New peptides

Abstract

SorCS2-related lipidated cyclic peptides, cyclic peptides, lipidated linear peptides, linear peptides, and related embodiments that may be useful in medicine.

Description

[Technical field]

[0001] (Technical field) The present invention relates to novel peptides, their use as pharmaceutical agents, for example in the treatment or prevention of Alzheimer's disease, Huntington's disease, Parkinson's disease, frontotemporal dementia, or depression, and related aspects. [Background technology]

[0002] (background) Neurodegenerative diseases refer to conditions in which progressive loss of neuronal function and synapses resulting in apoptosis occurs in different brain regions. These include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD), among others. Neurodegenerative diseases are characterized by lack of neurotrophic signaling and aggregation of misfolded proteins, as well as loss of neurotrophic signaling as a result of the aggregates blocking neurotrophic signaling.

[0003] In healthy neurons, various signaling pathways initiated by neurotrophic growth factors converge on activation of the transcription factor cAMP response element binding protein (CREB), resulting in growth, neuroplasticity, and survival (Benito, 2010; Sakamoto, 2011). Consistent with this, decreased activation of the downstream transcription factor CREB is observed in Huntington's disease, Alzheimer's disease, and FTD (Sugars, 2004; Pugazhenthi, 2011; Ljungberg, 2012).

[0004] Interestingly, unique mutations associated with neurodegenerative diseases attenuate the general clearance mechanisms of misfolded proteins and damaged organelles in cells (Boland, 2018). This includes the lysosomal network, the proteasome system, and chaperone-mediated autophagy. For example, in Huntington's disease, mutations involving abnormal repetition of CAG-repeats in exon 1 of the HTT gene cause the protein huntingtin to aggregate in the nucleus, thereby disrupting the autolysosomal network and reducing axonal transport of autophagosomes (Qin, 2004; Wong, 2014). Similarly, heterozygous loss-of-function mutations in the GRN gene are associated with FTLD, which result in lysosomal dysfunction that causes the aggregation of the protein TDP-43 (van Swieten, 2008; Beel, 2018).

[0005] Therefore, strategies for treating neurodegenerative diseases may involve increasing the activation of CREB and increasing the clearance of misfolded protein aggregates.

[0006] Recently, sortilin-related Vps10p domain-containing receptor 2 (SorCS2), a member of the Vps10p domain receptor family, has emerged in neuroscience because of its profound involvement in neuronal viability and function (Glerup, 2014; Glerup, 2016; Leloup, 2018; Ma, 2017; Malik, 2019; Yang, 2021). The SorCS2 receptor mediates sorting and trafficking of various ligands and receptors that are important for neuritogenesis, synaptic plasticity, and axonal growth. Large cohort studies have highlighted the clinical relevance of SorCS2, linking it to several neurodegenerative and psychiatric disorders, including bipolar disorder, AD, HD, FTD, depression, schizophrenia, and attention-deficit / hyperactivity disorder (ADHD) (Baum, 2008; Ollila, 2009; Christoforou, 2011; Alemany, 2015; Reitz, 2015). Furthermore, SorCS2 has been functionally linked to severe neuroproteinopathies, ALS and HD (Mori, 2015; Ma, 2017; Salasova, 2021), as well as pain-related disorders, such as neuropathic pain (Richner, 2012; Ma, 2017; Miki, 2018). In proteinopathies, SorCS2 has been shown to mislocalize to disease aggregates, resulting in its deficiency and accelerated disease progression.

[0007] SorCS2 was further shown to be important in mediating brain-derived neurotrophic factor (BDNF)-neurotrophin signaling, which initiates survival and synaptic plasticity through activation of CREB (Glerup 2016). Interestingly, this mediation by SorCS2 was restricted to its intracellular domain. To the same extent, the cytoplasmic domains of other members of the VPS10p domain receptor family, SorCS1 and SorCS3 receptors, have also been previously linked to function (Savas 2015; Hermey 2003; Oetjen 2014).

[0008] Modulators of the SorCS2 pathway may also be useful as diagnostic or research tools.

