergic neurons after CLP1 treatment

[0070] Sequence Summary

[0071] SEQ ID NO: 1 Cyclic lipotropic peptide CLP1

[0072] SEQ ID NO: 2 Cyclic lipotropic peptide CLP2

[0073] SEQ ID NO: 3 Cyclic lipotropic peptide CLP3

[0074] SEQ ID NO: 4 Cyclic lipotropic peptide CLP4

[0075] SEQ ID NO: 5 Cyclic lipotropic peptide CLP5

[0076] SEQ ID NO: 6 Cyclic lipotropic peptide CLP6

[0077] SEQ ID NO: 7 Cyclic lipotropic peptide CLP7

[0078] SEQ ID NO: 8 Cyclic lipotropic peptide CLP8

[0079] SEQ ID NO: 9 Cyclic lipotropic peptide CLP9

[0080] SEQ ID NO: 10 Cyclic lipotropic peptide CLP10

[0081] SEQ ID NO: 11 Cyclic lipotropic peptide CLP11

[0082] SEQ ID NO: 12 Cyclic lipotropic peptide CLP12

[0083] SEQ ID NO: 13 Cyclic lipotropic peptide CLP13

[0084] SEQ ID NO: 14 Cyclic lipotropic peptide CLP14

[0085] SEQ ID NO: 15 Cyclic lipotropic peptide CLP15

[0086] SEQ ID NO: 16 Linear lipotropic peptide LLP1

[0087] SEQ ID NO: 17 Linear lipotropic peptide LLP2

[0088] SEQ ID NO: 18 Linear lipotropic peptide LLP3

[0089] SEQ ID NO: 19 Linear lipotropic peptide LLP4

[0090] SEQ ID NO: 20 Linear lipotropic peptide LLP5

[0091] SEQ ID NO: 21 Linear lipotropic peptide LLP6

[0092] SEQ ID NO: 22 Linear lipotropic peptide LLP7

[0093] SEQ ID NO: 23 Linear lipotropic peptide LLP8

[0094] SEQ ID NO: 24 Linear lipotropic peptide LLP9

[0095] SEQ ID NO: 25 Linear lipotropic peptide LLP10

[0096] SEQ ID NO: 26 Linear lipotropic peptide LLP11

[0097] SEQ ID NO: 27 Linear lipotropic peptide LLP12

[0098] SEQ ID NO: 28 Cyclic peptide CP1

[0099] SEQ ID NO: 29 Cyclic peptide CP2

[0100] SEQ ID NO: 30 Cyclic peptide CP3

[0101] SEQ ID NO: 31 Cyclic peptide CP4

[0102] SEQ ID NO: 32 Cyclic peptide CP5

[0103] SEQ ID NO: 33 Cyclic peptide CP6

[0104] SEQ ID NO: 34 Cyclic peptide CP7

[0105] SEQ ID NO: 35 Cyclic peptide CP8

[0106] SEQ ID NO: 36 Cyclic peptide CP9

[0107] SEQ ID NO: 37 Cyclic peptide CP10

[0108] SEQ ID NO: 38 Cyclic peptide CP11

[0109] SEQ ID NO: 39 Cyclic peptide CP12

[0110] SEQ ID NO: 40 Cyclic peptide CP13

[0111] SEQ ID NO: 41 Cyclic peptide CP14

[0112] SEQ ID NO: 42 Cyclic peptide CP15

[0113] SEQ ID NO: 43 Cyclic peptide CP16

[0114] SEQ ID NO: 44 Cyclic peptide CP17

[0115] SEQ ID NO: 45 Cyclic peptide CP18

[0116] SEQ ID NO: 46 Cyclic peptide CP19

[0117] SEQ ID NO: 47 Cyclic peptide CP20

[0118] SEQ ID NO: 48 Cyclic peptide CP21

[0119] SEQ ID NO: 49 Cyclic peptide CP22

[0120] SEQ ID NO: 50 Natural SorCS2 fragment

[0121] SEQ ID NO: 51 Variant peptide sequence 1

[0122] SEQ ID NO: 52 Mutated peptide sequence 2

[0123] SEQ ID NO: 53 Variant peptide sequence 3

[0124] SEQ ID NO: 54 Variant peptide sequence 4

[0125] SEQ ID NO: 55 Variant peptide sequence 5

[0126] SEQ ID NO: 56 Variant peptide sequence 6

[0127] SEQ ID NO: 57 Variant peptide sequence 7

[0128] SEQ ID NO: 58 Variant peptide sequence 8

[0129] SEQ ID NO: 59 Variant peptide sequence 9

[0130] SEQ ID NO: 60 Variant peptide sequence 10

[0131] SEQ ID NO: 61 Variant peptide sequence 11

[0132] SEQ ID NO: 62 Variant peptide sequence 12

[0133] SEQ ID NO: 63 Cyclic peptide CPX Detailed Implementation

[0134] This invention provides a method for treating or preventing ear or mastoid diseases or conditions in a subject, the method comprising administering a peptide or a pharmaceutically acceptable salt thereof, wherein the peptide is: (i) A lipid-cyclic peptide comprising the following sequence: in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51; (ii) A cyclic peptide comprising the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51, where X2 represents P and X3 is a term other than V; (iii) A cyclic peptide comprising 10 or fewer amino acid residues within a ring, and comprising the following sequence: in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51; (iv) A lipidated linear peptide comprising the following sequence: in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51; (v) A linear peptide comprising the following sequence: in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51, where X2 represents P and X3 is a term other than V; or (vi) A linear peptide comprising 10 or fewer amino acid residues in a main chain and containing the following sequence: in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51.

[0135] The present invention also provides a peptide or a pharmaceutically acceptable salt thereof for the treatment or prevention of diseases or conditions of the ear or mastoid process, wherein the peptide is: (i) A lipid-cyclic peptide comprising the following sequence: in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51; (ii) A cyclic peptide comprising the following sequence: in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51, where X2 represents P and X3 is a term other than V; (iii) A cyclic peptide comprising 10 or fewer amino acid residues within a ring, and comprising the following sequence: in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51; (iv) A lipidated linear peptide comprising the following sequence: in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51; (v) A linear peptide comprising the following sequence: in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51, where X2 represents P and X3 is a term other than V; or (vi) A linear peptide comprising 10 or fewer amino acid residues in a main chain and containing the following sequence: in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51.

[0136] The present invention also provides a pharmaceutical composition for treating or preventing ear or mastoid diseases or conditions, said pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof, wherein said peptide is: (i) A lipid-cyclic peptide comprising the following sequence: in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51; (ii) A cyclic peptide comprising the following sequence: in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51, where X2 represents P and X3 is a term other than V; (iii) A cyclic peptide comprising 10 or fewer amino acid residues within a ring, and comprising the following sequence: in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51; (iv) A lipidated linear peptide comprising the following sequence: in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51; (v) A linear peptide comprising the following sequence: in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51, where X2 represents P and X3 is a term other than V; or (vi) A linear peptide comprising 10 or fewer amino acid residues in a main chain and containing the following sequence: in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51.

[0137] The present invention further provides the use of a peptide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing diseases or conditions of the ear or mastoid process, wherein said peptide is: (i) A lipid-cyclic peptide comprising the following sequence: in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51; (ii) A cyclic peptide comprising the following sequence: in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51, where X2 represents P and X3 is a term other than V; (iii) A cyclic peptide comprising 10 or fewer amino acid residues within a ring, and comprising the following sequence: in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51; (iv) A lipidated linear peptide comprising the following sequence: in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51; (v) A linear peptide comprising the following sequence: in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51, where X2 represents P and X3 is a term other than V; or (vi) A linear peptide comprising 10 or fewer amino acid residues in a main chain and containing the following sequence: in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51.

[0138] peptides

[0139] In one embodiment, the peptide is a lipolated cyclic peptide comprising the following sequence:

[0140] in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 51 or its salt.

[0141] The esterified cyclic peptide may contain the following sequences:

[0142] in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or its salts. Specifically, the peptide is backbone-cyclic, and all residues of the peptide backbone are linked only by peptide bonds.

[0143] In another embodiment, the peptide is a lipolated cyclic peptide comprising the following sequence:

[0144] in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 51 or its salt, wherein X2 represents P and X3 is an item other than V.

[0145] The cyclic peptide may contain the following sequences:

[0146] in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or its salts, wherein X2 represents P and X3 is a term other than V. In particular, the peptide is backbone-cyclic, and all residues of the peptide backbone are linked only by peptide bonds.

[0147] In another embodiment, the peptide is a cyclic peptide containing 10 or fewer amino acid residues within a ring, and comprises the following sequence: in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 51 or its salt.

[0148] The cyclic peptide may contain 10 or fewer amino acid residues within its ring and include the following sequence:

[0149] in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or its salts. Specifically, the peptide is backbone-cyclic, and all residues of the peptide backbone are linked only by peptide bonds.

[0150] In another embodiment, the peptide is a lipolated linear peptide comprising the following sequence:

[0151] in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 51 or its salt.

[0152] The lipotropic linear peptide may contain the following sequence:

[0153] in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or its salts. Specifically, all residues of the peptide backbone are linked only by peptide bonds.

[0154] In another embodiment, the peptide is a linear peptide comprising the following sequence:

[0155] in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 51 or its salt, wherein X2 represents P and X3 is an item other than V.

[0156] The linear peptide may contain the following sequence:

[0157] in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or a salt thereof, or a conserved substitution variant containing SEQ ID No. 51 or a salt thereof, wherein X2 represents P and X3 is a term other than V. Specifically, all residues of the peptide backbone are linked only by peptide bonds.

[0158] In another embodiment, the peptide is a linear peptide comprising 10 or fewer amino acid residues within the main chain and containing the following sequence:

[0159] in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 51 or its salt.

[0160] The main chain of the linear peptide may contain 10 or fewer amino acid residues and include the following sequence:

[0161] in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or its salts. Specifically, all residues of the peptide backbone are linked only by peptide bonds.

[0162] A peptide is a polymer of amino acid residues, usually linked only by peptide bonds.

[0163] In some embodiments, the peptide may be modified. Specific modifications include N-terminal acetylation and / or C-terminal amidation. In some embodiments, the peptide does not contain side chain modifications. In other embodiments, the peptide is unmodified.

[0164] Some of the peptides described herein are cyclic. Peptides can typically be cyclized in four different ways: side-chain-side-chain, tail-side-chain (i.e., C-terminal-side-chain), side-chain-head (i.e., N-terminal-side-chain), and head-tail. In this document, the terms "head-tail cyclized peptide" and "main chain cyclized peptide" are used interchangeably.

[0165] In one embodiment, the cyclic peptide is a backbone-cyclized peptide. In one embodiment, the cyclic peptide is formed by forming an amide bond between its N-terminal and C-terminal portions, i.e., head-to-tail cyclization. In some embodiments, the peptide is side-chain-to-side-chain cyclized, and the backbone of the peptide is linked only by peptide bonds. In some embodiments, the peptide is tail-to-side-chain cyclized, and the backbone of the peptide is linked only by peptide bonds. In some embodiments, the peptide is side-chain-head cyclized, and the backbone of the peptide is linked only by peptide bonds.

[0166] In some implementations, the peptide backbone is cyclic, and the peptide backbone is linked only by peptide bonds.

[0167] In some embodiments, the cyclic peptide contains 25 or fewer amino acid residues within the ring, such as 20 or fewer amino acid residues within the ring (e.g., 20 amino acid residues within the ring), particularly 15 or fewer amino acid residues within the ring (e.g., 15 amino acid residues within the ring), especially 12 or fewer amino acid residues within the ring (e.g., 12 amino acid residues within the ring), such as 11 or fewer amino acid residues within the ring (e.g., 11 amino acid residues within the ring).

[0168] In some embodiments, the cyclic peptide comprises six or more amino acid residues within the ring, such as seven or more amino acid residues within the ring (e.g., seven amino acid residues within the ring), particularly eight or more amino acid residues within the ring (e.g., eight amino acid residues within the ring), especially nine or more amino acid residues within the ring (e.g., nine amino acid residues within the ring), such as ten or more amino acid residues within the ring (e.g., ten amino acid residues within the ring). In some embodiments, the cyclic peptide comprises eleven or more amino acid residues within the ring (e.g., eleven amino acid residues within the ring).

[0169] In some embodiments, the linear peptide comprises 25 or fewer amino acid residues in the main chain, such as 20 or fewer amino acid residues in the main chain (e.g., 20 amino acid residues in the main chain), particularly 15 or fewer amino acid residues in the main chain (e.g., 15 amino acid residues in the main chain), particularly 12 or fewer amino acid residues in the main chain (e.g., 12 amino acid residues in the main chain), such as 11 or fewer amino acid residues in the main chain (e.g., 11 amino acid residues in the main chain).

[0170] In some embodiments, the linear peptide comprises six or more amino acid residues in the main chain, such as seven or more amino acid residues (e.g., seven amino acid residues in the main chain), particularly eight or more amino acid residues (e.g., eight amino acid residues in the main chain), especially nine or more amino acid residues (e.g., nine amino acid residues in the main chain), or ten or more amino acid residues (e.g., ten amino acid residues in the main chain). In some embodiments, the linear peptide comprises eleven or more amino acid residues (e.g., eleven amino acid residues in the main chain).

[0171] In some implementations, all residues within the cyclic peptide are located within the ring.

[0172] In some implementations, the peptide comprises the following sequence:

[0173] in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 52 or its salt.

[0174] In some implementations, the peptide comprises the following sequence:

[0175] in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or its salt.

[0176] In some implementations, the peptide comprises the following sequence:

[0177] in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 53 or its salt.

[0178] In some implementations, the peptide comprises the following sequence:

[0179] in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or its salt.

[0180] In some implementations, the peptide comprises the following sequence:

[0181] in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or its salt, or a conservative substitution variant containing SEQ ID No. 54 or its salt.

[0182] In some implementations, the peptide comprises the following sequence: in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or its salt.

[0183] In some implementations, the peptide comprises the following sequence:

[0184] in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or its salt, or a conservative substitution variant containing SEQ ID No. 55 or its salt.

[0185] In some implementations, the peptide comprises the following sequence:

[0186] in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or its salt.

[0187] In some implementations, the peptide comprises the following sequence:

[0188] in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 56 or its salt.

[0189] In some implementations, the peptide comprises the following sequence:

[0190] in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or its salt.

[0191] In some implementations, the peptide comprises the following sequence:

[0192] in: X1 represents M and K. X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or its salt, or a conservative substitution variant containing SEQ ID No. 57 or its salt.

[0193] In some implementations, the peptide comprises the following sequence:

[0194] in: X1 represents M and K. X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or its salt.

[0195] In some implementations, the peptide comprises the following sequence:

[0196] in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substituted variant containing SEQ ID No. 58 or its salt.

[0197] In some implementations, the peptide comprises the following sequence:

[0198] in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or its salt.

[0199] In some implementations, the peptide comprises the following sequence:

[0200] in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 59 or its salt.

[0201] In some implementations, the peptide comprises the following sequence:

[0202] in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or its salt.

[0203] In some implementations, the peptide comprises the following sequence: (SEQ ID No. 60)

[0204] in: X1 represents M and K. X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 60 or its salt.

[0205] In some implementations, the peptide comprises the following sequence: (SEQ ID No. 60)

[0206] in: X1 represents M and K. X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or its salt.

[0207] In some implementations, the peptide comprises the following sequence: (SEQ ID No. 61)

[0208] in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 61 or its salt.

[0209] In some implementations, the peptide comprises the following sequence: (SEQ ID No. 61)

[0210] in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or its salt.

[0211] In some implementations, the peptide comprises the following sequence: (SEQ ID No. 62)

[0212] in: X1 represents M and K. X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 62 or its salt.

[0213] In some implementations, the peptide comprises the following sequence: (SEQ ID No. 62)

[0214] in: X1 represents M and K. X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or its salt.

[0215] In some implementations, X1 represents M. In other implementations, X1 represents K.

[0216] In some embodiments, X2 represents P. In other embodiments, X2 represents D. In further embodiments, X2 represents Q. In additional embodiments, X2 represents K. In some embodiments, X2 represents G.

[0217] 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 some embodiments, X3 represents V.

[0218] In some implementations, X4 represents E. In further implementations, X4 represents A.

[0219] Those skilled in the art will understand that certain amino acid residues can be replaced by other amino acid residues without significantly affecting their function (e.g., stability or activity). Such substitutions are generally referred to as conserved substitutions. Typically, variants with conserved substitutions retain at least 50%, for example, at least 80%, and especially at least 90% (e.g., at least 100%) of the functional capacity associated with the unsubstituted reference sequence. For example, increasing the functional capacity of BDNF, PGC1a, TFEB, and / or phosphorylated CREB (Ser133), for example, using the assay methods described herein (e.g., Example 10). Alternatively, the functional capacity may be t 1 / 2 AUC or C max For example, using the measurement methods described herein (e.g., Example 9), especially t in the brain 1 / 2 .

[0220] The functional capability may be the ability to increase BDNF, PGC1a, TFEB and / or phosphorylated CREB (Ser133), for example using the assay methods described herein (e.g., Example 10), or the functional capability may be t 1 / 2 AUC and / or C max For example, using the measurement methods described herein (e.g., Example 9), particularly t in the brain 1 / 2 .

[0221] A conservative substitution variant may contain two conservative substitutions. A conservative substitution variant may contain two conservative substitutions located within a specific sequence region (e.g., SEQ ID No: 51 to 62). Alternatively, a conservative substitution variant may contain one conservative substitution. A conservative substitution variant may contain one conservative substitution located within a specific sequence region (e.g., SEQ ID No: 51 to 62).

[0222] In some implementations, the peptide does not contain conserved substitutions.

[0223] Specific conservative substitutions can be determined empirically, although common suitable substitutions are known, for example, as shown in Table 1.

[0224] Table 1 – Common Conservative Substitutions

[0225] Therefore, in some implementations, the variant includes a substitution for X1 at position -2. X1 can replace M, such as I, (K), L, R, T, V. Alternatively, X1 can replace K, such as E, (M), N, Q, R, T. X1 can be replaced by E, N, Q, R, T, I, L, or V.

[0226] In some implementations, the variant includes a substitution for T at position -1, for example, by A, K, M, N, R, or S, particularly A, K, M, N, or R.

[0227] In some implementations, the variant includes a substitution for E at position 0, such as being replaced by A, D, G, K, Q, or V, particularly G, K, Q, or V.

[0228] In some implementations, the variant includes a substitution for X2 at position 1. X2 may replace P, such as H, L, (Q), R, or S, particularly H, L, (Q), or R. Alternatively, X2 may replace D, such as A, E, (G), H, N, V, or Y. X2 may replace Q, such as E, H, (K), L, (P), or R. X2 may replace K, such as E, M, N, (Q), R, or T. X2 may replace 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, particularly A, E, H, L, M, N, R, T, V, or Y.

[0229] In some implementations, the variant includes a substitution for X3 at position 2. X3 may replace I, such as F, (L), M, N, or (V). Alternatively, X3 may replace L, such as F, H, (I), M, P, Q, R, (V), or W. X3 may replace A, such as D, E, G, S, or T, particularly D, E, G, or T. X3 may replace T, such as (A), K, M, N, R, or S, particularly (A), K, M, N, or R. X3 may replace 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, particularly D, E, F, G, H, K, M, N, P, Q, or W.

[0230] In some implementations, the variant includes a substitution for E at position 3, for example, by A, D, G, K, Q, or V, particularly G, K, Q, or V.

[0231] In some implementations, the variant includes a substitution for H at position 4, for example, by replacing it with D, L, N, P, Q, R, or Y.

[0232] In some implementations, the variant includes a substitution for X4 at position 5. X4 may replace E, such as (A), D, G, K, Q, or V. Alternatively, X4 may replace D, such as H, N, or Y. X4 may replace A, such as D, (E), G, S, or T, particularly D, E, G, or T. X4 may be replaced by G, K, Q, S, T, or V, particularly G, K, Q, T, or V.

[0233] In some implementations, the variant includes a substitution for E at position 6, such as being replaced by A, D, G, K, Q, or V.

[0234] In some implementations, the variant includes a substitution for D at position 7, for example, by replacing it with A, E, G, H, N, V, or Y.

[0235] In some implementations, the variant includes a substitution for V at position 8, for example, by replacing it with D, E, I, L, or M.

[0236] 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 pharmaceutically acceptable salts.

[0237] Suitably, the peptide comprises 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 pharmaceutically acceptable salts. More suitably, the peptide comprises CLP1 or a pharmaceutically acceptable salt thereof.

[0238] Table 2 – Overview of Lipid-Based Peptides CLP1 In CLP1, C18DA-γGlu-OEG-OEG- can be C18DA-L-γGlu-OEG-OEG. Alternatively, in CLP1, C18DA-γGlu-OEG-OEG- can be C18DA-D-γGlu-OEG-OEG. Or, in CLP1, C18DA-γGlu-OEG-OEG- can be a mixture of C18DA-L-γGlu-OEG-OEG and C18DA-D-γGlu-OEG-OEG.