[0009] WO2017101956 relates to linear peptides and methods for modulating phosphorylation of the Vps10 domain-containing receptors SorCS1, SorCS2, or SorCS3.

[0010] WO2022029281 describes cyclic peptides and methods for modulating SorCS1, SorCS2, or SorCS3.

[0011] There remains a need for alternative or improved modulators of the SorCS2 pathway that may be more conveniently manufactured and exhibit high potency, selectivity, improved safety profiles, or desirable pharmacokinetic parameters, such as high brain availability and / or low clearance rates that reduce the dose or frequency of administration required for therapeutic effect in vivo. Summary of the Invention

[0012] (Summary of the invention) In a first embodiment, the sequence: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a conservatively substituted variant of said peptide, comprising:

[0013] In a second embodiment, the sequence: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a conservatively substituted variant of said peptide, wherein when X2 represents P, then X3 is other than V.

[0014] In a third embodiment, the amino acid sequence comprises 10 or fewer amino acid residues in the ring and has the sequence: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a conservatively substituted variant of said peptide, comprising:

[0015] In a fourth embodiment, the sequence: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a conservatively substituted variant of said peptide, comprising:

[0016] In a fifth embodiment, the sequence: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a conservatively substituted variant of said peptide, wherein if X2 represents P then X3 is other than V.

[0017] In a sixth embodiment, the peptide comprises 10 or fewer amino acid residues in the backbone and has the sequence: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a conservatively substituted variant of said peptide is provided.

[0018] It will be understood that the peptides of the present invention can form salts under appropriate conditions, and therefore salts of the peptides of the present invention, particularly pharma- ceutically acceptable salts, are also provided. The peptides and their salts (e.g., pharma-ceutically acceptable salts) can exist in a dissociated form in an appropriate solvent, such as water.

[0019] Modulators of the SorCS2 pathway may be useful in medicine. Thus, the present invention provides the use of the lipidated cyclic, linear, cyclic and linear peptides described above, and pharma- ceutical acceptable salts thereof, as medicaments, in particular in the treatment or prevention of Alzheimer's disease, Huntington's disease, Parkinson's disease, frontotemporal dementia or depression.

[0020] Also provided are protected cyclic peptides, protected linear peptides, and linear peptides which, when cyclized, provide cyclic peptides as described above, all of which may be useful in the preparation of the cyclic and linear peptides described above. [Brief description of the drawings]