[0239] Table 3 – Overview of Non-Lipid-Based Peptides Described in WO2022029281 Ideally, peptides and their conserved substitution variants exhibit improved functional capabilities, such as increased BDNF, PGC1a, TFEB, and / or phosphorylated CREB (Ser133) and / or t compared to CPX. 1 / 2 AUC or C max Functional capabilities (especially BDNF, PGC1a, TFEB, phosphorylated CREB (Ser133), t) 1 / 2 AUC and C max(All items). Most preferably, the functional capabilities exhibited by peptides and their conserved substitution variants, such as increasing BDNF, PGC1a, TFEB and / or phosphorylating CREB (Ser133) and / or t 1 / 2 AUC or C max Functional capabilities (especially BDNF, PGC1a, TFEB, phosphorylated CREB (Ser133), t) 1 / 2 AUC and C max All items are at least equivalent to CLP1.

[0240] Ideally, the peptides used in this invention exhibit one or more (e.g., all) of the following properties: -In vitro stability– No fibrosis at pH 6.5 and 7.5, suitably also no fibrosis at pH 4.5, pH 6.5 and pH 7.5 (e.g. by the method of Example 5). -In vivo stability – at least 1 hour t 1 / 2 Suitablely, at least 4 hours, especially at least 8 hours (e.g., by the method of Example 9). 1 / 2 Ideally, it should be measured in the brain.

[0241] Lipidification

[0242] As mentioned above, some of the peptides used in this invention are lipolated. Lipidation pathways have been reviewed in the literature, including: Østergaard, 1993; Bech, 2018; van Witteloostuijn, 2016. Kurtzhals, 2023 provides more information on lipolation. To define the lipid groups that may be used in this invention, the contents of Østergaard, 1993; Bech, 2018; van Witteloostuijn, 2016 and Kurtzhals, 2023 are cited in full herein.

[0243] Although many residues can be used for lipolysis, including Cys and Tyr, lipolysis typically occurs on the side chain of Lys residues. The lipolysis site is ideally located near the N-terminus of the peptide chain. In this invention, the lipolyzed Lys residue is suitably located at X1 (position -2) or X2 (position 1).

[0244] Esterification may involve replacing natural amino residues with residues that are more easily esterified.

[0245] Linking groups are commonly used to separate lipid chains from peptides.

[0246] Linkers may contain γGlu residues, especially L-γGlu. Alternatively, linkers may contain (i) L-Asp, L-Glu, or D-Glu, especially L-Glu or D-Glu, or (ii) butyrylsulfonamide. Linkers may contain multiple residues (e.g., 2, 3, or 4), such as multiple L-γGlu residues (e.g., 2, 3, or 4), but may also conveniently contain a single residue, such as a single γGlu residue (e.g., a single L-γGlu).

[0247] The linking group may also contain spacers, such as OEG units, for example, 1 to 4 OEG units, such as 2 OEG units. The linking group may contain β-Ala units instead of OEG units.

[0248] Common lipid chains include carboxylic acids, such as C16, C18, and C20 acids, and dicarboxylic acids, such as C18DA and C20DA diacids. However, in some cases, other chain lengths and types can be used, such as isosteres of carboxylic acids, like sulfonic acids or tetraazoles. Suitable lipid chains are C16DA, C18DA, or C20DA, especially C18DA or C20DA.

[0249] Suitable, the peptide is esterified with C18DA-γGlu-OEG-OEG, for example, C18DA-L-γGlu-OEG-OEG or such as C18DA-D-γGlu-OEG-OEG.

[0250] Normally, this peptide has a single lipidation.

[0251] The optimal choice of lipidation type and location may depend on the structure of a specific peptide.

[0252] Methods for preparing peptides

[0253] The peptides used according to the present invention can be prepared by any method known in the art. Therefore, the peptides can be prepared by standard peptide preparation techniques, such as solution synthesis or Merrifield-type solid-phase synthesis (as shown in Examples 1 and 2).

[0254] In one embodiment, the peptides used in this invention are prepared or generated by synthetic methods. Methods for synthesizing peptides are well known in the art. Detailed descriptions and practical suggestions for generating synthetic peptides can be found in the following literature: *Synthetic Peptides: A User's Guide (Advances in Molecular Biology)*, edited by Grant GA, Oxford University Press, 2002; or *Pharmaceutical Formulation: Development of Peptides and Proteins*, edited by Frokjaer and Hovgaard, Taylor and Francis Press, 1999. In one embodiment, the peptides used in this invention are generated by synthetic methods, particularly by sequence-assisted peptide synthesis (SAPS), solution synthesis, or solid-phase peptide synthesis (SPPS), such as Merrifield-type solid-phase synthesis.

[0255] Linear peptides, after purification, such as by reversed-phase HPLC, can be further processed into cyclic peptides. Techniques for peptide cyclization and obtaining cyclic peptides, such as by using a solid-phase support, are known (as shown in Example 2).

[0256] A suitable amino acid sequence is one that, upon cyclization, forms the target cyclic peptide (e.g., CLP1 to CLP11, CP1 to CP15, or CP22). Side-chain cyclized, head-side-chain cyclized, or tail-side-chain cyclized peptides require a linear sequence with a normal N-terminal to C-terminal residue order. However, main-chain cyclized peptides, such as those composed of CP1, can be formed from linear peptides like MTEPIEHEEDV and VMTEPIEHEED.

[0257] Linear peptides are generally linked only by peptide bonds. Cyclic peptides are generally linked only by peptide bonds. Cyclic peptides can have their main chain cyclicated.

[0258] The synthesis of linear peptides may require or benefit from side-chain protecting groups on residues containing some or all of the reactive side chains. Depending on the specific sequence, side-chain protecting groups can be removed or introduced after removal before the formation of cyclic peptides (e.g., main-chain cyclic peptides). If side-chain protecting groups are present during the formation of cyclic peptides (e.g., main-chain cyclic peptides), they can subsequently be removed, resulting in unprotected cyclic peptides. In the preparation of non-main-chain cyclic peptides, protecting groups can be present at the N-terminus or C-terminus as needed.

[0259] The linear peptides and / or cyclic peptides (or their suitable protected forms) may be present in the form of salts, particularly pharmaceutically acceptable salts.

[0260] This invention provides a linear peptide or a protected form thereof, which, upon cyclization, yields the cyclic peptide or its protected form described herein. This invention also provides a linear peptide or a protected form of its side chains, which, upon cyclization, yields the cyclic peptide or its protected form described herein.

[0261] This invention provides a lipotropic linear peptide or its protected form thereof, which, upon cyclization, yields the lipotropic cyclic peptide or its protected form described herein. This invention also provides a lipotropic linear peptide or its side-chain protected form thereof, which, upon cyclization, yields the lipotropic cyclic peptide or its side-chain protected form described herein.

[0262] The present invention also includes protected cyclic peptides and protected esterified cyclic peptides.

[0263] Amino acid protecting groups are well known to those skilled in the art, for example, in Isidro-Llobet et al. Chem Rev 2009 109 2455-2504 and Chandrudu et al., Molecules This was discussed in 2013 18(4):4373-4388. Common sidechain 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).

[0264] Intermediates used to prepare peptides (i.e., esterified cyclic peptides, cyclic peptides, esterified linear peptides, or linear peptides and variants thereof) include such peptides or their protected forms, covalently bonded to a solid support. The covalent bonding to the solid support can be direct or achieved through spacer groups.

[0265] Medical Use

[0266] As illustrated in the embodiments herein, the peptides of the present invention can promote the clearance of pathogenic aggregates, improve neuronal survival, and enhance mitochondrial and lysosomal function.

[0267] The suitable peptides used in this invention (esterified cyclic peptides, cyclic peptides, esterified linear peptides, or linear peptides and variants thereof) or their pharmaceutically acceptable salts are all capable of increasing BDNF levels. More specifically, in the assay of Example 10, BDNF levels increased by at least 30% between 0 and 24 hours after administration.

[0268] The suitable peptides used in this invention (esterified cyclic peptides, cyclic peptides, esterified linear peptides, or linear peptides and variants thereof) or pharmaceutically acceptable salts thereof are capable of increasing phosphorylated CREB (Ser133) levels. More specifically, in the assay of Example 10, phosphorylated CREB (Ser133) levels increased by at least 30% between 0 and 24 hours after administration.

[0269] The suitable peptides used in this invention (esterified cyclic peptides, cyclic peptides, esterified linear peptides, or linear peptides and variants thereof) or their pharmaceutically acceptable salts are capable of increasing PGC1a levels. More specifically, in the assay of Example 10, PGC1a levels increased by at least 30% between 0 and 24 hours after administration.

[0270] The suitable peptides used in this invention (esterified cyclic peptides, cyclic peptides, esterified linear peptides, or linear peptides and variants thereof) or their pharmaceutically acceptable salts are all capable of increasing TFEB levels. More specifically, in the assay of Example 10, TFEB levels increased by at least 30% between 0 and 24 hours after administration.

[0271] The suitable peptides used in this invention (esterified cyclic peptides, cyclic peptides, esterified linear peptides, or linear peptides and variants thereof) or their pharmaceutically acceptable salts are all capable of reducing NfL levels. More preferably, in the determination of Example 31, NfL levels are reduced by at least 10%, particularly by at least 20%.

[0272] Specifically, the peptides of this invention have been shown to mimic the neurotrophic effects induced by the intracellular domain of SorCS2. In spontaneously deaf mouse strains, the absence of SorCS2 has been identified as a pathogenic factor leading to hearing loss, suggesting that SorCS2 may be crucial for maintaining the morphology and function of the cochlea. More importantly, the neurotrophic effects of the peptides of this invention are expected to translate to IHC-SGN in the hearing loss system, thereby restoring synaptic connections, dendritic morphology, and cell number to restore cochlear function following traumatic hearing loss. The significant beneficial effects of the peptides of this invention on mitochondrial function, a key component of IHC-SGN pathology in hearing loss (Wong, 2019), further support this. These data support the hypothesis that modulating the SorCS2 pathway may have therapeutic benefits for patients with ear or mastoid diseases or conditions.

[0273] Ideally, the ear or mastoid disease or condition is one that can be treated or prevented according to the present invention. Ideally, the ear or mastoid disease or condition is one that is sensitive to SorCS2 pathway modulation.

[0274] Diseases and conditions of the ear or mastoid process can be classified according to the 11th edition of the International Statistical Classification of Diseases and Related Health Problems (ICD), which is used in this article to define specific diseases and conditions of the ear or mastoid process.

[0275] In one implementation, a disease or condition of the ear or mastoid process is an inner ear disease.

[0276] In one embodiment, the inner ear disease or condition is an acute, episodic, or chronic vestibular syndrome. Vestibular syndromes are characterized by vertigo, dizziness, or a feeling of unsteadiness. Examples of such vestibular syndromes include vestibular neuritis, labyrinthitis, Meniere's disease, vestibular migraine, benign paroxysmal positional vertigo, superior semicircular canal dehiscence syndrome, disembarkation syndrome, autoimmune inner ear diseases, vestibular paroxysmal syndrome, and persistent postural-perceptual vertigo. In one embodiment, the inner ear disease or condition is Meniere's disease. In one embodiment, the inner ear disease or condition is a vertigo syndrome.

[0277] In one implementation, a disease or condition of the ear or mastoid process is a disease accompanied by hearing loss or impairment.

[0278] In one implementation, the hearing loss is sensorineural hearing loss, where the cause of the hearing loss lies in the vestibular-cochlear nerve, the inner ear, or the central processing center of the brain.

[0279] In one implementation, the hearing loss is acquired, for example, caused by noise, illness, trauma, or drug side effects (ototoxic hearing loss). In another implementation, the hearing loss is congenital, present at birth.

[0280] In one implementation, the hearing loss is hereditary. Hereditary hearing loss can be categorized into syndromic and non-syndromic types. Examples of syndromes associated with 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 associated with non-syndromic hearing loss include, but are not limited to: GJB2 , GJB6 , STRC , KCNQ4 , TECTA and POU3F4 And changes in mitochondrial DNA (mtDNA).

[0281] In one implementation, hereditary hearing loss is caused by mitochondrial conditions. Mitochondrial conditions associated with 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 with red ragged fibrosis (MERRF).

[0282] In one implementation, hearing loss is an auditory synaptic disorder or neuropathy in which the subject’s outer hair cells function normally, but the neural transmission of auditory information lacks synchronicity due to damage to the inner hair cells or their synapses, spiral ganglion cells or auditory nerve.

[0283] In one implementation, the hearing loss is implicit hearing loss, where the hearing loss cannot be detected by standard hearing threshold tests.

[0284] In one implementation, the disease or condition of the ear or mastoid process is a cochlear synaptic lesion. In some implementations, a cochlear synaptic lesion may be associated with age, sensorineural hearing loss, or noise-induced hearing loss. In some implementations, a cochlear synaptic lesion may be associated with inflammatory or neurodegenerative conditions, including Huntington's disease, Parkinson's disease, or Alzheimer's disease.

[0285] In one implementation, the disease or condition of the ear or mastoid process is age-related hearing loss.

[0286] The effects of administering the peptides of this invention on vestibular function can be measured using balance tests (such as the Romberg's test and the Unterberger test) or video nystagmography. Quality of life tests can also be used to measure the improvement in the number of days affected by vertigo symptoms.

[0287] The effects of the peptides of this invention on hearing loss can be quantified in a variety of ways. For example, hearing improvement can be measured using pure-tone audiometry (PTA), auditory brainstem response (ABR; also known as auditory evoked potentials (AEP)) and / or otoacoustic emissions (OAE). Furthermore, hearing improvement can also be measured using speech detection threshold (SDT), speech recognition threshold (SRT), word recognition score (WR), 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.

[0288] The effects of administering the peptides of the present invention can be suitably quantified using a speech-in-noise (SIN) test, with results potentially improved compared to untreated subjects. Specifically, the effects of administering the peptides of the present invention can also be quantified using a words-in-noise (WIN) test, with results potentially improved compared to untreated subjects.

[0289] Absolute OAE amplitude may increase relative to untreated subjects.

[0290] The number of cochlear synapses, spiral ganglion neuronal fibers and / or cells, inner hair cells and / or outer hair cells may increase, especially in the high-frequency region of the cochlea.

[0291] In some embodiments, the peptide is used for preventative purposes. For example, the peptide used in this invention can be used to prevent or reduce ototoxicity before treatment with ototoxic drugs.

[0292] In other embodiments, the peptide is used for therapeutic purposes, such as treating hearing loss.

[0293] The term “treatment” as used in this article includes controlling, alleviating, reducing, or regulating a disease or condition or its symptoms.

[0294] The term “prevention” as used in this article refers to preventing the symptoms of a disease or condition in a subject, or preventing the recurrence of the symptoms of a disease or condition in a subject with the disease, but is not limited to the complete prevention of the disease.

[0295] Appropriately, the subject is a human being.

[0296] The human subject can be an infant, for example, less than 2 years old. Alternatively, the subject can be less than 18 years old, for example, 2 to 17 years old. The human subject can be an adult, for example, 18 to 65 years old. Alternatively, the human subject can be 66 years old or older.

[0297] The subject can be male. Alternatively, the subject can be female.

[0298] A change in the treated symptom indicates a “therapeutic effect” or “therapeutic efficacy,” as measured by the criteria defined by the term “treatment.” A “change” in the treated symptom is defined as an improvement of at least 5%, preferably 10%, more preferably at least 25%, even more preferably at least 50% (e.g., at least 75%), and most preferably at least 100% in one or more parameters of the treated symptom. Such a change can be based on an improvement in the severity of the individual’s treated symptom, or on the difference in the frequency of symptom improvement among individuals who received and did not receive treatment with lipotropic cyclic peptides, cyclic peptides, lipotropic linear peptides, linear peptides, variants of any of the foregoing, and / or pharmaceutically acceptable salts of any of the foregoing.

[0299] Suitablely, the esterified cyclic peptide, cyclic peptide, esterified linear peptide, linear peptide, and variants of any of the foregoing and / or a pharmaceutically acceptable salt of any of the foregoing are administered to a subject in need. Suitablely, the peptide of the invention or a pharmaceutically acceptable salt thereof is administered in a safe and effective amount (i.e., an amount that provides an acceptable balance between the intended benefit and adverse side effects). “Safe and effective amount” is intended to include an effective amount that achieves the desired effect in treatment and / or prevention. The desired effect is generally clinically significant and / or measurable, for example, in cases where: (a) the onset of a symptom, disease, or condition is prevented, particularly in cases where the subject is susceptible or at risk but has not yet been diagnosed; (b) the symptom, disease, or condition is suppressed, i.e., its development is slowed or prevented; and / or (c) the symptom, disease, or condition is relieved, even if the symptom, disease, or condition subsides or associated symptoms are alleviated. A safe and effective amount can be an amount sufficient to achieve the desired effect when the peptide of the present invention or its pharmaceutically acceptable salt is administered alone or in combination with one or more other active pharmaceutical ingredients, wherein the other active pharmaceutical ingredients are other peptides of the present invention or their pharmaceutically acceptable salts, or ingredients different from the peptides of the present invention.

[0300] In one embodiment of the invention, the esterified cyclic peptide, cyclic peptide, esterified linear peptide, linear peptide, variant of any of the foregoing and / or a pharmaceutically acceptable salt of any of the foregoing is administered at a dose of 1 µg / day to 200 mg / day.

[0301] In one embodiment of the invention, the dosage range of a single dose of the peptide is from 1 µg / kg body weight to 100 mg / kg body weight, for example, from 1 µg / kg body weight to 10 mg / kg body weight. A preferred dosage is from about 0.1 mg / kg to about 10 mg / kg, and a more preferred dosage is from about 0.1 mg / kg to about 5 mg / kg. The dosage according to the invention can be administered once or multiple times daily. The dosage can also be administered intermittently, i.e., not daily. Instead, one or more doses can be administered every two days, every three days, every four days, every five days, every six days, weekly, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, or at other intervals within these ranges (e.g., every 2 to 4 weeks or 4 to 6 weeks).

[0302] It should be understood that the preferred route of administration depends on the overall condition and age of the subject to be treated, the nature of the symptom to be treated, the location of the tissue to be treated in the body, and the peptide of the present invention selected.

[0303] In one embodiment of the invention, the administration route allows esterified cyclic peptides, cyclic peptides, esterified linear peptides, linear peptides, variants of any of the foregoing and / or pharmaceutically acceptable salts of any of the foregoing to cross the blood-brain barrier.

[0304] According to the present invention, the systemic therapeutic administration route enables the introduction of lipotropic cyclic peptides, cyclic peptides, lipotropic linear peptides, linear peptides, and variants of any of the foregoing and / or pharmaceutically acceptable salts of any of the foregoing into the bloodstream, ultimately targeting the desired site of action. Such administration routes can be any suitable route, such as parenteral administration (including subcutaneous, intramuscular, intrathecal, intracerebral, intravenous, and intradermal administration). Parenteral administration refers to any administration route other than oral / enteral, through which the drug avoids first-pass degradation in the liver. Therefore, parenteral administration includes any injection and infusion, such as rapid bolus or continuous infusion, such as intravenous, intramuscular, or subcutaneous administration.

[0305] In one embodiment, administration is subcutaneous, such as by injection. In one embodiment, administration is intramuscular, such as by injection. In one embodiment, administration is intradermal, such as by injection. In one embodiment, administration is intravenous, such as by injection.

[0306] Pharmaceutical Composition

[0307] While the esterified cyclic peptides, cyclic peptides, esterified linear peptides, linear peptides, variants of any of the foregoing and / or pharmaceutically acceptable salts of any of the foregoing of the present invention can be administered in the form of "raw" peptides, they are ideally present in the form of pharmaceutical compositions. Therefore, the present invention further provides a pharmaceutical formulation comprising the esterified cyclic peptides, cyclic peptides, esterified linear peptides, linear peptides, variants of any of the foregoing and / or pharmaceutically acceptable salts of any of the foregoing of the present invention, and a pharmaceutically acceptable carrier.

[0308] These pharmaceutical compositions can be prepared using conventional techniques, such as those described in Remington: The Science and Practice of Pharmacy 2005, Lippincott, Williams & Wilkins.

[0309] Pharmaceutically acceptable carriers include water. To improve stability, the pharmaceutical composition may be dry and temporarily reconstituted with water (or, for example, physiological saline) before use.

[0310] Pharmaceutically acceptable compositions for parenteral administration should have a physiologically acceptable pH and a physiologically acceptable osmotic pressure.

[0311] The pH value of an aqueous composition can be adjusted according to the composition's components and suitability for application. The pH value is typically at least 4, particularly at least 5, more specifically at least 5.5, for example at least 6. The pH value is typically 9 or lower, particularly 8.5 or lower, more specifically 8 or lower, for example 7.5 or lower. The pH value can be from 4 to 9, particularly 5 to 8.5, more specifically 5.5 to 8, for example 6.5 to 7.4 (e.g., 6.5 to 7.1).

[0312] For parenteral administration, ideally, a physiologically acceptable osmolarity solution should be used to avoid excessive cell deformation or lysis. Physiologically acceptable osmolarity generally means that the solution has an osmolarity that is approximately isotonic or slightly hypertonic. Suitably, the composition used for administration has an osmolarity of 250 to 750 mOsm / kg, particularly 250 to 550 mOsm / kg, more specifically 270 to 500 mOsm / kg, for example 270 to 400 mOsm / kg.

[0313] Other components, such as buffers or stabilizers, may also be present in the solution.

[0314] The phrase “pharmaceutically acceptable” as used in this article refers to materials, compositions, dosage forms, etc., that, within reasonable medical judgment, are suitable for contact with human and animal (e.g., human) tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0315] It should be understood that, for medicinal use, the salts of peptides should be pharmaceutically acceptable salts. Pharmaceutically acceptable salts are obvious to those skilled in the art. Pharmaceutically acceptable salts include those from Remington Pharmaceutical Sciences (…). Remington's Pharmaceutical Sciences Those salts described in (17th edition, Mack Publishing Company, Easton, PA, 1985, page 1418). Such pharmaceutically acceptable salts include acid addition salts formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid) and organic acids (such as succinic acid, maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid, or naphthalenesulfonic acid).

[0316] Pharmaceutically acceptable salts can also form with organic bases (such as basic amines, such as ammonia, meglumine, tromethamine, piperazine, arginine, choline, diethylamine, benzathine, or lysine).

[0317] Salts that are not considered pharmaceutically acceptable may still be useful, for example, in the preparation of peptides and their pharmaceutically acceptable salts.

[0318] Certain peptides can form salts with one or more equivalents of acids or bases. This invention encompasses all possible stoichiometric and non-stoichiometric forms within its scope.

[0319] When peptides contain both basic groups and free acids, they may be zwitterionic.

[0320] The pharmaceutical compositions of the present invention can be administered in combination with one or more other therapeutic agents. The combined administration of two or more active agents can be achieved in a variety of different ways. They can be administered together as a single composition or as part of a combination therapy as separate compositions. For example, one can be administered before or separately from another, after or sequentially, or simultaneously or in parallel.

[0321] The following terms will further illustrate the invention: Terms of this invention The following terms will further illustrate the invention: Clause 1 A method for treating or preventing a disease or condition of the ear or mastoid process in a subject, the method comprising administering a peptide or a pharmaceutically acceptable salt thereof, wherein said peptide is: (i) A lipid-cyclic peptide comprising the following sequence:

[0322] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51; (ii) A cyclic peptide comprising the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51, where X2 represents P and X3 is a term other than V; (iii) A cyclic peptide comprising 10 or fewer amino acid residues within a ring, and comprising the following sequence:

[0323] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51; (iv) A lipidated linear peptide comprising the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51; (v) A linear peptide comprising the following sequence:

[0324] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conserved substitution variant of the peptide, wherein X2 represents P and X3 is a term other than V; or (vi) A linear peptide comprising 10 or fewer amino acid residues in a main chain and containing the following sequence:

[0325] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51.

[0326] Clause 2 A peptide or a pharmaceutically acceptable salt thereof for the treatment or prevention of diseases or conditions of the ear or mastoid process, wherein said peptide is: (i) A lipid-cyclic peptide comprising the following sequence:

[0327] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51; (ii) A cyclic peptide comprising the following sequence:

[0328] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51, where X2 represents P and X3 is a term other than V; (iii) A cyclic peptide comprising 10 or fewer amino acid residues within a ring, and comprising the following sequence:

[0329] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51; (iv) A lipidated linear peptide comprising the following sequence:

[0330] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51; (v) A linear peptide comprising the following sequence:

[0331] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51, where X2 represents P and X3 is a term other than V; or (vi) A linear peptide comprising 10 or fewer amino acid residues in a main chain and containing the following sequence:

[0332] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51.

[0333] Clause 3 A pharmaceutical composition for treating or preventing ear or mastoid diseases or conditions, said pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof, wherein said peptide is: (i) A lipid-cyclic peptide comprising the following sequence:

[0334] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51; (ii) A cyclic peptide comprising the following sequence:

[0335] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51, where X2 represents P and X3 is a term other than V; (iii) A cyclic peptide comprising 10 or fewer amino acid residues within a ring, and comprising the following sequence:

[0336] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51; (iv) A lipidated linear peptide comprising the following sequence:

[0337] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51; (v) A linear peptide comprising the following sequence:

[0338] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51, where X2 represents P and X3 is a term other than V; or (vi) A linear peptide comprising 10 or fewer amino acid residues in a main chain and containing the following sequence:

[0339] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51.

[0340] Clause 4 Use of a peptide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of diseases or conditions of the ear or mastoid process, wherein said peptide is: (i) A lipid-cyclic peptide comprising the following sequence:

[0341] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51; (ii) A cyclic peptide comprising the following sequence:

[0342] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51, where X2 represents P and X3 is a term other than V; (iii) A cyclic peptide comprising 10 or fewer amino acid residues within a ring, and comprising the following sequence:

[0343] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51; (iv) A lipidated linear peptide comprising the following sequence:

[0344] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51; (v) A linear peptide comprising the following sequence:

[0345] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51, where X2 represents P and X3 is a term other than V; or (vi) A linear peptide comprising 10 or fewer amino acid residues in a main chain and containing the following sequence:

[0346] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51.

[0347] Clause A1 The method, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the purpose according to any one of Clauses 1 to 4, wherein said peptide is an esterified cyclic peptide comprising the following sequence:

[0348] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 51 or its salt.

[0349] Clause A2 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause A1, wherein the peptide is main-chain cyclic.

[0350] Clause A3 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to Clause A2, wherein the peptide is cyclic in its main chain and all residues of the peptide main chain are linked only by peptide bonds.

[0351] Clause A4 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to any one of Clauses A1 to A3, wherein the esterified cyclic peptide, variant or salt comprises 25 or fewer amino acid residues within the ring.

[0352] Clause A5 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or use according to Clause A4, wherein the esterified cyclic peptide, variant, or salt comprises 20 or fewer amino acid residues within the ring, for example, 20 amino acid residues within the ring.

[0353] Clause A6 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or use according to Clause A5, wherein the esterified cyclic peptide, variant, or salt comprises 15 or fewer amino acid residues within the ring, for example, 15 amino acid residues within the ring.

[0354] Clause A7 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or use according to Clause A6, wherein the esterified cyclic peptide, variant, or salt comprises 12 or fewer amino acid residues within the ring, for example, 12 amino acid residues within the ring.

[0355] Clause A8 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or use according to Clause A7, wherein the esterified cyclic peptide, variant, or salt comprises 11 or fewer amino acid residues within the ring.

[0356] Clause A9 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or use according to any one of Clauses A1 to A8, wherein the esterified cyclic peptide, variant or salt comprises at least 7 amino acid residues within the ring, for example, 7 amino acid residues within the ring.

[0357] Clause A10 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to Clause A9, wherein the esterified cyclic peptide, variant or salt comprises at least 8 amino acid residues within the ring, for example, 8 amino acid residues within the ring.

[0358] Clause A11 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or use according to Clause A10, wherein the esterified cyclic peptide, variant or salt comprises at least 9 amino acid residues within the ring, for example, 9 amino acid residues within the ring.

[0359] Clause A12 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or use according to Clause A11, wherein the esterified cyclic peptide, variant or salt comprises at least 10 amino acid residues within the ring, for example, 10 amino acid residues within the ring.

[0360] Clause A13 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to Clause A12, wherein the esterified cyclic peptide, variant or salt comprises at least 11 amino acid residues within the ring.

[0361] Clause A14 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to Clause A1, wherein the esterified cyclic peptide, variant or salt comprises 11 amino acid residues within the ring.

[0362] Clause A15 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or intended use according to any one of Clauses A9 through A14, wherein said esterified cyclic peptide, variant, or salt comprises the following sequence:

[0363] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 52 or its salt.

[0364] Clause A16 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or intended use according to any one of Clauses A9 through A14, wherein said esterified cyclic peptide, variant, or salt comprises the following sequence:

[0365] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 53 or its salt.

[0366] Clause A17 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or intended use according to any one of Clauses A10 to A14, wherein said esterified cyclic peptide, variant, or salt comprises the following sequence:

[0367] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or its salt, or a conservative substitution variant containing SEQ ID No. 54 or its salt.

[0368] Clause A18 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or intended use according to any one of Clauses A10 to A14, wherein said esterified cyclic peptide, variant, or salt comprises the following sequence:

[0369] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or its salt, or a conservative substitution variant containing SEQ ID No. 55 or its salt.

[0370] Clause A19 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or intended use according to any one of Clauses A10 to A14, wherein said esterified cyclic peptide, variant, or salt comprises the following sequence:

[0371] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 56 or its salt.

[0372] Clause A20 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or application according to any one of Clauses A11 to A14, wherein said esterified cyclic peptide, variant, or salt comprises the following sequence: (SEQ ID No. 57) in: X1 represents M and K. X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or its salt, or a conservative substitution variant containing SEQ ID No. 57 or its salt.

[0373] Clause A21 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or application according to any one of Clauses A11 to A14, wherein said esterified cyclic peptide, variant, or salt comprises the following sequence: (SEQ ID No. 58) in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substituted variant containing SEQ ID No. 58 or its salt.

[0374] Clause A22 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or intended use according to any one of Clauses A11 to A14, wherein said esterified cyclic peptide, variant, or salt comprises the following sequence: (SEQ ID No. 59) in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 59 or its salt.

[0375] Clause A23 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or application according to any one of Clauses A12 to A14, wherein said esterified cyclic peptide, variant, or salt comprises the following sequence: (SEQ ID No. 60) in: X1 represents M and K. X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 60 or its salt.

[0376] Clause A24 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or intended use according to any one of Clauses A12 to A14, wherein said esterified cyclic peptide, variant, or salt comprises the following sequence:

[0377] (SEQ ID No. 61)

[0378] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 61 or its salt.

[0379] Clause A25 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or intended use according to any one of Clauses A13 to A14, wherein said esterified cyclic peptide, variant, or salt comprises the following sequence: (SEQ ID No. 62) in: X1 represents M and K. X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 62 or its salt.

[0380] Clause A26 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the purpose, according to any one of Clauses A1 to A25, wherein X1 represents M.

[0381] Clause A27 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses A1 to A25, wherein X1 represents K.

[0382] Clause A28 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses A1 to A27, wherein X2 represents P.

[0383] Clause A29 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses A1 to A27, wherein X2 represents D.

[0384] Clause A30 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the intended use, according to any one of Clauses A1 to A27, wherein X2 represents Q.

[0385] Clause A31 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses A1 to A27, wherein X2 represents K.

[0386] Clause A32 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the intended use, according to any one of Clauses A1 to A27, wherein X2 represents G.

[0387] Clause A33 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses A1 to A32, wherein X3 represents I.

[0388] Clause A34 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses A1 to A32, wherein X3 represents L.

[0389] Clause A35 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses A1 to A32, wherein X3 represents A.

[0390] Clause A36 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses A1 to A32, wherein X3 represents T.

[0391] Clause A37 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses A1 to A32, wherein X3 represents V.

[0392] Clause A38 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the intended use, according to any one of Clauses A1 to A37, wherein X4 represents E.

[0393] Clause A39 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses A1 through A37, wherein X4 represents A.

[0394] Clause A40 The method, peptide used, pharmaceutical composition used, or application according to any one of Clauses A13 to A14, wherein the esterified cyclic peptide, variant, or salt comprises a 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, for example, consisting of a 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.

[0395] Clause A41 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or use according to any one of Clauses A13 to A14, wherein said esterified 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, for example 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.

[0396] Clause A42 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use thereof, according to any one of Clauses A1 to A41, wherein the variant or salt thereof contains two conservative substitutions.

[0397] Clause A43 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses A1 to A42, wherein the variant or salt thereof contains a substitution of X1 at position -2, for example, by E, N, Q, R, T, I, L or V.

[0398] Clause A44 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses A1 to A42, wherein the variant or salt thereof contains a substitution of T at position -1, for example, by A, K, M, N, R or S, particularly A, K, M, N or R.

[0399] Clause A45 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses A1 to A42, wherein the variant or salt thereof contains a substitution of E at position 0, for example, by A, D, G, K, Q or V, particularly G, K, Q or V.

[0400] Clause A46 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses A1 to A42, wherein the variant or salt thereof comprises a substitution of X2 at position 1, for example, by A, C, E, H, L, M, N, R, S, T, V or Y, particularly A, E, H, L, M, N, R, T, V or Y.

[0401] Clause A47 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses A1 to A42, wherein the variant or salt thereof comprises a substitution of X3 at position 2, for example, by D, E, F, G, H, K, M, N, P, Q, S or W, particularly D, E, F, G, H, K, M, N, P, Q or W.

[0402] Clause A48 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses A1 to A42, wherein the variant or salt thereof contains a substitution of E at position 3, for example, by A, D, G, K, Q or V, particularly G, K, Q or V.

[0403] Clause A49 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses A1 to A42, wherein the variant or salt thereof contains a substitution of H at position 4, for example, by D, L, N, P, Q, R or Y.

[0404] Clause A50 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses A1 to A42, wherein the variant or salt thereof contains a substitution of X4 at position 5, for example, by G, K, Q, S, T or V, particularly G, K, Q, T or V.

[0405] Clause A51 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any of Clauses A1 to A42, wherein the variant or salt thereof contains a substitution of E at position 6, for example, by A, D, G, K, Q or V.

[0406] Clause A52 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses A1 to A42, wherein the variant or salt thereof contains a substitution of D at position 7, for example, by A, E, G, H, N, V ​​or Y.

[0407] Clause A53 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses A1 to A42, wherein the variant or salt thereof contains a substitution of V at position 8, for example, by D, E, I, L or M.

[0408] Clause A54 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses A42 to A53, wherein the variant or salt thereof contains a substitution of X1 at position -2, for example, by E, N, Q, R, T, I, L or V.

[0409] Clause A55 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use thereof according to any one of Clauses A42 to A53, wherein the variant or salt thereof contains a substitution of T at position -1, for example, by A, K, M, N, R or S, particularly A, K, M, N or R.

[0410] Clause A56 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or use thereof according to any one of Clauses A42 to A53, wherein the variant or salt thereof contains a substitution of E at position 0, for example, by A, D, G, K, Q or V, particularly G, K, Q or V.

[0411] Clause A57 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses A42 to A53, wherein the variant or salt thereof comprises a substitution of X2 at position 1, for example by A, C, E, H, L, M, N, R, S, T, V or Y, particularly A, E, H, L, M, N, R, T, V or Y.

[0412] Clause A58 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses A42 to A53, wherein the variant or salt thereof comprises a substitution of X3 at position 2, for example, by D, E, F, G, H, K, M, N, P, Q, S or W, particularly D, E, F, G, H, K, M, N, P, Q or W.

[0413] Clause A59 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses A42 to A53, wherein the variant or salt thereof contains a substitution of E at position 3, for example, by A, D, G, K, Q or V, particularly G, K, Q or V.

[0414] Clause A60 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses A42 to A53, wherein the variant or salt thereof contains a substitution of H at position 4, for example, by D, L, N, P, Q, R or Y.

[0415] Clause A61 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses A42 to A53, wherein the variant or salt thereof contains a substitution of X4 at position 5, for example, by G, K, Q, S, T or V, particularly G, K, Q, T or V.

[0416] Clause A62 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses A42 to A53, wherein the variant or salt thereof contains a substitution of E at position 6, for example, by A, D, G, K, Q or V.

[0417] Clause A63 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses A42 to A53, wherein the variant or salt thereof contains a substitution of D at position 7, for example, by A, E, G, H, N, V ​​or Y.

[0418] Clause A64 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses A42 to A53, wherein the variant or salt thereof contains a substitution of V at position 8, for example, by D, E, I, L or M.

[0419] Clause A65 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to any one of Clauses A43 to A53, wherein the variant or salt thereof contains a conservative substitution.

[0420] Clause A66 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, according to any one of Clauses A1 to A41, wherein said peptide is an esterified cyclic peptide or a salt thereof.

[0421] Clause A67 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or use according to any one of Clauses A1 to A66, wherein the esterified cyclic peptide, variant or salt contains esterified K residues.

[0422] Clause A68 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use of the method pursuant to Clause A67, wherein the esterified K residue is X2 at position 1.

[0423] Clause A69 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use of the method pursuant to Clause A67, wherein the esterified K residue is X1 at position -2.

[0424] Clause A70 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the purpose according to any one of Clauses A1 to A69, wherein the lipid chain is a C16DA, C18DA or C20DA group.

[0425] Clause A71 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to Clause A70, wherein the lipid chain is a C18DA group.

[0426] Clause A72 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use according to any one of Clauses A1 to A71, wherein the lipid is linked to a K residue via γGlu.

[0427] Clause A73 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use of the method described in Clause A72, wherein the lipid is linked to a K residue via γGlu and 1 to 4 OEG groups.

[0428] Clause A74 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the use of the method described in Clause A73, wherein the lipid is linked to a K residue via γGlu and two OEG groups.

[0429] Clause A75 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the purpose of the use of any of Clauses A1 to A69, wherein the lipid is C18DA-γGlu-OEG-OEG-.

[0430] Clause A76 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to any one of Clauses A1 to A69, wherein the lipid is C18DA-γGlu-OEG-OEG-.

[0431] Clause A77 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to Clause A75 or A76, wherein the lipid is C18DA-L-γGlu-OEG-OEG-.

[0432] Clause A78 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to Clause A75 or A76, wherein the lipid is C18DA-D-γGlu-OEG-OEG-.

[0433] Clause A79 The method, the peptide used or its pharmaceutically acceptable salt used, the pharmaceutical composition used, or the intended use of the product constitutes CLP1 or its salt.

[0434] Clause A80 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the intended use according to Clause A1, which consists of CLP1, wherein the lipid is C18DA-L-γGlu-OEG-OEG-, or a salt thereof.

[0435] Clause A81 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the intended use according to Clause A1, which consists of CLP1, wherein the lipid is C18DA-D-γGlu-OEG-OEG-, or a salt thereof.

[0436] Clause A82 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the intended use, pursuant to Clause A1, comprises CLP2 or a salt thereof.

[0437] Clause A83 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause A1, wherein the esterified cyclic peptide or a salt thereof consists of CLP3 or a salt thereof.

[0438] Clause A84 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause A1, wherein the esterified cyclic peptide or its salt is composed of CLP4 or a salt thereof.

[0439] Clause A85 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause A1, wherein the esterified cyclic peptide or its salt is composed of CLP5 or a salt thereof.

[0440] Clause A86 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause A1, wherein the esterified cyclic peptide or a salt thereof consists of CLP6 or a salt thereof.

[0441] Clause A87 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use according to Clause A1, wherein the esterified cyclic peptide or a salt thereof consists of CLP7 or a salt thereof.

[0442] Clause A88 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, pursuant to Clause A1, wherein the esterified cyclic peptide or a salt thereof comprises CLP8 or a salt thereof.

[0443] Clause A89 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause A1, wherein the esterified cyclic peptide or its salt is composed of CLP9 or a salt thereof.

[0444] Clause A90 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use according to Clause A1, wherein the esterified cyclic peptide or its salt is composed of CLP10 or a salt thereof.

[0445] Clause A91 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use according to Clause A1, wherein the esterified cyclic peptide or a salt thereof consists of CLP11 or a salt thereof.

[0446] Clause A92 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses A1 to A91, wherein the salt is a pharmaceutically acceptable salt.

[0447] Clause A93 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any of the preceding Clauses A, wherein said peptide is an esterified cyclic peptide.

[0448] Clause A94 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any of the preceding Clauses A, wherein said peptide is an esterified variant peptide.

[0449] Clause A95 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any of the preceding Clauses A, wherein said peptide is a pharmaceutically acceptable salt of an esterified cyclic peptide.

[0450] Clause A96 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any of the preceding Clauses A, wherein said peptide is a pharmaceutically acceptable salt of an esterified variant peptide.

[0451] Clause A97 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to any one of Clauses A1 to A96, wherein the esterified cyclic peptide is not modified with side chains.

[0452] Clause A98 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to any one of Clauses A1 to A96, wherein the esterified cyclic peptide is unmodified.

[0453] Clause B1 The method, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the purpose according to any one of Clauses 1 to 4, wherein said peptide is a cyclic peptide comprising the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 51 or its salt, wherein X2 represents P and X3 is an item other than V.

[0454] Clause B2 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the intended use according to Clause B1, wherein the peptide is main-chain cyclic.

[0455] Clause B3 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use according to Clause B2, wherein the peptide is cyclic in its main chain and all residues of the peptide main chain are linked only by peptide bonds.

[0456] Clause B4 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition 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 ring.

[0457] Clause B5 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or use according to Clause B4, wherein the cyclic peptide, variant, or salt comprises 20 or fewer amino acid residues within a ring, for example, 20 amino acid residues within a ring.

[0458] Clause B6 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or use according to Clause B5, wherein the cyclic peptide, variant, or salt comprises 15 or fewer amino acid residues within a ring, for example, 15 amino acid residues within a ring.

[0459] Clause B7 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use according to Clause B6, wherein the cyclic peptide, variant or salt comprises 12 or fewer amino acid residues within the ring, for example, 12 amino acid residues within the ring.

[0460] Clause B8 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or use according to Clause B7, wherein the cyclic peptide, variant, or salt comprises 11 or fewer amino acid residues within a ring.

[0461] Clause B9 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition 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 a ring, for example, 7 amino acid residues within a ring.

[0462] Clause B10 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to Clause B9, wherein the cyclic peptide, variant or salt comprises at least 8 amino acid residues within a ring, for example, 8 amino acid residues within a ring.

[0463] Clause B11 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to Clause B10, wherein the cyclic peptide, variant or salt comprises at least 9 amino acid residues within a ring, for example, 9 amino acid residues within a ring.

[0464] Clause B12 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or use according to Clause B11, wherein the cyclic peptide, variant or salt comprises at least 10 amino acid residues within a ring, for example, 10 amino acid residues within a ring.