[0021] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1] Figures 1A-1C: Purification and qualitative check of CLP1: HPLC chromatogram (Figure 1A), LCMS chromatogram (Figure 1B), and full scan acquired positive ion mode spectrum (Figure 1C) of CLP1 with UV detection at 220 nm. [Diagram 2] Figures 2A and 2B: CLP1 increases levels of CREB transcriptional targets: 1 uM peptide CLP1 significantly increased levels of downstream targets of CREB: neurotrophic factor BDNF (Figure 2A) and mitochondrial master regulator PGC1a (Figure 2B) in mouse primary neurons after 16 and 24 hours. Peptide CPX had no effect at these time points. Mean values ​​± SEM. [Diagram 3] Figure 3A and Figure 3B: CLP1 removes soluble mutant HTT in Huntington's patient-derived fibroblasts (GM04719): Peptides CLP1 and CPX significantly reduced mutant huntingtin (mHTT) levels in Huntington's patient-derived fibroblasts (GM04719) by 50% and 25%, respectively, after 24 hours of treatment (Figure 3A). A significant reduction in total HTT was also observed (Figure 3B). [Figure 4] Figures 4A-G: Chemical and physical stability of CLP1 in three buffers: Stability of CLP1 in the buffer systems pH 4.5 (Figure 4A), pH 6.5 (Figure 4B), and pH 7.5 (Figure 4C) after 14 days at 40° C. CLP1 did not show fibrillation in any of these buffers using the ThT assay and showed good physical stability at pH 4.5 (Figure 4D), pH 6.5 (Figure 4E), and pH 7.5 (Figure 4F) compared to the positive control (Figure 4G). [Diagram 5] Figures 5A-C: CLP1 is stable in plasma and brain homogenate: CLP1 and CPX showed limited degradation in human plasma (Figure 5A) and mouse plasma (Figure 5B). CLP1 showed higher stability than CPX in mouse brain homogenate (Figure 5C). [Figure 6] Figures 6A-6D: Metabolic stability of CLP1 in hepatic S9 fractions: Stability of CLP1 in hepatic S9 fractions from five different species - intrinsic clearance of CLP1 (Figure 6A), intrinsic clearance of 7-ethoxycoumarin positive control (Figure 6B), residual fraction of CLP1 (Figure 6C), and residual fraction of 7-ethoxycoumarin positive control (Figure 6D). [Figure 7]Figures 7A and 7B: Brain-free fraction of CLP1: Brain-free fraction of CLP1 in mouse brain (Figure 7A) and human brain (Figure 7B) measured by LCMS. [Figure 8] Figures 8A-8C: Pharmacokinetics of CLP1 in wild-type mice: Plasma (Figure 8A), whole brain (Figure 8B), and cerebrospinal fluid (Figure 8C) concentrations of CLP1 1-24 hours post-injection by LCMS / MS. [Figure 9] Figure 9A-9C: Single injection of CLP1 in wild type mice: CLP1 showed a strong tendency to increase BDNF after 4 hours (Figure 9A). Post-hoc analysis showed a significant time-dependent effect of CLP1 on BDNF levels (p=0.0438) by two-way ANOVA analysis (not shown). CLP1 significantly increased PGC1a from 2 to 4 hours after injection (Figure 9B) and transcription factor EB (TFEB) from 2 to 8 hours after injection (Figure 8C). Mean ± SEM. [Figure 10] Figure 10A and Figure 10B: Daily treatment of CLP1 for 7 days in wild-type mice: CLP1 and CPX significantly increased PGC1a at both 0.2 mg / kg and 2 mg / kg daily doses for CLP1 and 13 mg / kg daily dose for CPX (Figure 10A), and significantly increased GRN at both 0.2 mg / kg and 2 mg / kg daily doses for CLP1 and 13 mg / kg daily dose for CPX (Figure 10C). CLP1 (0.2 mg / kg) and CPX (13 mg / kg) significantly increased BDNF levels after once-daily subcutaneous administration (Figure 10B). [Figure 11]11A-11F: CLP1 improves behavior in the R6 / 2 mouse model of Huntington's disease: Schematic of the PoC study of Example 11 (FIG. 11A). CLP1 and CPX did not change body weight (FIG. 11B). CLP1 significantly improved clasping behavior in R6 / 2-treated mice at weeks 9 and 14, whereas CPX improved clasping only at week 9 (FIG. 11C). No significant effect was observed in the rotarod (FIG. 11D). Kaplan-Meier curves show cumulative survival (FIG. 11E), where CLP1 extended the mean survival of treated R6 / 2 mice by 7 days and the median survival by 13 days in this severe mouse model of Huntington's disease (FIG. 11F). [Figure 12] 12A-12D: CLP1 improves behavior in a mouse model of Parkinson's disease (MPTP model): schematic diagram of the experimental design of Example 12 (FIG. 12A). Behavioral and biochemical analyses were evaluated on day 10. Treatment with CLP1 significantly increased the distance traveled in the open field test at 2 mg / kg (FIG. 12B). CLP1 fully restored grip strength at both 0.2 mg / kg and 2 mg / kg administration (FIG. 12C). The weight of animals after MPTP injection initially decreased and gradually increased during the test, but MPTP significantly changed the weight at the end point compared to untreated mice (sham), and CLP1-treated mice showed no significant weight change at the end point compared to the sham group (FIG. 12D). [Figure 13] Figures 13A and 13B: CLP1 increases 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 as a measure of dopaminergic neuronal survival. The number of positive cells was expressed as the average of three brain sections. Representative images of each group are shown (Figure 13A). TH staining quantification showed a significant effect of CLP1 (0.2 mg / kg) on ​​TH+ neuronal survival (Figure 13B). [Figure 14]14A-14F: CLP1 clears human α-synuclein PFFs in vivo and reduces their diffusion: Schematic diagram of the experimental design of Example 13 (FIG. 14A). The injection site was the amygdala, and both ipsilateral and contralateral diffusion of PFFs in the substantia nigra compacta and amygdala were assessed 32 days after treatment (FIG. 14B). Representative images of the substantia nigra (FIG. 14C) and amygdala (FIG. 14D) are shown. CLP1 significantly reduced the number of PFF inclusions in both the ipsilateral substantia nigra (SN) and the contralateral amygdala, while it also showed a clear trend to reduce ipsilateral inclusions in the amygdala (FIG. 14E). One brain was immunostained for TH+ neurons and imaged (FIG. 14F). TH staining indicates loss of dopaminergic terminals in the dopaminergic striatum in vehicle-treated rats, as the signal was almost completely lost at the injection site. CLP1 treatment significantly preserved dopaminergic terminals. [Figure 15] Figure 15: FSL data: 8-week-old FSL rats were treated once daily with 0.2 mg / kg or 2 mg / kg CLP1 or 13 mg / kg CPX in 4.38 mM L-His, 140 mM NaCl, 0.2% Tween-20, and 1500 IU hyaluronidase (pH 6.15) for 8 days. After treatment, hippocampal BDNF levels were assessed by Western blotting normalized to β-actin. Graph shows densitometric quantification of Western blot bands. BDNF levels were normalized to BDNF levels in control rats (FRL). [Figure 16] Figures 16A-F: CLP1 increases wakefulness in Wistar Kyoto rats: Effects of ketamine and CLP1 on wakefulness (Figure 16A), NREM sleep (Figure 16B), and REM sleep (Figure 16C) 0-3 hours post-injection, and on wakefulness (Figure 16D), NREM sleep (Figure 16E), and REM sleep (Figure 16F) 11-12 hours post-injection. [Figure 17]Figures 17A-D: Brain and plasma stability of CLP1-CLP10 and LLP1-LLP10: Stability of peptides CLP1 and LLP1-LLP10 in plasma (Figure 17A) and mouse brain homogenate (Figure 17C), and stability of peptides CLP1-CLP10 in plasma (Figure 17B) and mouse brain homogenate (Figure 17D). [Figure 18] Figures 18A-D: Effects of CLP1-CLP10 and LLP1-LLP10 on CREB target genes: Effects of CLP1-CLP10 (Figure 18A) and CLP1 and LLP1-LLP10 (Figure 18B) levels on BDNF (Figure 18B) and effects of CLP1-CLP10 (Figure 18C) and CLP1 and LLP1-LLP10 (Figure 18D) levels on PGC1a after 8-24 hours of stimulation with the respective peptides in primary cortical neurons. [Figure 19] Figures 19A and 19B: CLP1 and CLP10 remove soluble mutant HTT in Huntington patient-derived fibroblasts (GM04719): Peptides CLP1 and CLP10 significantly reduced mutant huntingtin (mHTT) levels by 50% (measured using the MW1 antibody specific for the polyglutamine stretch) in Huntington patient-derived fibroblasts (GM04719) after 24 hours of treatment (Figure 19A), demonstrating a reduction