[0465] Clause B13 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to Clause B12, wherein the cyclic peptide, variant or salt comprises at least 11 amino acid residues within the ring.

[0466] Clause B14 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to Clause B1, wherein the cyclic peptide, variant or salt comprises 11 amino acid residues within a ring.

[0467] Clause B15 The method, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the purpose according to any one of Clauses B9 through B14, wherein said cyclic peptide, variant, or salt comprises the following sequence:

[0468] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 52 or its salt.

[0469] Clause B16 According to any of the methods, pharmaceutically acceptable salts thereof used, pharmaceutical compositions used, or uses, cyclic peptides, variants, or salts comprising the following sequences:

[0470] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 53 or its salt.

[0471] Clause B17 According to any of the methods, pharmaceutically acceptable salts thereof used, pharmaceutical compositions used, or uses in accordance with Clauses B10 through B14, cyclic peptides, variants, or salts comprise the following sequences: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or its salt, or a conservative substitution variant containing SEQ ID No. 54 or its salt.

[0472] Clause B18 According to any of the methods, pharmaceutically acceptable salts thereof used, pharmaceutical compositions used, or uses, cyclic peptides, variants, or salts comprising the following sequences:

[0473] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or its salt, or a conservative substitution variant containing SEQ ID No. 55 or its salt.

[0474] Clause B19 According to any of the methods, pharmaceutically acceptable salts thereof used, pharmaceutical compositions used, or uses described in Clauses B10 through B14, cyclic peptides, variants, or salts may contain the following sequences:

[0475] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or its salt, or a conservative substitution variant containing SEQ ID No. 56 or its salt.

[0476] Clause B20 According to any of the methods, pharmaceutically acceptable salts thereof used, pharmaceutical compositions used, or uses, cyclic peptides, variants, or salts comprising the following sequences: (SEQ ID No. 57) in: X1 represents M and K. X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 57 or its salt.

[0477] Clause B21 According to any of the methods, pharmaceutically acceptable salts thereof used, pharmaceutical compositions used, or uses in accordance with Clauses B11 through B14, cyclic peptides, variants, or salts comprise the following sequences: (SEQ ID No. 58) in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substituted variant containing SEQ ID No. 58 or its salt.

[0478] Clause B22 According to any of the methods, pharmaceutically acceptable salts thereof used, pharmaceutical compositions used, or uses, cyclic peptides, variants, or salts comprising the following sequences: (SEQ ID No. 59) in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 59 or its salt.

[0479] Clause B23 According to any of the methods, pharmaceutically acceptable salts thereof used, pharmaceutical compositions used, or uses, cyclic peptides, variants, or salts comprising the following sequences: (SEQ ID No. 60) in: X1 represents M and K. X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 60 or its salt.

[0480] Clause B24 According to any of the methods, pharmaceutically acceptable salts thereof used, pharmaceutical compositions used, or uses, cyclic peptides, variants, or salts comprising the following sequences: (SEQ ID No. 61) in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 61 or its salt.

[0481] Clause B25 According to any of the methods, pharmaceutically acceptable salts thereof used, pharmaceutical compositions used, or uses, cyclic peptides, variants, or salts comprising the following sequences: (SEQ ID No. 62) in: X1 represents M and K. X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 62 or its salt.

[0482] Clause B26 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses B1 to B25, wherein X1 represents M.

[0483] Clause B27 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses B1 to B25, wherein X1 represents K.

[0484] Clause B28 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses B1 to B27, wherein X2 represents P.

[0485] Clause B29 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses B1 to B27, wherein X2 represents D.

[0486] Clause B30 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the intended use, according to any one of Clauses B1 through B27, wherein X2 represents Q.

[0487] Clause B31 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses B1 to B27, wherein X2 represents K.

[0488] Clause B32 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the intended use, according to any one of Clauses B1 to B27, wherein X2 represents G.

[0489] Clause B33 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses B1 to B32, wherein X3 represents I.

[0490] Clause B34 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses B1 to B32, wherein X3 represents L.

[0491] Clause B35 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses B1 to B32, wherein X3 represents A.

[0492] Clause B36 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses B1 to B32, wherein X3 represents T.

[0493] Clause B37 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used, or the use, according to any one of Clauses B1 to B27 or B29 to B32, wherein X3 represents V.

[0494] Clause B38 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses B1 through B37, wherein X4 represents E.

[0495] Clause B39 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses B1 through B37, wherein X4 represents A.

[0496] Clause B40 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or use according to any of Clauses B13 to B14, wherein said cyclic peptide, variant, or salt comprises a sequence of any of SEQ ID Nos. 1 to 10 and 28 to 39 or a salt thereof, or comprises a conserved substituted variant of any of SEQ ID Nos. 1 to 10 and 28 to 39 or a salt thereof, for example, consisting of a sequence of any of SEQ ID Nos. 1 to 10 and 28 to 39 or a salt thereof, or consisting of a conserved substituted variant of any of SEQ ID Nos. 1 to 10 and 28 to 39 or a salt thereof.

[0497] Clause B41 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or use according to any one of Clauses B13 to B14, wherein said 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, for example, 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.

[0498] Clause B42 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use thereof, according to any one of Clauses B1 to B41, wherein the variant or salt thereof contains two conservative substitutions.

[0499] Clause B43 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses B1 to B42, wherein the variant or salt thereof contains a substitution of X1 at position -2, for example, by E, N, Q, R, T, I, L or V.

[0500] Clause B44 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses B1 to B42, wherein the variant or salt thereof contains a substitution of T at position -1, for example, by A, K, M, N, R or S, particularly A, K, M, N or R.

[0501] Clause B45 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses B1 to B42, wherein the variant or salt thereof contains a substitution of E at position 0, for example, by A, D, G, K, Q or V, particularly G, K, Q or V.

[0502] Clause B46 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses B1 to B42, wherein the variant or salt thereof comprises a substitution of X2 at position 1, for example by A, C, E, H, L, M, N, R, S, T, V or Y, particularly A, E, H, L, M, N, R, T, V or Y.

[0503] Clause B47 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses B1 to B42, wherein the variant or salt thereof comprises a substitution of X3 at position 2, for example, by D, E, F, G, H, K, M, N, P, Q, S or W, particularly D, E, F, G, H, K, M, N, P, Q or W.

[0504] Clause B48 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses B1 to B42, wherein the variant or salt thereof contains a substitution of E at position 3, for example, by A, D, G, K, Q or V, particularly G, K, Q or V.

[0505] Clause B49 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses B1 to B42, wherein the variant or salt thereof contains a substitution of H at position 4, for example, by D, L, N, P, Q, R or Y.

[0506] Clause B50 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the use of any of Clauses B1 to B42, wherein the variant or salt thereof contains a substitution of X4 at position 5, for example, by G, K, Q, S, T or V, particularly G, K, Q, T or V.

[0507] Clause B51 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any of Clauses B1 to B42, wherein the variant or salt thereof contains a substitution of E at position 6, for example, by A, D, G, K, Q or V.

[0508] Clause B52 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the use thereof, according to any of Clauses B1 to B42, wherein the variant or salt thereof contains a substitution of D at position 7, for example, by A, E, G, H, N, V ​​or Y.

[0509] Clause B53 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the use thereof, according to any of Clauses B1 to B42, wherein the variant or salt thereof contains a substitution of V at position 8, for example, by D, E, I, L or M.

[0510] Clause B54 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses B42 to B53, wherein the variant or salt thereof contains a substitution of X1 at position -2, for example, by E, N, Q, R, T, I, L or V.

[0511] Clause B55 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses B42 to B53, wherein the variant or salt thereof contains a substitution of T at position -1, for example, by A, K, M, N, R or S, particularly A, K, M, N or R.

[0512] Clause B56 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses B42 to B53, wherein the variant or salt thereof contains a substitution of E at position 0, for example, by A, D, G, K, Q or V, particularly G, K, Q or V.

[0513] Clause B57 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses B42 to B53, wherein the variant or salt thereof comprises a substitution of X2 at position 1, for example, by A, C, E, H, L, M, N, R, S, T, V or Y, particularly A, E, H, L, M, N, R, T, V or Y.

[0514] Clause B58 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses B42 to B53, wherein the variant or salt thereof comprises a substitution of X3 at position 2, for example, by D, E, F, G, H, K, M, N, P, Q, S or W, particularly D, E, F, G, H, K, M, N, P, Q or W.

[0515] Clause B59 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses B42 to B53, wherein the variant or salt thereof contains a substitution of E at position 3, for example, by A, D, G, K, Q or V, particularly G, K, Q or V.

[0516] Clause B60 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses B42 to B53, wherein the variant or salt thereof contains a substitution of H at position 4, for example, by D, L, N, P, Q, R or Y.

[0517] Clause B61 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses B42 to B53, wherein the variant or salt thereof contains a substitution of X4 at position 5, for example, by G, K, Q, S, T or V, particularly G, K, Q, T or V.

[0518] Clause B62 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses B42 to B53, wherein the variant or salt thereof contains a substitution of E at position 6, for example, by A, D, G, K, Q or V.

[0519] Clause B63 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses B42 to B53, wherein the variant or salt thereof contains a substitution of D at position 7, for example, by A, E, G, H, N, V ​​or Y.

[0520] Clause B64 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any of Clauses B42 to B53, wherein the variant or salt thereof contains a substitution of V at position 8, for example, by D, E, I, L or M.

[0521] Clause B65 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use thereof, according to any one of Clauses B43 to B53, wherein the variant or salt thereof contains a conservative substitution.

[0522] Clause B66 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, according to any one of Clauses B1 to B41, wherein said peptide is a cyclic peptide or a salt thereof.

[0523] Clause B67 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause B1, wherein the cyclic peptide or salt is composed of SEQ ID No. 1 or a salt thereof.

[0524] Clause B68 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause B1, wherein the cyclic peptide or salt is composed of SEQ ID No. 2 or a salt thereof.

[0525] Clause B69 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause B1, wherein the cyclic peptide or salt is composed of SEQ ID No. 3 or a salt thereof.

[0526] Clause B70 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause B1, wherein the cyclic peptide or salt is composed of SEQ ID No. 4 or a salt thereof.

[0527] Clause B71 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use according to Clause B1, wherein the cyclic peptide or salt is composed of SEQ ID No. 5 or a salt thereof.

[0528] Clause B72 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause B1, wherein the cyclic peptide or salt is composed of SEQ ID No. 6 or a salt thereof.

[0529] Clause B73 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause B1, wherein the cyclic peptide or salt is composed of SEQ ID No. 7 or a salt thereof.

[0530] Clause B74 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause B1, wherein the cyclic peptide or salt is composed of SEQ ID No. 8 or a salt thereof.

[0531] Clause B75 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause B1, wherein the cyclic peptide or salt is composed of SEQ ID No. 9 or a salt thereof.

[0532] Clause B76 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause B1, wherein the cyclic peptide or salt is composed of SEQ ID No. 10 or a salt thereof.

[0533] Clause B77 The method, the peptide or its pharmaceutically acceptable salt used, the pharmaceutical composition used, or the use according to Clause B1, wherein the cyclic peptide or salt is composed of CP1 or its salt.

[0534] Clause B78 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the intended use according to Clause B1, wherein the cyclic peptide or salt is composed of CP2 or a salt thereof.

[0535] Clause B79 The method, the peptide or its pharmaceutically acceptable salt used, the pharmaceutical composition used, or the use according to Clause B1, wherein the cyclic peptide or salt is composed of CP3 or its salt.

[0536] Clause B80 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, in accordance with Clause B1, wherein the cyclic peptide or salt is composed of CP4 or a salt thereof.

[0537] Clause B81 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause B1, wherein the cyclic peptide or salt is composed of CP5 or a salt thereof.

[0538] Clause B82 The method, the peptide or its pharmaceutically acceptable salt used, the pharmaceutical composition used, or the use according to Clause B1, wherein the cyclic peptide or salt is composed of CP6 or its salt.

[0539] Clause B83 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause B1, wherein the cyclic peptide or salt is composed of CP7 or a salt thereof.

[0540] Clause B84 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, according to Clause B1, wherein the cyclic peptide or salt is composed of CP8 or a salt thereof.

[0541] Clause B85 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, pursuant to Clause B1, wherein the cyclic peptide or salt comprises CP9 or a salt thereof.

[0542] Clause B86 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause B1, wherein the cyclic peptide or salt comprises CP10 or a salt thereof.

[0543] Clause B87 The method, the peptide or its pharmaceutically acceptable salt used, the pharmaceutical composition used, or the use according to Clause B1, wherein the cyclic peptide or salt is composed of CP11 or its salt.

[0544] Clause B88 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, pursuant to Clause B1, wherein the cyclic peptide or salt comprises CP12 or a salt thereof.

[0545] Clause B89 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses B1 to B98, wherein the salt is a pharmaceutically acceptable salt.

[0546] Clause B90 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any of the preceding Clauses B, wherein said peptide is a cyclic peptide.

[0547] Clause B91 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any of the preceding Clauses B, wherein said peptide is a variant peptide.

[0548] Clause B92 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any of the preceding Clauses B, wherein said peptide is a pharmaceutically acceptable salt of a cyclic peptide.

[0549] Clause B93 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any of the preceding Clauses B, wherein the peptide is a pharmaceutically acceptable salt of the variant peptide.

[0550] Clause B94 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses B1 to B93, wherein the cyclic peptide is not modified with a side chain.

[0551] Clause B95 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses B1 to B93, wherein the cyclic peptide is unmodified.

[0552] Clause C1 The method, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the purpose according to any one of Clauses 1 to 28, wherein said peptide is a cyclic peptide comprising 10 or fewer amino acid residues within a ring and comprising the following sequence:

[0553] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 51 or its salt.

[0554] Clause C2 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause C1, wherein the peptide is main-chain cyclic.

[0555] Clause C3 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use of the method described in Clause C2, wherein the peptide is cyclic in its main chain and all residues of the peptide main chain are linked only by peptide bonds.

[0556] Clause C4 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition 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 ring.

[0557] Clause C5 The cyclic peptide, variant or salt thereof, contained in any of the methods, peptides or pharmaceutically acceptable salts thereof, pharmaceutical compositions or uses described in Clauses C1 to C3 comprises 7 amino acid residues within the ring.

[0558] Clause C6 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use according to any one of Clauses C1 to C3, wherein the cyclic peptide, variant or salt comprises 8 amino acid residues within a ring.

[0559] Clause C7 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use according to any one of Clauses C1 to C3, wherein the cyclic peptide, variant or salt comprises 9 amino acid residues within a ring.

[0560] Clause C8 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition 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 ring.

[0561] Clause C9 The method, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the purpose according to any one of Clauses C1 to C3 or C5 to C8, wherein said cyclic peptide, variant, or salt comprises the following sequence:

[0562] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 52 or its salt.

[0563] Clause C10 The method, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the purpose according to any one of Clauses C1 to C3 or C5 to C8, wherein said cyclic peptide, variant, or salt comprises the following sequence:

[0564] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 53 or its salt.

[0565] Clause C11 The method, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the purpose according to any one of Clauses C1 to C3 or C6 to C8, wherein said cyclic peptide, variant, or salt comprises the following sequence:

[0566] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or its salt, or a conservative substitution variant containing SEQ ID No. 54 or its salt.

[0567] Clause C12 A cyclic peptide, variant, or salt according to any one of Clauses C1 to C3 or C6 to C8, wherein said cyclic peptide, variant, or salt comprises the following sequence:

[0568] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or its salt, or a conservative substitution variant containing SEQ ID No. 55 or its salt.

[0569] Clause C13 The method, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the purpose according to any one of Clauses C1 to C3 or C6 to C8, wherein said cyclic peptide, variant, or salt comprises the following sequence:

[0570] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or its salt, or a conservative substitution variant containing SEQ ID No. 56 or its salt.

[0571] Clause C14 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the purpose according to any one of Clauses C1 to C3 or C7 to C8, wherein said cyclic peptide, variant, or salt comprises the following sequence: (SEQ ID No. 57) in: X1 represents M and K. X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 57 or its salt.

[0572] Clause C15 The method, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the purpose according to any one of Clauses C1 to C3 or C7 to C8, wherein said cyclic peptide, variant, or salt comprises the following sequence: (SEQ ID No. 58) in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substituted variant containing SEQ ID No. 58 or its salt.

[0573] Clause C16 The method, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the purpose according to any one of Clauses C1 to C3 or C7 to C8, wherein said cyclic peptide, variant, or salt comprises the following sequence: (SEQ ID No. 59) in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 59 or its salt.

[0574] Clause C17 The method, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the purpose according to any one of Clauses C1 to C3 or C8, wherein said cyclic peptide, variant, or salt comprises the following sequence: (SEQ ID No. 60) in: X1 represents M and K. X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 60 or its salt.

[0575] Clause C18 The method, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the purpose according to any one of Clauses C1 to C3 or C8, wherein said cyclic peptide, variant, or salt comprises the following sequence: (SEQ ID No. 61) in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 61 or its salt.

[0576] Clause C19 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses C1 to C18, wherein X1 represents M.

[0577] Clause C20 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses C1 through C18, wherein X1 represents K.

[0578] Clause C21 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses C1 to C20, wherein X2 represents P.

[0579] Clause C22 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses C1 through C20, wherein X2 represents D.

[0580] Clause C23 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use, according to any one of Clauses C1 through C20, wherein X2 represents Q.

[0581] Clause C24 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses C1 through C20, wherein X2 represents K.

[0582] Clause C25 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses C1 through C20, wherein X2 represents G.

[0583] Clause C26 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses C1 to C25, wherein X3 represents I.

[0584] Clause C27 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses C1 to C25, wherein X3 represents L.

[0585] Clause C28 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses C1 to C25, wherein X3 represents A.

[0586] Clause C29 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses C1 to C25, wherein X3 represents T.

[0587] Clause C30 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the purpose, according to any one of Clauses C1 to C25, wherein X3 represents V.

[0588] Clause C31 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses C1 to C30, wherein X4 represents E.

[0589] Clause C32 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses C1 to C30, wherein X4 represents A.

[0590] Clause C33 The method, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use according to any of Clauses C1 to C32, wherein the sequence of the cyclic peptide is (i) a portion of any of SEQ ID Nos. 1 to 10 and 28 to 39 or a salt thereof, or (ii) a conservatively substituted variant of any of SEQ ID Nos. 1 to 10 and 28 to 39 or a salt thereof.

[0591] Clause C34 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to Clause C33, wherein the sequence of said cyclic peptide is (i) a portion of SEQ ID No. 1 or a salt thereof, or (ii) a conserved substituted variant of SEQ ID No. 1 or a salt thereof.

[0592] Clause C35 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or use according to any one of Clauses C1 to C32, wherein said cyclic peptide, variant, or salt comprises a 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, for example, consisting of a 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.

[0593] Clause C36 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use thereof, according to any one of Clauses C1 to C35, wherein the variant or salt thereof contains two conservative substitutions.

[0594] Clause C37 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the use thereof, according to any one of Clauses C1 to C36, wherein the variant or salt thereof contains a substitution of X1 at position -2, for example, by E, N, Q, R, T, I, L or V.

[0595] Clause C38 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses C1 to C36, wherein the variant or salt thereof contains a substitution of T at position -1, for example, by A, K, M, N, R or S, particularly A, K, M, N or R.

[0596] Clause C39 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses C1 to C36, wherein the variant or salt thereof contains a substitution of E at position 0, for example, by A, D, G, K, Q or V, particularly G, K, Q or V.

[0597] Clause C40 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses C1 to C36, wherein the variant or salt thereof contains a substitution of X2 at position 1, for example, by A, C, E, H, L, M, N, R, S, T, V or Y, particularly A, E, H, L, M, N, R, T, V or Y.

[0598] Clause C41 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the use of any of Clauses C1 to C36, wherein the variant or salt thereof comprises a substitution of X3 at position 2, for example, by D, E, F, G, H, K, M, N, P, Q, S or W, particularly D, E, F, G, H, K, M, N, P, Q or W.

[0599] Clause C42 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses C1 to C36, wherein the variant or salt thereof contains a substitution of E at position 3, for example, by A, D, G, K, Q or V, particularly G, K, Q or V.

[0600] Clause C43 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses C1 to C36, wherein the variant or salt thereof contains a substitution of H at position 4, for example, by D, L, N, P, Q, R or Y.

[0601] Clause C44 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses C1 to C36, wherein the variant or salt thereof contains a substitution of X4 at position 5, for example, by G, K, Q, S, T or V, particularly G, K, Q, T or V.

[0602] Clause C45 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the use thereof, according to any one of Clauses C1 to C36, wherein the variant or salt thereof contains a substitution of E at position 6, for example, by A, D, G, K, Q or V.

[0603] Clause C46 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the use thereof, according to any one of Clauses C1 to C36, wherein the variant or salt thereof contains a substitution of D at position 7, for example, by A, E, G, H, N, V ​​or Y.

[0604] Clause C47 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the use thereof, according to any one of Clauses C1 to C36, wherein the variant or salt thereof contains a substitution of V at position 8, for example, by D, E, I, L or M.

[0605] Clause C48 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses C36 to C47, wherein the variant or salt thereof contains a substitution of X1 at position -2, for example, by E, N, Q, R, T, I, L or V.

[0606] Clause C49 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses C36 to C47, wherein the variant or salt thereof contains a substitution of T at position -1, for example, by A, K, M, N, R or S, particularly A, K, M, N or R.

[0607] Clause C50 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses C36 to C47, wherein the variant or salt thereof contains a substitution of E at position 0, for example, by A, D, G, K, Q or V, particularly G, K, Q or V.

[0608] Clause C51 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses C36 to C47, wherein the variant or salt thereof contains a substitution of X2 at position 1, for example, by A, C, E, H, L, M, N, R, S, T, V or Y, particularly A, E, H, L, M, N, R, T, V or Y.

[0609] Clause C52 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses C36 to C47, wherein the variant or salt thereof contains a substitution of X3 at position 2, for example, by D, E, F, G, H, K, M, N, P, Q, S or W, particularly D, E, F, G, H, K, M, N, P, Q or W.

[0610] Clause C53 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses C36 to C47, wherein the variant or salt thereof contains a substitution of E at position 3, for example, by A, D, G, K, Q or V, particularly G, K, Q or V.

[0611] Clause C54 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses C36 to C47, wherein the variant or salt thereof contains a substitution of H at position 4, for example, by D, L, N, P, Q, R or Y.

[0612] Clause C55 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses C36 to C47, wherein the variant or salt thereof contains a substitution of X4 at position 5, for example, by G, K, Q, S, T or V, particularly G, K, Q, T or V.

[0613] Clause C56 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses C36 to C47, wherein the variant or salt thereof contains a substitution of E at position 6, for example, by A, D, G, K, Q or V.

[0614] Clause C57 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses C36 to C47, wherein the variant or salt thereof contains a substitution of D at position 7, for example, by A, E, G, H, N, V ​​or Y.

[0615] Clause C58 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use thereof, according to any one of Clauses C36 to C47, wherein the variant or salt thereof contains a substitution of V at position 8, for example, by D, E, I, L or M.

[0616] Clause C59 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the use thereof, according to any one of Clauses C37 to C47, wherein the variant or salt thereof contains a conservative substitution.

[0617] Clause C60 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, according to any one of Clauses C1 to C35, wherein said peptide is a cyclic peptide or a salt thereof.

[0618] Clause C61 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause C1, wherein the cyclic peptide or salt is composed of CP13 or a salt thereof.

[0619] Clause C62 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause C1, wherein the cyclic peptide or salt is composed of CP14 or a salt thereof.

[0620] Clause C63 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, in accordance with Clause C1, wherein the cyclic peptide or salt comprises CP15 or a salt thereof.

[0621] Clause C64 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses C1 to C63, wherein the salt is a pharmaceutically acceptable salt.

[0622] Clause C65 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, according to any of the preceding Clauses C, wherein said peptide is a cyclic peptide.

[0623] Clause C66 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any of the preceding Clauses C, wherein the peptide is a variant peptide.

[0624] Clause C67 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any of the preceding Clauses C, wherein said peptide is a pharmaceutically acceptable salt of a cyclic peptide.

[0625] Clause C68 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any of the preceding Clauses C, wherein the peptide is a pharmaceutically acceptable salt of the variant peptide.

[0626] Clause C69 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses C1 to C68, wherein the cyclic peptide is not modified with a side chain.

[0627] Clause C70 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses C1 to C68, wherein the cyclic peptide is unmodified.

[0628] Clause D1 The method, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the purpose according to any one of Clauses 1 to 4, wherein said peptide is an esterified linear peptide comprising the following sequence:

[0629] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 51 or its salt.

[0630] Clause D2 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the purpose of the method described in Clause D1, wherein all residues of the peptide backbone are linked by peptide bonds only.

[0631] Clause D3 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use according to Clause D1 or D2, wherein the esterified linear peptide, variant or salt comprises 25 or fewer amino acid residues in the main chain.

[0632] Clause D4 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use according to Clause D3, wherein the esterified linear peptide, variant or salt comprises 20 or fewer amino acid residues in the main chain, for example, 20 amino acid residues in the main chain.

[0633] Clause D5 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use according to Clause D4, wherein the esterified linear peptide, variant or salt comprises 15 or fewer amino acid residues in the main chain, for example, 15 amino acid residues in the main chain.

[0634] Clause D6 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use according to Clause D5, wherein the esterified linear peptide, variant or salt comprises 12 or fewer amino acid residues in the main chain, for example, 12 amino acid residues in the main chain.

[0635] Clause D7 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use according to Clause D6, wherein the esterified linear peptide, variant or salt comprises 11 or fewer amino acid residues in the main chain.

[0636] Clause D8 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use according to any one of Clauses D1 to D7, wherein the esterified linear peptide, variant or salt comprises at least 7 amino acid residues in the main chain, for example, 7 amino acid residues in the main chain.

[0637] Clause D9 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to Clause D8, wherein the esterified linear peptide, variant or salt comprises at least 8 amino acid residues in the main chain, for example, 8 amino acid residues in the main chain.

[0638] Clause D10 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to Clause D9, wherein the esterified linear peptide, variant or salt comprises at least 9 amino acid residues in the main chain, for example, 9 amino acid residues in the main chain.

[0639] Clause D11 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to Clause D10, wherein the esterified linear peptide, variant or salt comprises at least 10 amino acid residues in the main chain, for example, 10 amino acid residues in the main chain.

[0640] Clause D12 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to Clause D11, wherein the esterified linear peptide, variant or salt comprises at least 11 amino acid residues in the main chain.

[0641] Clause D13 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to Clause D12, wherein the esterified linear peptide, variant or salt comprises 11 amino acid residues in the main chain.

[0642] Clause D14 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or intended use according to any one of Clauses D8 through D13, wherein said esterified linear peptide, variant, or salt comprises the following sequence:

[0643] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 52 or its salt.

[0644] Clause D15 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or intended use according to any one of Clauses D8 through D13, wherein said esterified linear peptide, variant, or salt comprises the following sequence:

[0645] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 53 or its salt.

[0646] Clause D16 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or intended use according to any one of Clauses D9 through D13, wherein said esterified linear peptide, variant, or salt comprises the following sequence:

[0647] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or its salt, or a conservative substitution variant containing SEQ ID No. 54 or its salt.

[0648] Clause D17 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or intended use according to any one of Clauses D9 through D13, wherein said esterified linear peptide, variant, or salt comprises the following sequence: (SEQ ID No. 55) in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or its salt, or a conservative substitution variant containing SEQ ID No. 55 or its salt.

[0649] Clause D18 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or intended use according to any one of Clauses D9 through D13, wherein said esterified linear peptide, variant, or salt comprises the following sequence:

[0650] in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 56 or its salt.

[0651] Clause D19 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or intended use according to any one of Clauses D10 through D13, wherein said esterified linear peptide, variant, or salt comprises the following sequence: (SEQ ID No. 57) in: X1 represents M and K. X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or its salt, or a conservative substituted variant or salt containing SEQ ID No. 57.

[0652] Clause D20 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or intended use according to any one of Clauses D10 through D13, wherein said esterified linear peptide, variant, or salt comprises the following sequence: (SEQ ID No. 58) in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substituted variant containing SEQ ID No. 58 or its salt.

[0653] Clause D21 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or intended use according to any one of Clauses D10 through D13, wherein said esterified linear peptide, variant, or salt comprises the following sequence: (SEQ ID No. 59) in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 59 or its salt.

[0654] Clause D22 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the purpose according to any one of Clauses D11 through D23, wherein said esterified linear peptide, variant, or salt comprises the following sequence: (SEQ ID No. 60) in: X1 represents M and K. X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 60 or its salt.

[0655] Clause D23 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or intended use according to any one of Clauses D11 through D13, wherein said esterified linear peptide, variant, or salt comprises the following sequence: (SEQ ID No. 61) in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 61 or its salt.

[0656] Clause D24 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or intended use according to any one of Clauses D12 to D13, wherein said esterified linear peptide, variant, or salt comprises the following sequence: (SEQ ID No. 62) in: X1 represents M and K. X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 62 or its salt.

[0657] Clause D25 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses D1 through D24, wherein X1 represents M.

[0658] Clause D26 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses D1 through D24, wherein X1 represents K.

[0659] Clause D27 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses D1 through D26, wherein X2 represents P.

[0660] Clause D28 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses D1 through D26, wherein X2 represents D.

[0661] Clause D29 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses D1 through D26, wherein X2 represents Q.

[0662] Clause D30 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used, or the intended use, according to any one of Clauses D1 through D26, wherein X2 represents K.

[0663] Clause D31 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses D1 to D26, wherein X2 represents G.

[0664] Clause D32 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses D1 to D31, wherein X3 represents I.

[0665] Clause D33 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses D1 to D31, wherein X3 represents L.

[0666] Clause D34 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses D1 to D31, wherein X3 represents A.

[0667] Clause D35 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses D1 to D31, wherein X3 represents T.

[0668] Clause D36 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses D1 to D31, wherein X3 represents V.

[0669] Clause D37 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses D1 through D36, wherein X4 represents E.

[0670] Clause D38 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses D1 through D36, wherein X4 represents A.

[0671] Clause D39 The method, peptide used, pharmaceutical composition used, or application according to any one of Clauses D13 to D14, wherein the esterified linear peptide, variant, or salt comprises a 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, for example, consisting of a 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.

[0672] Clause D40 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use according to any one of Clauses D13 to D14, wherein said esterified 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, for example, 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.

[0673] Clause D41 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or use according to any of Clauses D13 to D14, wherein said esterified linear peptide, variant, or salt comprises a sequence of any of LLP1 to LLP12 or a salt thereof, or comprises a conserved substituted variant of any of LLP1 to LLP12 or a salt thereof, for example, consisting of a sequence of any of LLP1 to LLP12 or a salt thereof, or consisting of a conserved substituted variant of any of LLP1 to LLP12 or a salt thereof.

[0674] Clause D42 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the use thereof, according to any one of Clauses D1 to D41, wherein the variant or salt thereof contains two conservative substitutions.

[0675] Clause D43 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses D1 to D42, wherein the variant or salt thereof contains a substitution of X1 at position -2, for example, by E, N, Q, R, T, I, L or V.

[0676] Clause D44 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the use of any of Clauses D1 to D42, wherein the variant or salt thereof contains a substitution of T at position -1, for example, by A, K, M, N, R or S, particularly A, K, M, N or R.

[0677] Clause D45 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses D1 to D42, wherein the variant or salt thereof contains a substitution of E at position 0, for example, by A, D, G, K, Q or V, particularly G, K, Q or V.

[0678] Clause D46 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses D1 to D42, wherein the variant or salt thereof comprises a substitution of X2 at position 1, for example, by A, C, E, H, L, M, N, R, S, T, V or Y, particularly A, E, H, L, M, N, R, T, V or Y.

[0679] Clause D47 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses D1 to D42, wherein the variant or salt thereof comprises a substitution of X3 at position 2, for example, by D, E, F, G, H, K, M, N, P, Q, S or W, particularly D, E, F, G, H, K, M, N, P, Q or W.

[0680] Clause D48 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses D1 to D42, wherein the variant or salt thereof contains a substitution of E at position 3, for example, by A, D, G, K, Q or V, particularly G, K, Q or V.

[0681] Clause D49 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the use thereof, according to any one of Clauses D1 to D42, wherein the variant or salt thereof contains a substitution of H at position 4, for example, by D, L, N, P, Q, R or Y.

[0682] Clause D50 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the use of any of Clauses D1 to D42, wherein the variant or salt thereof contains a substitution of X4 at position 5, for example, by G, K, Q, S, T or V, particularly G, K, Q, T or V.

[0683] Clause D51 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses D1 to D42, wherein the variant or salt thereof contains a substitution of E at position 6, for example, by A, D, G, K, Q or V.

[0684] Clause D52 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the use of any of Clauses D1 to D42, wherein the variant or salt thereof contains a substitution of D at position 7, for example, by A, E, G, H, N, V ​​or Y.

[0685] Clause D53 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses D1 to D42, wherein the variant or salt thereof contains a substitution of V at position 8, for example, by D, E, I, L or M.

[0686] Clause D54 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses D42 to D53, wherein the variant or salt thereof contains a substitution of X1 at position -2, for example, by E, N, Q, R, T, I, L or V.

[0687] Clause D55 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses D42 to D53, wherein the variant or salt thereof contains a substitution of T at position -1, for example, by A, K, M, N, R or S, particularly A, K, M, N or R.

[0688] Clause D56 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses D42 to D53, wherein the variant or salt thereof contains a substitution of E at position 0, for example, by A, D, G, K, Q or V, particularly G, K, Q or V.

[0689] Clause D57 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses D42 to D53, wherein the variant or salt thereof contains a substitution of X2 at position 1, for example, by A, C, E, H, L, M, N, R, S, T, V or Y, particularly A, E, H, L, M, N, R, T, V or Y.

[0690] Clause D58 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses D42 to D53, wherein the variant or salt thereof contains a substitution of X3 at position 2, for example, by D, E, F, G, H, K, M, N, P, Q, S or W, particularly D, E, F, G, H, K, M, N, P, Q or W.

[0691] Clause D59 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses D42 to D53, wherein the variant or salt thereof contains a substitution of E at position 3, for example, by A, D, G, K, Q or V, particularly G, K, Q or V.

[0692] Clause D60 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses D42 to D53, wherein the variant or salt thereof contains a substitution of H at position 4, for example, by D, L, N, P, Q, R or Y.

[0693] Clause D61 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses D42 to D53, wherein the variant or salt thereof contains a substitution of X4 at position 5, for example, by G, K, Q, S, T or V, particularly G, K, Q, T or V.

[0694] Clause D62 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses D42 to D53, wherein the variant or salt thereof contains a substitution of E at position 6, for example, by A, D, G, K, Q or V.

[0695] Clause D63 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses D42 to D53, wherein the variant or salt thereof contains a substitution of D at position 7, for example, by A, E, G, H, N, V ​​or Y.

[0696] Clause D64 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses D42 to D53, wherein the variant or salt thereof contains a substitution of V at position 8, for example, by D, E, I, L or M.

[0697] Clause D65 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the use thereof, according to any one of Clauses D43 to D53, wherein the variant or salt thereof contains a conservative substitution.

[0698] Clause D66 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, according to any one of Clauses D1 to D41, wherein said peptide is an esterified linear peptide or a salt thereof.

[0699] Clause D67 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to any one of Clauses D1 to D66, wherein the esterified linear peptide, variant or salt contains an esterified K residue.

[0700] Clause D68 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause D67, wherein the esterified K residue is X2 at position 1.

[0701] Clause D69 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use of the method pursuant to Clause D67, wherein the esterified K residue is X1 at position -2.

[0702] Clause D70 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the purpose according to any one of Clauses D1 to D69, wherein the lipid chain is a C16DA, C18DA or C20DA group.

[0703] Clause D71 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to Clause D70, wherein the lipid chain is a C18DA group.

[0704] Clause D72 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses D1 to D71, wherein the lipid is linked to a K residue via γGlu.

[0705] Clause D73 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use of the method according to Clause D72, wherein the lipid is linked to a K residue via γGlu and 1 to 4 OEG groups.

[0706] Clause D74 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the use of the method pursuant to Clause D73, wherein the lipid is linked to a K residue via γGlu and two OEG groups.

[0707] Clause D75 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the purpose of any of Clauses D1 to D69, wherein the lipid is C18DA-γGlu-OEG-OEG-.

[0708] Clause D76 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the purpose according to any one of Clauses D1 to D69, wherein the lipid is C18DA-γGlu-OEG-OEG-.

[0709] Clause D77 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the purpose, according to one of Clauses D75 or D76, wherein the lipid is C18DA-L-γGlu-OEG-OEG-.

[0710] Clause D78 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to one of Clauses D75 or D76, wherein the lipid is C18DA-D-γGlu-OEG-OEG-.

[0711] Clause D79 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to any one of Clauses D1 to D78, wherein the esterified linear peptide, variant or salt is N-terminally acetylated.

[0712] Clause D80 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use according to any one of Clauses D1 to D78, wherein the esterified linear peptide, variant or salt is not N-terminally modified.

[0713] Clause D81 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to any one of Clauses D1 to D80, wherein the esterified linear peptide, variant or salt is C-terminally amidated.

[0714] Clause D82 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to any one of Clauses D1 to D80, wherein the esterified linear peptide, variant or salt is not C-terminally modified.

[0715] Clause D83 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause D1, wherein the esterified linear peptide or salt is composed of LLP1 or a salt thereof.

[0716] Clause D84 A lipotropic linear peptide or salt pursuant to Clause D1, wherein the lipotropic linear peptide or salt comprises LLP2 or a salt thereof.

[0717] Clause D85 The method, the peptide or its pharmaceutically acceptable salt used, the pharmaceutical composition used, or the use of the method pursuant to Clause D1, wherein the esterified linear peptide or salt is composed of LLP3 or its salt.

[0718] Clause D86 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause D1, wherein the esterified linear peptide or salt is composed of LLP4 or a salt thereof.

[0719] Clause D87 The method, the peptide or its pharmaceutically acceptable salt used, the pharmaceutical composition used, or the use according to Clause D1, wherein the esterified linear peptide or salt is composed of LLP5 or its salt.

[0720] Clause D88 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, pursuant to Clause D1, wherein the esterified linear peptide or salt comprises LLP6 or a salt thereof.

[0721] Clause D89 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause D1, wherein the esterified linear peptide or salt is composed of LLP7 or a salt thereof.

[0722] Clause D90 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause D1, wherein the esterified linear peptide or salt is composed of LLP8 or a salt thereof.

[0723] Clause D91 The method, the peptide or its pharmaceutically acceptable salt used, the pharmaceutical composition used, or the use according to Clause D1, wherein the esterified linear peptide or salt is composed of LLP9 or its salt.

[0724] Clause D92 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause D1, wherein the esterified linear peptide or salt is composed of LLP10 or a salt thereof.

[0725] Clause D93 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause D1, wherein the esterified linear peptide or salt is composed of LLP11 or a salt thereof.

[0726] Clause D94 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause D1, wherein the esterified linear peptide or salt is composed of LLP12 or a salt thereof.

[0727] Clause D95 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses D1 to D95, wherein the salt is a pharmaceutically acceptable salt.

[0728] Clause D96 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any of the preceding Clauses D, wherein said peptide is an esterified linear peptide.

[0729] Clause D97 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any of the preceding Clauses D, wherein said peptide is an esterified variant peptide.

[0730] Clause D98 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any of the preceding Clauses D, wherein said peptide is a pharmaceutically acceptable salt of an esterified linear peptide.

[0731] Clause D99 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any of the preceding Clauses D, wherein said peptide is a pharmaceutically acceptable salt of an esterified variant peptide.

[0732] Clause D100 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the purpose of the use of any of Clauses D1 to D99, wherein the esterified linear peptide is not modified with side chains.

[0733] Clause D101 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses D1 to D99, wherein the esterified linear peptide is unmodified.

[0734] Clause E1 The method, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the purpose according to any one of Clauses 1 to 4, wherein said peptide is a linear peptide comprising the following sequence:

[0735] in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 51 or its salt, wherein X2 represents P and X3 is an item other than V.

[0736] Clause E2: The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, in accordance with Clause E1, wherein all residues of the peptide backbone are linked only by peptide bonds.

[0737] Clause E3 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use according to Clause E1 or E2, wherein the linear peptide, variant or salt comprises 25 or fewer amino acid residues in the main chain.

[0738] Clause E4 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use according to Clause E3, wherein the linear peptide, variant or salt comprises 20 or fewer amino acid residues in the main chain, for example, 20 amino acid residues in the main chain.

[0739] Clause E5: The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use as described in Clause E4, wherein the linear peptide, variant or salt comprises 15 or fewer amino acid residues in the main chain, for example, 15 amino acid residues in the main chain.

[0740] Clause E6 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use according to Clause E5, wherein the linear peptide, variant or salt comprises 12 or fewer amino acid residues in the main chain, for example, 12 amino acid residues in the main chain.

[0741] Clause E7 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use as described in Clause E6, wherein the linear peptide, variant or salt comprises 11 or fewer amino acid residues in the main chain.

[0742] Clause E8 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use thereof according to any one of Clauses E1 to E7, wherein the linear peptide, variant or salt comprises at least 7 amino acid residues in the main chain, for example, 7 amino acid residues in the main chain.

[0743] Clause E9 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to Clause E8, wherein the linear peptide, variant or salt comprises at least 8 amino acid residues in the main chain, for example, 8 amino acid residues in the main chain.

[0744] Clause E10 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or use according to Clause E9, wherein the linear peptide, variant or salt comprises at least 9 amino acid residues in the main chain, for example, 9 amino acid residues in the main chain.

[0745] Clause E11 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or use according to Clause E10, wherein the linear peptide, variant or salt comprises at least 10 amino acid residues in the main chain, for example, 10 amino acid residues in the main chain.

[0746] Clause E12 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to Clause E11, wherein the linear peptide, variant or salt comprises at least 11 amino acid residues in the main chain.

[0747] Clause E13 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to Clause E12, wherein the linear peptide, variant or salt comprises 11 amino acid residues in the main chain.

[0748] Clause E14 The method, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the purpose according to any one of Clauses E8 through E13, wherein said linear peptide, variant, or salt comprises the following sequence:

[0749] in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 52 or its salt.