in total HTT levels (Figure 19B). [Figure 20] Figures 20A-D: Pharmacokinetics of selected peptides in wild type mice: Plasma (Figure 20A) and whole brain (Figure 20C) concentrations of cyclic peptides from 1 to 48 hours by LCMS / MS. Calculated PK quantities in plasma (Figure 20B) and brain (Figure 20D). [Figure 21] Figures 21A-C: In vivo efficacy of selected peptides in wild-type mice: CLP1 significantly increased BDNF levels (Figure 21A) and tropomyosin receptor kinase B (TrkB) levels together with CLP4 (Figure 21C). All mutants significantly increased the levels of PGC1a (Figure 21B). [Figure 22]Figures 22A-D: Physical stability of CLP10 in three buffers: Using the ThT assay, CLP10 showed fibrillation in pH 4.5 buffer (Figure 22A) but was stable in both pH 6.5 (Figure 22B) and pH 7.5 (Figure 22C) buffer systems. A positive control is shown in Figure 22D. [Diagram 23] Figures 23A and 23B: Brain-free fractions of CLP1 and CLP10: Brain-free fractions of CLP1 and CLP10 in mouse brain (Figure 23A) and human brain (Figure 23B) measured by LCMS. [Figure 24] Figures 24A and 24B: Pharmacokinetics of CLP10: CLP10 levels are stable in both plasma (Figure 24A) and brain (Figure 24B) 24 hours after injection. [Diagram 25] Figure 25: Lipidated peptides LLP11, LLP12, and CLP11 increase BDNF in vivo: BDNF levels in wild-type mice 4-8 hours after injection. [Figure 26] FIG. 26: Identification of shorter sequences (CP13-CP17) with activity: Activity of CLP1 and non-lipidated cyclic peptides (CP13-CP17 and CPX). [Figure 27] Figures 27A and 27B: Stability of non-lipidated cyclic peptides CP1-CP12: Stability of the peptides in mouse brain (Figure 27A) and plasma (Figure 27B). [Figure 28] Figures 28A-C: In vivo potency of non-lipidated cyclic peptides CP5-CP12: CP6, CP7, and CP10 significantly increased TFEB (Figure 28A). CP5, CP7, and CP9 significantly increased BDNF (Figure 28B). CP5, CP6, CP7, CP8, and CP10 significantly increased PGC1a levels (Figure 28C). [Figure 29] FIG. 29: Effect of amino acid mutations on activity (CP18-CP22): BDNF levels in primary cortical neurons following treatment with non-lipidated cyclic peptides (CP18-CP22 and CPX) compared to CLP1. [Diagram 30]Figure 30: Effect of different lipidation on activity (CLP12-CLP15): BDNF levels in primary cortical neurons after treatment with lipidated cyclic peptides (CLP12-CP15) compared to CLP1. [Diagram 31] Figures 31A-C: CLP1 increases GRN and rescues lysosomal defects in a GRN heterozygous mouse model of FTD: Subcutaneous administration of CLP1 (0.2 mg / kg) daily for 7 days in GRN heterozygous mice increases GRN levels (Figure 31A) and normalizes lysosomal proteins LAMP1 (Figure 31B) and p62 (Figure 31C). [Diagram 32] Figures 32A-I: CLP1 rescues behavioral phenotypes in the Huntington's disease model zQ175: zQ175 mice exhibit weight loss compared to wild-type littermates, and treatment does not affect body weight (Figure 32A). Fall latency in rotarod behavioral assessment during testing (Figure 32B). At 12 months of age, fall latency in treated groups (CPX and CLP1) tended to be higher compared to zQ175+vehicle. Number of errors made during crossing in the beam test (Figure 32C). CLP1 rescued the number of errors made at 12 months of age, again significantly compared to the CPX-treated group. Principal component analysis plots (Figure 32D) and hierarchical dendrogram analysis (Figure 32E) of the home cage analysis data show rescue of behavioral phenotypes of the zQ175 HD mouse model by CLP1 treatment, but CPX treatment also results in significant rescue. Individual behavioral parameters of CPX and CLP1 (FIGS. 32F and 32G, respectively). All zQ175 mice showed higher NfL levels in the CSF and blood compared to WT mice (FIGS. 32H and 32I), and treatment with CLP1 and CPX showed a trend toward reducing this. [Diagram 33] Figure 33A and Figure 33B: CLP1 increases GBA in human iPSC-derived dopaminergic neurons: TFEB and GCase levels in hIPSC-derived dopaminergic neurons after treatment with CLP1.