[0750] Clause E15 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or intended use according to any one of Clauses E8 through E13, wherein said linear peptide, variant, or salt comprises the following sequence:

[0751] in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 53 or its salt.

[0752] Clause E16 The method, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the purpose according to any one of Clauses E9 through E13, wherein said linear peptide, variant, or salt comprises the following sequence:

[0753] in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or its salt, or a conservative substitution variant containing SEQ ID No. 54 or its salt.

[0754] Clause E17 The method, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the purpose according to any one of Clauses E9 through E13, wherein said linear peptide, variant, or salt comprises the following sequence: (SEQ ID No. 55) in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or its salt, or a conservative substitution variant containing SEQ ID No. 55 or its salt.

[0755] Clause E18 The method, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the purpose according to any one of Clauses E9 through E13, wherein said linear peptide, variant, or salt comprises the following sequence:

[0756] in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 56 or its salt.

[0757] Clause E19 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or intended use according to any one of Clauses E10 through E13, wherein said linear peptide, variant, or salt comprises the following sequence: (SEQ ID No. 57) in: X1 represents M and K. X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or its salt, or a conservative substitution variant containing SEQ ID No. 57 or its salt.

[0758] Clause E20 The method, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the purpose according to any one of Clauses E10 through E13, wherein said linear peptide, variant, or salt comprises the following sequence: (SEQ ID No. 58) in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substituted variant containing SEQ ID No. 58 or its salt.

[0759] Clause E21 The method, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the application according to any one of Clauses E10 through E13, wherein said linear peptide, variant, or salt comprises the following sequence: (SEQ ID No. 59) in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 59 or its salt.

[0760] Clause E22 The method, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the application according to any one of Clauses E11 through E13, wherein said linear peptide, variant, or salt comprises the following sequence: (SEQ ID No. 60) in: X1 represents M and K. X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 60 or its salt.

[0761] Clause E23 The method, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the purpose according to any one of Clauses E11 through E13, wherein said linear peptide, variant, or salt comprises the following sequence: (SEQ ID No. 61) in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 61 or its salt.

[0762] Clause E24 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or intended use according to any of Clauses E12 to E13, wherein said linear peptide, variant, or salt comprises the following sequence: (SEQ ID No. 62) in: X1 represents M and K. X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 62 or its salt.

[0763] Clause E25 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses E1 through E24, wherein X1 represents M.

[0764] Clause E26 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, according to any one of Clauses E1 through E24, wherein X1 represents K.

[0765] Clause E27 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, according to any one of Clauses E1 through E25, wherein X2 represents P.

[0766] Clause E28 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, according to any one of Clauses E1 through E25, wherein X2 represents D.

[0767] Clause E29 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the intended use, according to any one of Clauses E1 through E25, wherein X2 represents Q.

[0768] Clause E30 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses E1 through E25, wherein X2 represents K.

[0769] Clause E31 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use, according to any one of Clauses E1 through E25, wherein X2 represents G.

[0770] Clause E32 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses E1 to E31, wherein X3 represents I.

[0771] Clause E33 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses E1 to E31, wherein X3 represents L.

[0772] Clause E34 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses E1 to E31, wherein X3 represents A.

[0773] Clause E35 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, according to any one of Clauses E1 to E31, wherein X3 represents T.

[0774] Clause E36 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use, according to any one of Clauses E1 to E26 or E28 to E31, wherein X3 represents V.

[0775] Clause E37 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use, according to any one of Clauses E1 through E36, wherein X4 represents E.

[0776] Clause E38 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses E1 through E36, wherein X4 represents A.

[0777] Clause E39 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or use according to any of Clauses E12 to E13, wherein said linear peptide, variant, or salt comprises a sequence of any of SEQ ID Nos. 1 to 10 and 16 to 39 or a salt thereof, or comprises a conserved substituted variant of any of SEQ ID Nos. 1 to 10 and 16 to 39 or a salt thereof, for example, consisting of a sequence of any of SEQ ID Nos. 1 to 10 and 16 to 39 or a salt thereof, or consisting of a conserved substituted variant of any of SEQ ID Nos. 1 to 10 and 16 to 39 or a salt thereof.

[0778] Clause E40 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use according to any one of Clauses E12 to E13, wherein said 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, for example, 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.

[0779] Clause E41 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to any one of Clauses E1 to E40, wherein the variant or salt thereof contains two conservative substitutions.

[0780] Clause E42 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses E1 to E41, wherein the variant or salt thereof contains a substitution of X1 at position -2, for example, by E, N, Q, R, T, I, L or V.

[0781] Clause E43 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses E1 to E41, wherein the variant or salt thereof contains a substitution of T at position -1, for example, by A, K, M, N, R or S, particularly A, K, M, N or R.

[0782] Clause E44 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses E1 to E41, wherein the variant or salt thereof contains a substitution of E at position 0, for example, by A, D, G, K, Q or V, particularly G, K, Q or V.

[0783] Clause E45 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses E1 to E41, wherein the variant or salt thereof contains a substitution of X2 at position 1, for example, by A, C, E, H, L, M, N, R, S, T, V or Y, particularly A, E, H, L, M, N, R, T, V or Y.

[0784] Clause E46 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use thereof according to any one of Clauses E1 to E41, wherein the variant or salt thereof comprises a substitution of X3 at position 2, for example by D, E, F, G, H, K, M, N, P, Q, S or W, particularly D, E, F, G, H, K, M, N, P, Q or W.

[0785] Clause E47 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses E1 to E41, wherein the variant or salt thereof contains a substitution of E at position 3, for example, by A, D, G, K, Q or V, particularly G, K, Q or V.

[0786] Clause E48 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses E1 to E41, wherein the variant or salt thereof contains a substitution of H at position 4, for example, by D, L, N, P, Q, R or Y.

[0787] Clause E49 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses E1 to E41, wherein the variant or salt thereof contains a substitution of X4 at position 5, for example, by G, K, Q, S, T or V, particularly G, K, Q, T or V.

[0788] Clause E50 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the use thereof, according to any one of Clauses E1 to E41, wherein the variant or salt thereof contains a substitution of E at position 6, for example, by A, D, G, K, Q or V.

[0789] Clause E51 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses E1 to E41, wherein the variant or salt thereof contains a substitution of D at position 7, for example, by A, E, G, H, N, V ​​or Y.

[0790] Clause E52 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses E1 to E41, wherein the variant or salt thereof contains a substitution of V at position 8, for example, by D, E, I, L or M.

[0791] Clause E53 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses E41 to E52, wherein the variant or salt thereof contains a substitution of X1 at position -2, for example, by E, N, Q, R, T, I, L or V.

[0792] Clause E54 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses E41 to E52, wherein the variant or salt thereof contains a substitution of T at position -1, for example, by A, K, M, N, R or S, particularly A, K, M, N or R.

[0793] Clause E55 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses E41 to E52, wherein the variant or salt thereof contains a substitution of E at position 0, for example, by A, D, G, K, Q or V, particularly G, K, Q or V.

[0794] Clause E56 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses E41 to E52, wherein the variant or salt thereof comprises a substitution of X2 at position 1, for example, by A, C, E, H, L, M, N, R, S, T, V or Y, particularly A, E, H, L, M, N, R, T, V or Y.

[0795] Clause E57 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses E41 to E52, wherein the variant or salt thereof comprises a substitution of X3 at position 2, for example, by D, E, F, G, H, K, M, N, P, Q, S or W, particularly D, E, F, G, H, K, M, N, P, Q or W.

[0796] Clause E58 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses E41 to E52, wherein the variant or salt thereof contains a substitution of E at position 3, for example, by A, D, G, K, Q or V, particularly G, K, Q or V.

[0797] Clause E59 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses E41 to E52, wherein the variant or salt thereof contains a substitution of H at position 4, for example, by D, L, N, P, Q, R or Y.

[0798] Clause E60 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses E41 to E52, wherein the variant or salt thereof contains a substitution of X4 at position 5, for example, by G, K, Q, S, T or V, particularly G, K, Q, T or V.

[0799] Clause E61 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses E41 to E52, wherein the variant or salt thereof contains a substitution of E at position 6, for example, by A, D, G, K, Q or V.

[0800] Clause E62 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses E41 to E52, wherein the variant or salt thereof contains a substitution of D at position 7, for example, by A, E, G, H, N, V ​​or Y.

[0801] Clause E63 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses E41 to E52, wherein the variant or salt thereof contains a substitution of V at position 8, for example, by D, E, I, L or M.

[0802] Clause E64 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses E42 to E52, wherein the variant or salt thereof contains a conservative substitution.

[0803] Clause E65 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, according to any one of Clauses E1 through E40, wherein the peptide is a linear peptide or a salt thereof.

[0804] Clause E66 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to any one of Clauses E1 to E65, wherein the linear peptide, variant or salt is N-terminally acetylated.

[0805] Clause E67 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to any one of Clauses E1 to E65, wherein the linear peptide, variant or salt is not N-terminally modified.

[0806] Clause E68 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to any one of Clauses E1 to E67, wherein the linear peptide, variant or salt is C-terminally amidated.

[0807] Clause E69 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or use made in accordance with any one of Clauses E1 to E67, wherein the linear peptide, variant or salt is not C-terminally modified.

[0808] Clause E70 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause E1, wherein the linear peptide or salt is composed of SEQ ID No. 1 or a salt thereof.

[0809] Clause E71 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause E1, wherein the linear peptide or salt is composed of SEQ ID No. 2 or a salt thereof.

[0810] Clause E72 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause E1, wherein the linear peptide or salt is composed of SEQ ID No. 3 or a salt thereof.

[0811] Clause E73 The method, the peptide or pharmaceutically acceptable salt thereof used, the pharmaceutical composition or use thereof, according to Clause E1, wherein the linear peptide or salt is composed of SEQ ID No. 4 or a salt thereof.

[0812] Clause E74 The method, the peptide or its pharmaceutically acceptable salt used, the pharmaceutical composition used, or the use according to Clause E1, wherein the linear peptide or salt is composed of SEQ ID No. 5 or its salt.

[0813] Clause E75 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the intended use according to Clause E1, wherein the linear peptide or salt comprises SEQ ID No. 6 or a salt thereof.

[0814] Clause E76 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause E1, wherein the linear peptide or salt is composed of SEQ ID No. 7 or a salt thereof.

[0815] Clause E77 The method, the peptide or pharmaceutically acceptable salt thereof used, the pharmaceutical composition or use thereof, according to Clause E1, wherein the linear peptide or salt is composed of SEQ ID No. 8 or a salt thereof.

[0816] Clause E78 The method, the peptide or its pharmaceutically acceptable salt used, the pharmaceutical composition used, or the use according to Clause E1, wherein the linear peptide or salt is composed of SEQ ID No. 9 or its salt.

[0817] Clause E79 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use according to Clause E1, wherein the linear peptide or salt is composed of SEQ ID No. 10 or a salt thereof.

[0818] Clause E80 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause E1, wherein the linear peptide or salt is composed of SEQ ID No. 16 or a salt thereof.

[0819] Clause E81 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause E1, wherein the linear peptide or salt is composed of SEQ ID No. 17 or a salt thereof.

[0820] Clause E82 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause E1, wherein the linear peptide or salt is composed of SEQ ID No. 18 or a salt thereof.

[0821] Clause E83 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause E1, wherein the linear peptide or salt is composed of SEQ ID No. 19 or a salt thereof.

[0822] Clause E84 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause E1, wherein the linear peptide or salt is composed of SEQ ID No. 20 or a salt thereof.

[0823] Clause E85 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause E1, wherein the linear peptide or salt is composed of SEQ ID No. 21 or a salt thereof.

[0824] Clause E86 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause E1, wherein the linear peptide or salt is composed of SEQ ID No. 22 or a salt thereof.

[0825] Clause E87 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause E1, wherein the linear peptide or salt is composed of SEQ ID No. 23 or a salt thereof.

[0826] Clause E88 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause E1, wherein the linear peptide or salt is composed of SEQ ID No. 24 or a salt thereof.

[0827] Clause E89 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause E1, wherein the linear peptide or salt is composed of SEQ ID No. 25 or a salt thereof.

[0828] Clause E90 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause E1, wherein the linear peptide or salt is composed of SEQ ID No. 26 or a salt thereof.

[0829] Clause E91 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause E1, wherein the linear peptide or salt is composed of SEQ ID No. 27 or a salt thereof.

[0830] Clause E92 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause E1, wherein the linear peptide or salt is composed of SEQ ID No. 28 or a salt thereof.

[0831] Clause E93 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause E1, wherein the linear peptide or salt is composed of SEQ ID No. 29 or a salt thereof.

[0832] Clause E94 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause E1, wherein the linear peptide or salt is composed of SEQ ID No. 30 or a salt thereof.

[0833] Clause E95 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause E1, wherein the linear peptide or salt is composed of SEQ ID No. 31 or a salt thereof.

[0834] Clause E96 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause E1, wherein the linear peptide or salt is composed of SEQ ID No. 32 or a salt thereof.

[0835] Clause E97 The method, the peptide or pharmaceutically acceptable salt thereof used, the pharmaceutical composition or use thereof, according to Clause E1, wherein the linear peptide or salt is composed of SEQ ID No. 33 or a salt thereof.

[0836] Clause E98 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause E1, wherein the linear peptide or salt is composed of SEQ ID No. 34 or a salt thereof.

[0837] Clause E99 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause E1, wherein the linear peptide or salt is composed of SEQ ID No. 35 or a salt thereof.

[0838] Clause E100 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause E1, wherein the linear peptide or salt is composed of SEQ ID No. 36 or a salt thereof.

[0839] Clause E101 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause E1, wherein the linear peptide or salt is composed of SEQ ID No. 37 or a salt thereof.

[0840] Clause E102 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause E1, wherein the linear peptide or salt is composed of SEQ ID No. 38 or a salt thereof.

[0841] Clause E103 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses E1 to E102, wherein the salt is a pharmaceutically acceptable salt.

[0842] Clause E104 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, according to any of the preceding clauses E, wherein the peptide is a linear peptide.

[0843] Clause E105 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, according to any of the preceding clauses E, wherein the peptide is a variant peptide.

[0844] Clause E106 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any of the preceding clauses E, wherein the peptide is a pharmaceutically acceptable salt of a linear peptide.

[0845] Clause E107 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any of the preceding clauses E, wherein the peptide is a pharmaceutically acceptable salt of the variant peptide.

[0846] Clause E108 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses E1 to E107, wherein the linear peptide is not modified with a side chain.

[0847] Clause E109 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, according to any one of Clauses E1 to E107, wherein the linear peptide is unmodified.

[0848] Clause F1 The method, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the purpose according to any one of Clauses 1 to 28, wherein said peptide is a linear peptide comprising 10 or fewer amino acid residues in a main chain and comprising the following sequence:

[0849] in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 51 or its salt.

[0850] Clause F2 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause F1, wherein all residues of the peptide backbone are linked only by peptide bonds.

[0851] Clause F3 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use according to Clause F1 or F2, wherein the linear peptide, variant or salt comprises 6 amino acid residues in the main chain.

[0852] Clause F4 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use according to Clause F1 or F2, wherein the linear peptide, variant or salt comprises 7 amino acid residues in the main chain.

[0853] Clause F5 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use according to Clause F1 or F2, wherein the linear peptide, variant or salt comprises 8 amino acid residues in the main chain.

[0854] Clause F6 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use according to Clause F1 or F2, wherein the linear peptide, variant or salt comprises 9 amino acid residues in the main chain.

[0855] Clause F7 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use according to Clause F1 or F2, wherein the linear peptide, variant or salt comprises 10 amino acid residues in the main chain.

[0856] Clause F8 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or intended use according to any one of Clauses F1, F2, or F4 through F7, wherein said linear peptide, variant, or salt comprises the following sequence:

[0857] in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 52 or its salt.

[0858] Clause F9 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or intended use according to any one of Clauses F1, F2, or F4 through F7, wherein said linear peptide, variant, or salt comprises the following sequence:

[0859] in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 53 or its salt.

[0860] Clause F10 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or intended use according to any of Clauses F1, F2, or F5 through F7, wherein said linear peptide, variant, or salt comprises the following sequence:

[0861] in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or its salt, or a conservative substitution variant containing SEQ ID No. 54 or its salt.

[0862] Clause F11 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or application according to any one of Clauses F1, F2, or F5 through F7, wherein said linear peptide, variant, or salt comprises the following sequence:

[0863] in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or its salt, or a conservative substitution variant containing SEQ ID No. 55 or its salt.

[0864] Clause F12 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or application according to any one of Clauses F1, F2, or F6 through F7, wherein said linear peptide, variant, or salt comprises the following sequence:

[0865] in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 56 or its salt.

[0866] Clause F13 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or intended use according to any of Clauses F1, F2, F6, or F7, wherein said linear peptide, variant, or salt comprises the following sequence: (SEQ ID No. 57) in: X1 represents M and K. X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. Or its salt, or a conservative substitution variant containing SEQ ID No. 57 or its salt.

[0867] Clause F14 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or intended use according to any of Clauses F1, F2, F6, or F7, wherein said linear peptide, variant, or salt comprises the following sequence: (SEQ ID No. 58) in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substituted variant containing SEQ ID No. 58 or its salt.

[0868] Clause F15 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or intended use according to any of Clauses F1, F2, F6, or F7, wherein said linear peptide, variant, or salt comprises the following sequence: (SEQ ID No. 59) in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 59 or its salt.

[0869] Clause F16 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or intended use according to any of Clauses F1, F2, or F7, wherein said linear peptide, variant, or salt comprises the following sequence: (SEQ ID No. 60) in: X1 represents M and K. X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 60 or its salt.

[0870] Clause F17 The method, peptide used, or pharmaceutically acceptable salt thereof, pharmaceutical composition used, or intended use according to any of Clauses F1, F2, or F7, wherein said linear peptide, variant, or salt comprises the following sequence: (SEQ ID No. 61) in: X2 represents P, D, Q, K, G X3 represents I, L, A, T, V X4 represents E and A. or its salt, or a conservative substitution variant containing SEQ ID No. 61 or its salt.

[0871] Clause F18 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses F1 through F17, wherein X1 represents M.

[0872] Clause F19 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, according to any one of Clauses F1 through F17, wherein X1 represents K.

[0873] Clause F20 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the intended use, according to any one of Clauses F1 through F19, wherein X2 represents P.

[0874] Clause F21 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the intended use, according to any one of Clauses F1 through F19, wherein X2 represents D.

[0875] Clause F22 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the intended use, according to any one of Clauses F1 through F19, wherein X2 represents Q.

[0876] Clause F23 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the intended use, according to any one of Clauses F1 through F19, wherein X2 represents K.

[0877] Clause F24 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, according to any one of Clauses F1 through F19, wherein X2 represents G.

[0878] Clause F25 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses F1 through F24, wherein X3 represents I.

[0879] Clause F26 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses F1 through F24, wherein X3 represents L.

[0880] Clause F27 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses F1 through F24, wherein X3 represents A.

[0881] Clause F26 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses F1 through F24, wherein X3 represents T.

[0882] Clause F29 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the intended use, according to any one of Clauses F1 through F24, wherein X3 represents V.

[0883] Clause F30 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used, or the intended use, according to any one of Clauses F1 through F29, wherein X4 represents E.

[0884] Clause F31 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, according to any one of Clauses F1 through F29, wherein X4 represents A.

[0885] Clause F32 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to any of Clauses F1 to F31, wherein the linear peptide, variant or salt comprises the sequence of any of SEQ ID No. 40 to 42 or a salt thereof, or comprises a conservatively substituted variant of any of SEQ ID No. 40 to 42 or a salt thereof.

[0886] Clause F33 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to Clause F32, wherein the linear peptide, variant or salt comprises a sequence of any one of SEQ ID No. 40 to 42 or a salt thereof, or a conserved substituted variant of any one of SEQ ID No. 40 to 42 or a salt thereof.

[0887] Clause F34 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the use thereof, according to any one of Clauses F1 to F33, wherein the variant or salt thereof contains two conservative substitutions.

[0888] Clause F35 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses F1 to F34, wherein the variant or salt thereof contains a substitution of X1 at position -2, for example, by E, N, Q, R, T, I, L or V.

[0889] Clause F36 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses F1 to F34, wherein the variant or salt thereof contains a substitution of T at position -1, for example, by A, K, M, N, R or S, particularly A, K, M, N or R.

[0890] Clause F37 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses F1 to F34, wherein the variant or salt thereof contains a substitution of E at position 0, for example, by A, D, G, K, Q or V, particularly G, K, Q or V.

[0891] Clause F38 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses F1 to F34, wherein the variant or salt thereof contains a substitution of X2 at position 1, for example, by A, C, E, H, L, M, N, R, S, T, V or Y, particularly A, E, H, L, M, N, R, T, V or Y.

[0892] Clause F39 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses F1 to F34, wherein the variant or salt thereof contains a substitution of X3 at position 2, for example, by D, E, F, G, H, K, M, N, P, Q, S or W, particularly D, E, F, G, H, K, M, N, P, Q or W.

[0893] Clause F40 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses F1 to F34, wherein the variant or salt thereof contains a substitution of E at position 3, for example, by A, D, G, K, Q or V, particularly G, K, Q or V.

[0894] Clause F41 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses F1 to F34, wherein the variant or salt thereof contains a substitution of H at position 4, for example, by D, L, N, P, Q, R or Y.

[0895] Clause F42 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses F1 to F34, wherein the variant or salt thereof contains a substitution of X4 at position 5, for example, by G, K, Q, S, T or V, particularly G, K, Q, T or V.

[0896] Clause F43 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses F1 to F34, wherein the variant or salt thereof contains a substitution of E at position 6, for example, by A, D, G, K, Q or V.

[0897] Clause F44 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any of Clauses F1 to F34, wherein the variant or salt thereof contains a substitution of D at position 7, for example, by A, E, G, H, N, V ​​or Y.

[0898] Clause F45 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any of Clauses F1 to F34, wherein the variant or salt thereof contains a substitution of V at position 8, for example, by D, E, I, L or M.

[0899] Clause F46 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses F34 to F45, wherein the variant or salt thereof contains a substitution of X1 at position -2, for example, by E, N, Q, R, T, I, L or V.

[0900] Clause F47 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses F34 to F45, wherein the variant or salt thereof contains a substitution of T at position -1, for example, by A, K, M, N, R or S, particularly A, K, M, N or R.

[0901] Clause F48 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses F34 to F45, wherein the variant or salt thereof contains a substitution of E at position 0, for example, by A, D, G, K, Q or V, particularly G, K, Q or V.

[0902] Clause F49 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses F34 to F45, wherein the variant or salt thereof comprises a substitution of X2 at position 1, for example, by A, C, E, H, L, M, N, R, S, T, V or Y, particularly A, E, H, L, M, N, R, T, V or Y.

[0903] Clause F50 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any one of Clauses F34 to F45, wherein the variant or salt thereof contains a substitution of X3 at position 2, for example, by D, E, F, G, H, K, M, N, P, Q, S or W, particularly D, E, F, G, H, K, M, N, P, Q or W.

[0904] Clause F51 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses F34 to F45, wherein the variant or salt thereof contains a substitution of E at position 3, for example, by A, D, G, K, Q or V, particularly G, K, Q or V.

[0905] Clause F52 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses F34 to F45, wherein the variant or salt thereof contains a substitution of H at position 4, for example, by D, L, N, P, Q, R or Y.

[0906] Clause F53 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses F34 to F45, wherein the variant or salt thereof contains a substitution of X4 at position 5, for example, by G, K, Q, S, T or V, particularly G, K, Q, T or V.

[0907] Clause F54 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses F34 to F45, wherein the variant or salt thereof contains a substitution of E at position 6, for example, by A, D, G, K, Q or V.

[0908] Clause F55 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses F34 to F45, wherein the variant or salt thereof contains a substitution of D at position 7, for example, by A, E, G, H, N, V ​​or Y.

[0909] Clause F56 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to any of Clauses F34 to F45, wherein the variant or salt thereof contains a substitution of V at position 8, for example, by D, E, I, L or M.

[0910] Clause F57 The method, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the use thereof, according to any one of Clauses F35 to F45, wherein the variant or salt thereof contains a conservative substitution.

[0911] Clause F58 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to any one of Clauses F1 to F57, wherein the linear peptide, variant or salt is N-terminally acetylated.

[0912] Clause F59 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use according to any one of Clauses F1 to F57, wherein the linear peptide, variant or salt is not N-terminally modified.

[0913] Clause F60 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to any one of Clauses F1 to F59, wherein the linear peptide, variant or salt is C-terminally amidated.

[0914] Clause F61 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or use made in accordance with any one of Clauses F1 to F59, wherein the linear peptide, variant or salt is not modified at the C-terminus.

[0915] Clause F62 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, according to any one of Clauses F1 to F33, wherein the peptide is a linear peptide.

[0916] Clause F63 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause F1, wherein the linear peptide or salt is composed of SEQ ID No. 40 or a salt thereof.

[0917] Clause F64 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause F1, wherein the linear peptide or salt is composed of SEQ ID No. 41 or a salt thereof.

[0918] Clause F65 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to Clause F1, wherein the linear peptide or salt is composed of SEQ ID No. 42 or a salt thereof.

[0919] Clause F66 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, according to any one of Clauses F1 to F65, wherein the salt is a pharmaceutically acceptable salt.

[0920] Clause F67 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any of the preceding Clauses F, wherein said peptide is a linear peptide.

[0921] Clause F68 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any of the preceding Clauses F, wherein the peptide is a variant peptide.

[0922] Clause F69 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any of the preceding Clauses F, wherein the peptide is a pharmaceutically acceptable salt of a linear peptide.

[0923] Clause F70 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof according to any of the preceding Clauses F, wherein the peptide is a pharmaceutically acceptable salt of the variant peptide.

[0924] Clause F71 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses F1 to F70, wherein the linear peptide is not modified with a side chain.

[0925] Clause F72 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, according to any one of Clauses F1 to F70, wherein the linear peptide is unmodified.

[0926] Clause G1 The method 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, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, wherein the esterified cyclic peptide, cyclic peptide, esterified linear peptide, linear peptide, variant of any of the foregoing and / or salt of any of the foregoing is capable of increasing BDNF levels.

[0927] Clause G2 The method according to Clause G1, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, wherein the esterified cyclic peptide, cyclic peptide, esterified linear peptide, linear peptide, variant of any of the foregoing and / or salt of any of the foregoing is capable of increasing BDNF levels by at least 20% between 0 and 24 hours after administration in the determination of Example 10.

[0928] Clause H1 The method 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, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, wherein the esterified cyclic peptide, cyclic peptide, esterified linear peptide, linear peptide, variant of any of the foregoing and / or salt of any of the foregoing is capable of increasing phosphorylated CREB (Ser133) levels.

[0929] Clause H2 The method according to Clause H1, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, wherein the esterified cyclic peptide, cyclic peptide, esterified linear peptide, linear peptide, variant of any of the foregoing and / or salt of any of the foregoing is capable of increasing CREB levels by at least 30% between 0 and 24 hours after administration in the determination of Example 10.

[0930] Clause I1 The method 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, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, wherein the esterified cyclic peptide, cyclic peptide, esterified linear peptide, linear peptide, variant of any of the foregoing and / or salt of any of the foregoing is capable of increasing PGC1a levels.

[0931] Clause I2 The method according to Clause I1, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, wherein the lipo-cyclic peptide, cyclic peptide, lipo-linear peptide, linear peptide, variant of any of the foregoing and / or salt of any of the foregoing is capable of increasing PGC1a levels by at least 30% between 0 and 24 hours after administration in the determination of Example 10.

[0932] Clause J1 The method 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, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, wherein the esterified cyclic peptide, cyclic peptide, esterified linear peptide, linear peptide, variant of any of the foregoing and / or salt of any of the foregoing is capable of increasing TFEB levels.

[0933] Clause J2 The method according to Clause J1, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, wherein the esterified cyclic peptide, cyclic peptide, esterified linear peptide, linear peptide, variant of any of the foregoing and / or salt of any of the foregoing is capable of increasing TFEB levels by at least 30% between 0 and 24 hours after administration in the determination of Example 10.

[0934] Clause K1 The method 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, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, wherein the esterified cyclic peptide, cyclic peptide, esterified linear peptide, linear peptide, variant of any of the foregoing and / or salt of any of the foregoing is capable of reducing NfL levels.

[0935] Clause K2 The method according to Clause K1, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, wherein the esterified cyclic peptide, cyclic peptide, esterified linear peptide, linear peptide, variant of any of the foregoing and / or salt of any of the foregoing are capable of reducing NfL levels by at least 10% in the determination of Example 31.

[0936] Clause L1 The method according to any of the foregoing clauses, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, wherein the esterified cyclic peptide, cyclic peptide, esterified linear peptide, linear peptide, variant of any of the foregoing, and / or salt of any of the foregoing has an improved ability to increase BDNF, PGC1a, TFEB, and / or phosphorylated CREB (Ser133) compared to CPX.

[0937] Clause L2 The method according to any of the foregoing clauses, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, wherein the esterified cyclic peptide, cyclic peptide, esterified linear peptide, linear peptide, variant of any of the foregoing and / or salt of any of the foregoing has an improved effect compared to CPX. 1 / 2 AUC or C max Especially in the brain.

[0938] Clause L3 The method according to any of the preceding clauses, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, wherein the lipolated cyclic peptide, cyclic peptide, lipolated linear peptide, linear peptide, variant of any of the foregoing, and / or salt of any of the foregoing has an improved effect on the brain compared to CPX. 1 / 2 .

[0939] Clause L4 The method according to any of the preceding clauses, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, wherein the esterified cyclic peptide, cyclic peptide, esterified linear peptide, linear peptide, variant of any of the foregoing and / or salt of any of the foregoing has an ability at least equivalent to CLP1 to increase BDNF, PGC1a, TFEB and / or phosphorylated CREB (Ser133).

[0940] Clause L5 The method according to any of the preceding clauses, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, wherein the esterified cyclic peptide, cyclic peptide, esterified linear peptide, linear peptide, variant of any of the foregoing, and / or a salt of any of the foregoing has a t value at least equivalent to CLP1. 1 / 2 AUC or C max Especially in the brain.

[0941] Clause L6 The method according to any of the preceding clauses, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, wherein the esterified cyclic peptide, cyclic peptide, esterified linear peptide, linear peptide, variant of any of the foregoing, and / or a salt of any of the foregoing has a t value at least equivalent to CLP1. 1 / 2 Especially in the brain.

[0942] Clause L7 The method according to any of the preceding clauses, the peptide used or its pharmaceutically acceptable salt, the pharmaceutical composition used or the use thereof, wherein the lipotropic cyclic peptide, cyclic peptide, lipotropic linear peptide, linear peptide, variant of any of the foregoing and / or salt of any of the foregoing does not exhibit fibrosis at pH 6.5 and 7.5, suitably at pH 4.5, pH 6.5 and pH 7.5 (e.g. by the method of Example 5).

[0943] Clause L8 The method according to any of the foregoing clauses, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, wherein the esterified cyclic peptide, cyclic peptide, esterified linear peptide, linear peptide, variant of any of the foregoing, and / or salt of any of the foregoing exhibits a t-value of at least 1 hour. 1 / 2 Suitable for at least 4 hours, especially at least 8 hours (e.g., by the method of Example 9).

[0944] Clause L9 The method described in Clause Q8, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the intended use, wherein the esterified cyclic peptide, cyclic peptide, esterified linear peptide, linear peptide, variant of any of the foregoing, and / or a salt of any of the foregoing exhibits at least 1 hour of activity in the brain. 1 / 2 Suitable for at least 4 hours, especially at least 8 hours (e.g., by the method of Example 9).

[0945] Clause M1: The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use of any of Clauses 1 to L9, wherein the disease or condition of the ear or mastoid is a disease or condition accompanied by hearing loss or impairment.

[0946] Clause M2: The hearing loss described in Clause M1 is sensorineural hearing loss, based on the method, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the intended use.

[0947] Clause M3: The hearing loss described in Clause M1 or M2 is acquired hearing loss, referring to the method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the intended use.

[0948] Clause M4: The hearing loss described in Clause M1 or M2 is congenital hearing loss, referring to the method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the intended use.

[0949] Clause M5 The hearing loss is hereditary hearing loss, as described in any of Clauses M1 through M4, by means of the method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the purpose thereof.

[0950] Clause M6 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to Clause M5, wherein the hereditary hearing loss is a syndromic type of hearing loss.

[0951] Clause M7 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use as described in 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, Jervelland Lange-Nielsen Syndrome, Alport Syndrome, and X-Linked Congenital Stapes Fixation with Perilymph Gusher.

[0952] Clause M8 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to Clause M5, wherein the hereditary hearing loss is nonsyndromic hearing loss.

[0953] Clause M9 The nonsyndromic hearing loss described in Clause M8, based on the method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the intended use, is associated with a mutation in one or more genes selected from GJB2, GJB6, STRC, KCNQ4, TECTA and POU3F4.

[0954] Clause M10 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use according to any one of Clauses M1 to M5, wherein the hearing loss is related to mitochondrial disease.

[0955] Clause M11 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended 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 with red ragged fibromyalgia (MERRF).

[0956] Clause M12 The hearing loss is an auditory synaptic disorder or neuropathy, as described in any of Clauses M1 to M11, by means of the method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the purpose thereof.

[0957] Clause M13 The hearing loss described is invisible hearing loss, referring to the method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the purpose described in any of Clauses M1 to M12.

[0958] Clause M14 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use according to Clause M1, wherein the disease or condition of the ear or mastoid is a vestibular syndrome.

[0959] Clause M15 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use as described in Clause M14, wherein the vestibular syndrome is Meniere's disease.

[0960] Clause M16 The vestibular syndrome is a vertigo syndrome, as described in Clause M14, based on the method, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the intended use.

[0961] Clause M17 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the purpose, according to any one of Clauses 1 to M16, wherein the administration of said peptide results in improved hearing.

[0962] Clause M18 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use as described in Clause M17, wherein the hearing improvement is measured using pure-tone audiometry.

[0963] Clause M19 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to Clause M17 or M18, wherein the hearing improvement is measured using auditory brainstem response.

[0964] Clause M20 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use according to any one of Clauses M17 through M19, wherein the hearing improvement is measured using otoacoustic emissions.

[0965] Clause M21 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use according to any one of Clauses M17 to M20, wherein the hearing improvement is an improvement in one or more of the speech awareness threshold, speech recognition threshold and / or word recognition rate.

[0966] Clause M22 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or use of any of Clauses M17 through M21, wherein the hearing improvement is measured using one or more of the following tests: Noise Hearing Test, American English Matrix Test, Noise Digit Test, Noise Word Test, and Noise Speech Recognition Test.

[0967] Clause M23 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the purpose, according to any one of Clauses 1 to M22, wherein the administration of said peptide increases the number of cochlear zona synapses.

[0968] Clause M24 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the purpose, according to any one of Clauses 1 to M23, wherein the administration of said peptide increases the number of spiral ganglion neurons.

[0969] Clause M25 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the purpose, according to any one of Clauses 1 to M24, wherein the administration of said peptide increases the number of inner hair cells and / or outer hair cells.

[0970] Clause M26 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the purpose thereof, according to any one of Clauses 1 through M25, is for the treatment of a patient.

[0971] Clause M27 For prevention, the method, the peptide or its pharmaceutically acceptable salt used, the pharmaceutical composition used, or the purpose, according to any one of Clauses 1 through M25.

[0972] Clause M28: The method, the peptide or its pharmaceutically acceptable salt used, the pharmaceutical composition used, or the use thereof, according to any one of Clauses 1 through M27, is used in human subjects.

[0973] Clause M29 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use thereof, according to any one of Clauses 1 to M28, wherein the age of the human subject is less than 2 years.

[0974] Clause M30 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use of any of Clauses 1 to M28, wherein the subject is 2 to 17 years old.

[0975] Clause M31 The method, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the intended use according to any one of Clauses 1 to M28, wherein the age of the human subject is 18 to 65 years.

[0976] Clause M32 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use of any of Clauses 1 through M28, wherein the age of the human subject is 66 years or older.

[0977] Clause M33 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use according to any of the preceding clauses, wherein the disease or condition of the ear or mastoid is a cochlear synaptic lesion.

[0978] Clause M34 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use as described in Clause M33, wherein the cochlear synaptic lesion is related to age, sensorineural hearing loss or noise-induced hearing loss.

[0979] Clause M35 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use as described in Clause M33, wherein the cochlear synaptic lesion is associated with an inflammatory or neurodegenerative condition such as Huntington's disease, Parkinson's disease or Alzheimer's disease.

[0980] Clause M36 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use according to any of the preceding clauses, wherein the disease or condition of the ear or mastoid is age-related hearing loss.

[0981] Clause M36 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use according to any of the preceding clauses, wherein the hearing loss is due to noise exposure.

[0982] Clause M37 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use according to any of the preceding clauses, wherein the hearing loss is due to exposure to an ototoxic drug.

[0983] Clause M38 The method, peptide or pharmaceutically acceptable salt thereof, pharmaceutical composition or use according to any of the preceding clauses, wherein the speech under noise (SIN) test is improved relative to untreated subjects.

[0984] Clause M39 Based on the method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or intended use of Clause M38, wherein the noise-under-word (WIN) test is improved relative to untreated subjects.

[0985] Clause M40 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use according to any of the preceding clauses, wherein the absolute OAE amplitude is increased relative to untreated subjects.

[0986] Clause M41 The method, peptide used or a pharmaceutically acceptable salt thereof, pharmaceutical composition used or use according to any of the preceding clauses, wherein the peptide is cyclic in its main chain and the peptide main chain is linked only by peptide bonds.

[0987] Clause M42 The method, peptide or pharmaceutically acceptable salt thereof used, pharmaceutical composition or use according to any of the preceding clauses, wherein all residues within the cyclic peptide are within the ring.

[0988] The present invention will be described in more detail with reference to the following embodiments, but the present invention is not limited thereto. Modifications to the embodiments may be made without departing from the scope of the present invention.

[0989] Furthermore, the singular forms “a,” “an,” and “the” used in this specification and the appended claims include the plural forms unless the context clearly specifies otherwise. Thus, for example, reference to “a peptide” includes two or more such peptides, and so on.

[0990] All publications, patents, and patent applications cited in this article, whether above or below, are incorporated herein by reference in their entirety.

[0991] Example

[0992] statistics

[0993] Unless otherwise stated, use the two-tailed Student's t-test to assess significance.

[0994] The error bars represent SEM. p<0.05 p<0.01 p<0.001 p<0.0001.

[0995] Example 1: Peptide Synthesis

[0996] Linear peptides were synthesized using standard Fmoc (fluorenyl methoxycarbonyl) chemical methods.

[0997] Resin preparation: 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 stirred with N2 at 20 °C for 2 hours, then methanol (MeOH) (0.5 mL) was added, and stirring with N2 was continued for 30 min. The resin was washed three times with dimethylformamide (DMF) (15 mL).

[0998] Deprotection: Fmoc removal was performed on the resin using 15 mL of 20% piperidine DMF solution, followed by stirring with nitrogen for 30 min. The resin was then washed four times with 15 mL of DMF and filtered.

[0999] Couplet: A DMF solution (5 mL) of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate (HBTU) (2.85 eq), DIPEA (6 eq), and Fmoc-protected amino acids (3 eq) was added to the resin, and the mixture was stirred under nitrogen at 20 °C for 30 min to perform continuous amino acid coupling. The resin was then washed four times with DMF (15 mL).

[1000] Repeat the Fmoc deprotection and coupling steps for each subsequent amino acid until the desired peptide sequence is obtained.

[1001] The resin was then washed four times with dimethylformamide (DMF) (15 mL).

[1002] Repeat the Fmoc removal and coupling steps until the desired peptide sequence is obtained.

[1003] The resulting linear peptides with protected side chains and bound to the resin were used directly in the next reaction step.

[1004] The Fmoc-protected amino acid building blocks used are as follows: 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-Ile-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. Unless otherwise specified, all amino acids used are native L-forms. The addition of lipids to lysine residues was performed using orthogonally protected Lys(Dde-Lys(Fmoc)-OH), where Dde is attached to the α-amino group and the Fmoc group is attached to the side-chain amino group. After coupling with the protected Lys, the Fmoc group was first removed, and then the lipids were coupled to the exposed amino group. Subsequently, Dde was removed, and the peptide chain was extended using the standard Fmoc chemistry method.

[1005] Example 2: Peptide cleavage, cyclization, and purification

[1006] After final amino acid coupling and Fmoc removal, the resin from Example 1 was washed five times with DMF, three times with MeOH, and dried under vacuum. To prepare cyclic peptides, the peptide resin was treated with a lysis mixture (1% trifluoroacetic acid (TFA) / 99% DCM) (15 mL) for 15 minutes, and the peptide containing the TFA-DCM mixture was collected. The lysis was repeated three times. For linear peptides, lysis and direct deprotection were performed using a strong acid (95% TFA). For cyclic peptides, the peptide (dissolved in 1% TFA / 99% DCM) was diluted with DCM (200 mL), and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylammonium tetrafluoroborate (TBTU) (2 eq), 1-hydroxybenzotriazine hydrate (HOBT) (2 eq), and DIPEA (6 eq) were added to couple the head and tail of the peptide. The mixture was stirred at 20°C for 1 hour. The cyclization reaction was monitored by LC-MS.

[1007] After stirring, the mixture was washed twice with 1 M hydrochloric acid (HCl) (30 mL) and dried under reduced pressure. 5 mL of lysis buffer (92.5% TFA / 2.5% 3-mercaptopropionic acid / 2.5% triisopropylsilane / 2.5% H2O) was added to the flask containing the side-chain protected cyclic peptide, and the mixture was stirred at 20 °C for 2 hours. The peptide was precipitated with ice-cold methyl tert-butyl ether (40 mL), centrifuged (3000 rpm, 2 min), and washed twice with ice-cold methyl tert-butyl ether (40 mL).

[1008] The crude peptide was dried under vacuum for 2 hours and purified by preparative HPLC. The target peptide fractions were then lyophilized to obtain a white solid. Preparative HPLC (Prep-HPLC) methods: (System: Gilson GX-281; ​​Column: Gemini, C18, 110Å, 5 µm or Luna, C18, 100Å, 10 µm; Gradient: Gradient run time 50 min; 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 aqueous solution; Solvent B: Acetonitrile.)

[1009] Qualitative analysis of the peptides was performed by HPLC and LCMS (see Figure 1): HPLC Chromatographic column: Gemini C18, 110 Å, 5 µm, 150 × 4.6 mm; Gradient: Gradient run time 20 min; 0.00–20.00 min 15–45% B, 20.10–23.00 min 95% B, 23.00–23.10 min 95–15% B, 23.10–28.00 min 15% B; Flow rate: 1.0 mL / min; Diode array, 220 / 254 nm; Column temperature: 30 °C; Solvent A: 0.1% TFA aqueous solution; Solvent B: 0.075% TFA acetonitrile solution.

[1010] LCMS analysis method for final products:(System: Agilent Infinity II 1260 HPLC series; Column: Xbridge C18, 130Å, 3.5 µm, 2.1 × 30 mm; Detector: Agilent LCMS (G6125C), single quadrupole TIC scan; Scan range: m / z minimum 100, m / z maximum 2000, positive ion mode, electrospray ionization; Gradient: gradient run time 1 min; 0.00–1.00 min 10–80% B; Column washing and equilibration: 1.00–1.01 min 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 aqueous solution; Solvent B: 0.075% TFA acetonitrile solution)

[1011] result

[1012] The table below shows a summary of LC-MS and HPLC purity data. Figures 1A to 1C Exemplary chromatograms and mass spectra of CLP1 are shown.

[1013] Table 4 – Summary of HPLC purification and MS characterization of peptides Single isotope

[1014] Example 3: CLP1 treatment leads to an increase in CREB target genes

[1015] SorCS2 has recently been shown to play a crucial role in BDNF / TrkB signaling, serving as a prerequisite for downstream kinase activation (Glerup, 2016). The neurotrophic factor response to BDNF is primarily mediated by the activation of the transcription factor CREB (Finkbeiner, 1997; Walton, 2000; Benito, 2010; Sakamoto, 2011). CREB activation is well-known for promoting neuronal survival, synapse formation, and growth. BDNF production via CREB is a key mediator in this process (Tao, 1998), establishing a positive feedback loop. Similarly, CREB activation has been shown to induce mitochondrial biosynthesis by upregulating the master regulator PGC1a (Wu, 2006; Kang, 2017). In fact, the cyclic peptide mimic of the SorCS2 receptor fragment, CPX, increases BDNF levels in wild-type neurons 4 hours after stimulation (WO2022029281). Since CLP1 is a cyclic liposome mimic of the SorCS2 receptor fragment, which is crucial for BDNF signaling, we evaluated whether CLP1 treatment would lead to increased BDNF and PGC1a production in wild-type neurons due to CREB activation. We compared the effects of the cyclic and stable liposome CLP1 with those of the cyclic peptide CPX.

[1016] Cortical neurons were isolated from p0 wild-type mice and seeded at a density of 200,000 neurons per well in 24-well plates. After 7 days of in vitro culture, neurons were stimulated with neurobasal A15 medium containing 1 μM CLP1 or CPX and incubated at 37°C and 5% CO2 for 8, 16, or 24 hours. Subsequently, neurons were lysed with RIPA lysis buffer containing cOmplete mixed protease inhibitors. Western blotting was used to analyze BDNF and PGC1a levels, normalized to β-actin.

[1017] like Figure 2A and Figure 2B As shown, 24 hours after stimulation, CLP1 significantly upregulated two evaluated CREB downstream target genes: BDNF by 180% (p=0.0174) and PGC1a by 611% (p<0.0001). CPX did not increase either BDNF or PGC1a levels, possibly because its effects occurred before the evaluation time point. This indicates that CLP1 signaling has a longer duration compared to CPX.

[1018] Example 4: CLP1 clears soluble mHTT in fibroblasts derived from Huntington's disease patients

[1019] Autophagy is the process of clearing misfolded proteins, aggregates, or damaged organelles. In addition to promoting mitochondrial biosynthesis, PGC1a has been shown to promote lysosomal biosynthesis by regulating TFEB (a major regulator of lysosomal biosynthesis) (Ghosh, 2015; Lynch, 2020). This study assessed the reduction in mHTT (mutant huntingtin protein) levels induced by CLP1 in the expression of the Huntington's disease-causing gene, and whether this reduction was the cause of PGC1a upregulation and TFEB regulation. Simultaneously, this study introduced CPX (WO2022029281), previously shown to reduce mutant HTT levels, to compare its efficacy. Patient-derived fibroblasts GM04476 (from the Coriell Biobank) were seeded in 96-well plates at a density of 30,000–50,000 cells per well. The following day, cells were treated with 1 μM CLP1 or CPX and incubated at 37°C and 5% CO2 for 24 hours. Cells were then lysed using RIPA lysis buffer containing a cOmplete mixed protease inhibitor. Total huntingtin protein levels were analyzed using the antibody mab2166 (Sigma-Aldrich), and mutant huntingtin protein levels were detected using an antibody (MW1 ab) that can only detect mutant alleles in Western blotting. All levels were normalized to β-actin. Figure 3A and Figure 3B As shown, both CLP1 and CPX reduced the level of mutant huntingtin protein to 50% (p=0.0048) and 75% (p=0.0209), respectively, and reduced the level of total huntingtin protein (including mutant and healthy alleles) to ~65% (p=0.0036, CLP1 group) and 75% (p=0.0056, CPX group), respectively. This indicates that CLP1 is more effective than CPX, and that CLP1 is more specific for degrading mutant huntingtin protein than for healthy huntingtin protein. Therefore, CLP1 holds promise as a treatment for patients with HD.

[1020] Example 5: Chemical and physical stability of CLP1

[1021] To better understand the chemical basis of CLP1 stability and degradation, the chemical and physical stability of CLP1 in three buffer systems was evaluated. CLP1 solutions were prepared in three buffer systems with different pH values, and the samples were incubated statically at 40°C. Chemical stability was assessed using UPLC-UV on the day of preparation (t0) and after two weeks of incubation (t14). Physical stability was assessed using thioflavin T (ThT) determination during four days of shaking incubation at 40°C.

[1022] For each assay, samples were dissolved to a peptide concentration of 1 mg / mL in 25% acetonitrile (ACN) solution (for analytical standards) or in one of the following 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; or 50 mM sodium phosphate buffer, pH 7.5 (40.6 mM Na₂HPO₄ + 9.4 mM NaH₂PO₄). All buffers were prepared using ultrapure water with a resistivity of 18.2 MΩ·cm (Milli-Q® Reference A+ system, Merck). Samples were centrifuged at 13300 rpm (17000 g) for 10 min prior to UPLC-UV measurements. For physical stability studies, samples were filtered through a 0.22 μm cellulose membrane (13 Ø, Frisenette) prior to ThT measurements.

[1023] Determination of chemical stability by UPLC-UV method: Chromatographic column: Kinetex 1.7 μm C18 100 Å 150x2.1 mm column from Phenomenex; Mobile phase A: ultrapure water + 0.1% TFA; Mobile phase B: acetonitrile + 0.1% TFA; Injection volume: 2 μL CLP1; Flow rate: 0.3 mL / min; Detection wavelength: 220 nm.

[1024] gradient: Time %B curve 0.00 5 5 17.0 80 5 17.5 5 1 23.0 5 ThT assay microplate reader settings: Excitation wavelength: 450 nm; dichroic filter: 465 nm; emission wavelength: 486 nm; focal length: 3.5 mm; gain: 1000; number of cycles: 1000; cycle time: 360 s; number of flashes per aperture: 20; oscillation: 300 rpm, oscillation for 5 seconds, pause for 5 seconds between each cycle; temperature: 40℃.

[1025] result( Figures 4A to 4C The results showed that CLP1 degraded most significantly at pH 4.5 (AUC decreased by 9%). CLP1 exhibited similarly good chemical stability at pH 6.5 and 7.5 (AUC decreased by 1%). Its physical stability was assessed using a ThT assay to evaluate fibrillation behavior over 96 hours. No fibrillation was observed in any of the buffer solutions, indicating good physical stability. Figures 4D to 4GEach curve represents an independent, repeated experiment.

[1026] Example 6: CLP1 Freedom Fraction and Stability

[1027] A crucial aspect of drug development is pharmacokinetics, including absorption, distribution, metabolism, and excretion (ADME). This study evaluated the stability of CLP1 in human plasma, mouse plasma, and mouse brain homogenate samples. Since CLP1 is stabilized by substitution of two amino acids compared to CPX, CPX was used as a reference in these stability assays. Furthermore, the stability of CLP1 in the S9 fraction of liver from mice, dogs, rats, humans, and monkeys was also evaluated. Brain binding (free fraction) in mouse and human brain homogenates was also assessed.

[1028] plasma stability

[1029] Before use, thaw frozen mouse or human plasma in a 37°C water bath. Centrifuge the plasma at 4000 rpm for 5 min and remove any blood clots (if any). Incubate the mouse or human plasma with 2 μM CLP1 or CPX or 2 μM brombutazone (a degraded positive control) in a 37°C water bath. At each time point, add stop solution (200 ng / mL tolbutamide and 200 ng / mL labetalol in methanol) to precipitate proteins, mix well, centrifuge, and collect the supernatant for LCMS analysis. Figure 5A and Figure 5B As shown, the half-lives (t½) of both CLP1 and CPX exceed 28.9 hours, indicating their high stability in plasma. Remaining percentage (%) = 100 × (PAR for specified incubation time / PAR for T0 time), where PAR is the peak area ratio of the analyte to the internal standard (IS), and the half-life is determined by t½. 1 / 2 =0.693k was calculated.

[1030] Mouse brain stability

[1031] Before use, thaw the frozen mouse brain homogenate in a 37°C water bath. Incubate the mouse brain homogenate with 1 μM CLP1 or CPX or 2 μM 7-ethoxycoumarin (degradation positive control) in a 37°C water bath. At each time point, add stop solution (200 ng / mL tolbutamide and 200 ng / mL labetalol in methanol) to precipitate proteins, mix well, centrifuge, and collect the supernatant for LCMS analysis. Figure 5C As shown, the half-life (t½) of CLP1 is 40.7 hours, while that of CPX is 28.9 hours. This indicates that CLP1 has higher brain stability and is superior to CPX.

[1032] Example 7: Metabolic stability of CLP1 in liver fractions

[1033] Since most drug metabolism occurs in the liver, in vitro liver formulations can serve as models for assessing drug metabolic stability. To test metabolic stability, the S9 fraction, which comprises a mixture of unfractionated microsomes and cytosol containing various drug-metabolizing enzymes, is commonly used. The liver S9 fraction is often used as the preferred testing system for in vitro ADME studies.

[1034] Liver S9 stability

[1035] 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) and dissolved in 100 mM potassium phos...

Claims

1. A method for treating or preventing a disease or condition of the ear or mastoid process in a subject, the method comprising administering a peptide or a pharmaceutically acceptable salt thereof, wherein the peptide is: (i) A lipid-cyclic peptide comprising the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51; (ii) A cyclic peptide comprising the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51, where X2 represents P and X3 is a term other than V; (iii) A cyclic peptide comprising 10 or fewer amino acid residues within a ring, and comprising the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51; (iv) A lipidated linear peptide comprising the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51; (v) A linear peptide comprising the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51, where X2 represents P and X3 is a term other than V; or (vi) A linear peptide comprising 10 or fewer amino acid residues in a main chain and containing the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No.

51.

2. A peptide or a pharmaceutically acceptable salt thereof for the treatment or prevention of diseases or conditions of the ear or mastoid process, wherein said peptide is: (i) A lipid-cyclic peptide comprising the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51; (ii) A cyclic peptide comprising the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51, where X2 represents P and X3 is a term other than V; (iii) A cyclic peptide comprising 10 or fewer amino acid residues within a ring, and comprising the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51; (iv) A lipidated linear peptide comprising the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51; (v) A linear peptide comprising the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51, where X2 represents P and X3 is a term other than V; or (vi) A linear peptide comprising 10 or fewer amino acid residues in a main chain and containing the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No.

51.

3. A pharmaceutical composition for treating or preventing ear or mastoid diseases or conditions, said pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof, wherein said peptide is: (i) A lipid-cyclic peptide comprising the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51; (ii) A cyclic peptide comprising the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51, where X2 represents P and X3 is a term other than V; (iii) A cyclic peptide comprising 10 or fewer amino acid residues within a ring, and comprising the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51; (iv) A lipidated linear peptide comprising the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51; (v) A linear peptide comprising the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51, where X2 represents P and X3 is a term other than V; or (vi) A linear peptide comprising 10 or fewer amino acid residues in a main chain and containing the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No.

51.

4. Use of a peptide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of diseases or conditions of the ear or mastoid process, wherein said peptide is: (i) A lipid-cyclic peptide comprising the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51; (ii) A cyclic peptide comprising the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51, where X2 represents P and X3 is a term other than V; (iii) A cyclic peptide comprising 10 or fewer amino acid residues within a ring, and comprising the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51; (iv) A lipidated linear peptide comprising the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51; (v) A linear peptide comprising the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51, where X2 represents P and X3 is a term other than V; or (vi) A linear peptide comprising 10 or fewer amino acid residues in a main chain and containing the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No.

51.

5. The method of any one of claims 1 to 4, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, wherein said peptide is an esterified cyclic peptide comprising the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No.

51.

6. The method of claim 5, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, wherein the esterified cyclic peptide comprises the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. The peptide contains 15 or fewer amino acid residues within a ring, the peptide is main-chain cyclized, and all residues of the peptide backbone are linked only by peptide bonds.

7. The method of claim 6, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, wherein the esterified cyclic peptide comprises the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. The peptide contains 15 or fewer amino acid residues within a ring, the peptide is main-chain cyclized, and all residues of the peptide backbone are linked only by peptide bonds.

8. The method of claim 7, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, wherein the lipid of said esterified cyclic peptide is C18DA-γGlu-OEG-OEG-.

9. The method, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use according to any one of claims 1 to 8, wherein the esterified cyclic peptide is selected from: The cyclic peptide is backbone-cyclized, and all residues of the peptide backbone are linked only by peptide bonds.

10. The method of claim 9, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, wherein the cyclic esterified peptide is composed of peptide CLP1: (K Composed of TEQIEHEEDV) SEQ ID No. 1, in which = C18DA-γGlu-OEG-OEG-, and wherein the peptide is backbone-cyclic, and all residues of the peptide backbone are linked only by peptide bonds.

11. The method of claim 10, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, wherein the cyclic esterified peptide is composed of peptide CLP1: (K Composed of TEQIEHEEDV) SEQ ID No. 1, in which = C18DA-L-γGlu-OEG-OEG-, and wherein the peptide is backbone-cyclic, and all residues of the peptide backbone are linked only by peptide bonds.

12. The method of claim 10, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, wherein the cyclic esterified peptide is composed of peptide CLP1: (K Composed of TEQIEHEEDV) SEQ ID No. 1, in which = C18DA-D-γGlu-OEG-OEG-, and wherein the peptide is backbone-cyclic, and all residues of the peptide backbone are linked only by peptide bonds.

13. The method of claim 9, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, wherein the cyclic esterified peptide is composed of peptide CLP4: (K Composed of TEDVEHEEDV) SEQ ID No. 4, in which = C18DA-γGlu-OEG-OEG-, and wherein the peptide is backbone-cyclic, and all residues of the peptide backbone are linked only by peptide bonds.

14. The method of claim 9, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, wherein the cyclic esterified peptide is composed of peptide CLP5: (K Composed of TEDIEHEEDV) SEQ ID No. 5, in which = C18DA-γGlu-OEG-OEG-, and wherein the peptide is backbone-cyclic, and all residues of the peptide backbone are linked only by peptide bonds.

15. The method of claim 9, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, wherein the cyclic esterified peptide is peptide CLP9: (MTEK Composed of VEHEEDV) SEQ ID No. 9, in which = C18DA-γGlu-OEG-OEG-, and wherein the peptide is backbone-cyclic, and all residues of the peptide backbone are linked only by peptide bonds.

16. The method of claim 9, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, wherein the cyclic esterified peptide is composed of peptide CLP10: (MTEK Composed of IEHEEDV) SEQ ID No. 10, in which = C18DA-γGlu-OEG-OEG-, and wherein the peptide is backbone-cyclic, and all residues of the peptide backbone are linked only by peptide bonds.

17. The method of any one of claims 1 to 4, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, wherein said peptide is a cyclic peptide comprising the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51, where X2 represents P and X3 is a term other than V.

18. The method of claim 17, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, wherein the cyclic peptide comprises the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Where X2 represents P, X3 is a term other than V, the peptide contains 15 or fewer amino acid residues within a ring, the peptide is cyclized in its main chain, and all residues of the peptide main chain are linked only by peptide bonds.

19. The method of claim 18, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, wherein the cyclic peptide comprises the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Where X2 represents P, X3 is a term other than V, the peptide contains 15 or fewer amino acid residues within a ring, the peptide is cyclized in its main chain, and all residues of the peptide main chain are linked only by peptide bonds.

20. The method according to any one of claims 17 to 19, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, selected from: The peptide is backbone-cyclic, and all residues of the peptide backbone are linked only by peptide bonds.

21. The method of claim 20, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, wherein the cyclic peptide is composed of peptide CP7: (MTEKVEHEEDV) SEQ ID No. 34, wherein the peptide is backbone-circular and all residues of the peptide backbone are linked only by peptide bonds.

22. The method of claim 20, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, wherein the cyclic peptide is composed of peptide CP9: (MTEQIEHEEDV) SEQ ID No. 36, wherein the peptide is backbone-cyclic and all residues of the peptide backbone are linked only by peptide bonds.

23. The method of claim 19, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, wherein the cyclic peptide is composed of peptide CP10: (MTEDIEHEEDV) SEQ ID No. 37, wherein the peptide is backbone-cyclic and all residues of the peptide backbone are linked only by peptide bonds.

24. The method of any one of claims 1 to 4, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, wherein said peptide is a cyclic peptide comprising 10 or fewer amino acid residues within a ring and comprising the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No.

51.

25. The method of claim 24, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, wherein the cyclic peptide comprises the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. The peptide is backbone-cyclic, and all residues of the peptide backbone are linked only by peptide bonds.

26. The method of claim 25, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, wherein the cyclic peptide comprises the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. The peptide is backbone-cyclic, and all residues of the peptide backbone are linked only by peptide bonds.

27. The method of any one of claims 24 to 26, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, wherein the cyclic peptide is selected from: The peptide is backbone-cyclic, and all residues of the peptide backbone are linked only by peptide bonds.

28. The method of any one of claims 1 to 4, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, wherein said peptide is an esterified linear peptide comprising the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No.

51.

29. The method of claim 28, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, wherein the esterified linear peptide comprises the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. The peptide contains 15 or fewer amino acid residues, and all residues of the peptide backbone are linked only by peptide bonds.

30. The method of claim 29, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, wherein the esterified linear peptide comprises the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. The peptide contains 15 or fewer amino acid residues, and all residues of the peptide backbone are linked only by peptide bonds.

31. The method of claim 30, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, wherein the lipid of said esterified cyclic peptide is C18DA-γGlu-OEG-OEG-.

32. The method, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use, according to any one of claims 28 to 31, wherein the esterified linear peptide is selected from: All residues of the peptide backbone are connected only by peptide bonds.

33. The method of any one of claims 1 to 4, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, wherein said peptide is a linear peptide comprising the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No. 51, where X2 represents P and X3 is a term other than V.

34. The method of claim 33, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, wherein the linear peptide comprises the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. When X2 represents P, X3 is a term other than V, the peptide contains 15 or fewer amino acid residues, and all residues of the peptide backbone are linked only by peptide bonds.

35. The method of claim 34, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, wherein the linear peptide comprises the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. When X2 represents P, X3 is a term other than V, the peptide contains 15 or fewer amino acid residues, and all residues of the peptide backbone are linked only by peptide bonds.

36. The method, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use according to any one of claims 1 to 4, wherein said peptide is a linear peptide comprising 10 or fewer amino acid residues in the main chain and comprising the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. Or a conservative substitution variant containing SEQ ID No.

51.

37. The method of claim 36, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, wherein the linear peptide comprises the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. All residues of the peptide backbone are connected only by peptide bonds.

38. The method of claim 37, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, wherein the linear peptide comprises the following sequence: in: X2 represents P, D, Q, K, and G. X3 represents I, L, A, T, V X4 represents E and A. All residues of the peptide backbone are connected only by peptide bonds.

39. The method, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use according to any one of claims 1 to 38, wherein the ear or mastoid disease or condition is a vestibular syndrome, such as Meniere's disease or vertigo syndrome.

40. The method, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use according to any one of claims 1 to 39, wherein the ear or mastoid disease or condition is a disease or condition accompanied by hearing loss or impairment.

41. The method of claim 40, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, wherein the hearing loss is sensorineural hearing loss.

42. The method of claim 40 or claim 41, the peptide used or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used or the use thereof, wherein the hearing loss is caused by mitochondrial disease.

43. The method, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use according to any one of claims 40 to 42, wherein the hearing loss is invisible hearing loss.

44. The method, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, according to any one of claims 40 to 43, wherein the hearing loss is an auditory synaptic lesion.

45. The method, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, according to any one of claims 1 to 44, wherein the administration of said peptide results in improved hearing.

46. ​​The method, the peptide used, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition used, or the use thereof, according to any one of claims 1 to 45, wherein the administration of said peptide results in an increase in the number of cochlear zona synapses, spiral ganglion neuronal fibers, spiral ganglion neuronal cells, inner hair cells, and / or outer hair cells.

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