[0022] (Brief explanation of the sequence) SEQ ID NO:1 Cyclic lipidated peptide CLP1 SEQ ID NO:2 Cyclic lipidated peptide CLP2 SEQ ID NO: 3 Cyclic lipidated peptide CLP3 SEQ ID NO: 4 Cyclic lipidated peptide CLP4 SEQ ID NO: 5 Cyclic lipidated peptide CLP5 SEQ ID NO:6 Cyclic lipidated peptide CLP6 SEQ ID NO: 7 Cyclic lipidated peptide CLP7 SEQ ID NO: 8 Cyclic lipidated peptide CLP8 SEQ ID NO: 9 Cyclic lipidated peptide CLP9 SEQ ID NO: 10 Cyclic lipidated peptide CLP10 SEQ ID NO: 11 Cyclic lipidated peptide CLP11 SEQ ID NO: 12 Cyclic lipidated peptide CLP12 SEQ ID NO: 13 Cyclic lipidated peptide CLP13 SEQ ID NO: 14 Cyclic lipidated peptide CLP14 SEQ ID NO: 15 Cyclic lipidated peptide CLP15 SEQ ID NO: 16 Linear lipidated peptide LLP1 SEQ ID NO: 17 Linear lipidated peptide LLP2 SEQ ID NO: 18 Linear lipidated peptide LLP3 SEQ ID NO: 19 Linear lipidated peptide LLP4 SEQ ID NO: 20 Linear lipidated peptide LLP5 SEQ ID NO: 21 Linear lipidated peptide LLP6 SEQ ID NO: 22 Linear lipidated peptide LLP7 SEQ ID NO: 23 Linear lipidated peptide LLP8 SEQ ID NO: 24 Linear lipidated peptide LLP9 SEQ ID NO: 25 Linear lipidated peptide LLP10 SEQ ID NO: 26 Linear lipidated peptide LLP11 SEQ ID NO: 27 Linear lipidated peptide LLP12 SEQ ID NO:28 Cyclic peptide CP1 SEQ ID NO:29 Cyclic peptide CP2 SEQ ID NO: 30 Cyclic peptide CP3 SEQ ID NO: 31 Cyclic peptide CP4 SEQ ID NO: 32 Cyclic peptide CP5 SEQ ID NO: 33 Cyclic peptide CP6 SEQ ID NO: 34 Cyclic peptide CP7 SEQ ID NO: 35 Cyclic peptide CP8 SEQ ID NO: 36 Cyclic peptide CP9 SEQ ID NO: 37 Cyclic peptide CP10 SEQ ID NO: 38 Cyclic peptide CP11 SEQ ID NO: 39 Cyclic peptide CP12 SEQ ID NO: 40 Cyclic peptide CP13 SEQ ID NO: 41 Cyclic peptide CP14 SEQ ID NO: 42 Cyclic peptide CP15 SEQ ID NO: 43 Cyclic peptide CP16 SEQ ID NO: 44 Cyclic peptide CP17 SEQ ID NO: 45 Cyclic peptide CP18 SEQ ID NO: 46 Cyclic peptide CP19 SEQ ID NO: 47 Cyclic peptide CP20 SEQ ID NO: 48 Cyclic peptide CP21 SEQ ID NO: 49 Cyclic peptide CP22 SEQ ID NO: 50 Native SorCS2 fragment SEQ ID NO:51 Variable peptide sequence 1 SEQ ID NO:52 Variable peptide sequence 2 SEQ ID NO:53 Variable peptide sequence 3 SEQ ID NO:54 Variable peptide sequence 4 SEQ ID NO:55 Variable peptide sequence 5 SEQ ID NO:56 Variable peptide sequence 6 SEQ ID NO:57 Variable peptide sequence 7 SEQ ID NO:58 Variable peptide sequence 8 SEQ ID NO:59 Variable peptide sequence 9 SEQ ID NO: 60 Variable peptide sequence 10 SEQ ID NO:61 Variable peptide sequence 11 SEQ ID NO:62 Variable peptide sequence 12 SEQ ID NO:63 Cyclic peptide CPX DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] Detailed Description of the Invention In a first embodiment, the sequence: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt, comprising:

[0024] The lipidated cyclic peptide has the sequence: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, particularly where the peptide is backbone cyclized and all residues of the peptide backbone are connected only by peptide bonds.

[0025] In a second embodiment, the sequence: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a conservatively substituted variant of said peptide or salt, comprising:

[0026] The cyclic peptide has the sequence: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, where when X2 represents P, then X3 is other than V. In particular, where the peptide is backbone cyclized and all residues of the peptide backbone are connected only by peptide bonds.

[0027] In a third embodiment, the amino acid sequence comprises 10 or fewer amino acid residues in the ring and has the sequence: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt, comprising:

[0028] A cyclic peptide contains 10 or fewer amino acid residues in a ring and has the sequence: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, particularly where the peptide is backbone cyclized and all residues of the peptide backbone are connected only by peptide bonds.

[0029] In a fourth embodiment, the sequence: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt, comprising:

[0030] The lipidated linear peptide has the sequence: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, particularly where all residues of the peptide backbone are connected only by peptide bonds.

[0031] In a fifth embodiment, the sequence: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a conservatively substituted variant of said peptide or salt, wherein when X2 represents P, then X3 is other than V.

[0032] The linear peptide has the sequence: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt, where when X2 represents P, then X3 is other than V. In particular, where all residues of the peptide backbone are connected only by peptide bonds.

[0033] In a sixth embodiment, the method comprises the steps of: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt.

[0034] A linear peptide contains 10 or fewer amino acid residues in the backbone and has the sequence: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, particularly where all residues of the peptide backbone are connected only by peptide bonds.

[0035] (peptide) A "peptide" is a polymer of amino acid residues, usually joined only by peptide bonds.

[0036] In some embodiments, the peptide may be modified. Particular 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.

[0037] Certain peptides described herein are cyclic. Peptides can generally be cyclized in four different ways: side chain to side chain, tail to side chain (i.e., C-terminus to side chain), side chain to head (i.e., N-terminus to side chain), and head to tail. As used herein, the term "head-to-tail cyclized peptide" is used interchangeably with the term "backbone cyclized peptide".

[0038] In one embodiment, the cyclic peptide is a backbone cyclized peptide.In one embodiment, the cyclic peptide is formed by the formation of an amide bond between its N-terminal portion and its C-terminal portion, i.e., head-to-tail cyclization.In some embodiments, the peptide is cyclized from side chain to side chain, and the backbone of the peptide is only connected by peptide bonds.In some embodiments, the peptide is cyclized from tail to side chain, and the backbone of the peptide is only connected by peptide bonds.In some embodiments, the peptide is cyclized from side chain to head, and the backbone of the peptide is only connected by peptide bonds.

[0039] In some embodiments, the cyclic peptide comprises 25 or fewer amino acid residues in the ring, such as 20 or fewer amino acid residues in the ring (e.g., including 20 amino acid residues in the ring), particularly 15 or fewer amino acid residues in the ring (e.g., including 15 amino acid residues in the ring), particularly 12 or fewer amino acid residues in the ring (e.g., including 12 amino acid residues in the ring), such as 11 or fewer amino acid residues in the ring (e.g., including 11 amino acid residues in the ring).

[0040] In some embodiments, cyclic peptide comprises 6 or more amino acid residues in the ring, for example, 7 or more amino acid residues in the ring (for example, comprises 7 amino acid residues in the ring), particularly 8 or more amino acid residues in the ring (for example, comprises 8 amino acid residues in the ring), particularly 9 or more amino acid residues in the ring (for example, comprises 9 amino acid residues in the ring), for example, 10 or more amino acid residues in the ring (for example, comprises 10 amino acid residues in the ring).In some embodiments, cyclic peptide comprises 11 or more amino acid residues in the ring (for example, comprises 11 amino acid residues in the ring).

[0041] In some embodiments, the linear peptide comprises 25 or fewer amino acid residues in the backbone, such as 20 or fewer amino acid residues in the backbone (e.g., 20 amino acid residues in the backbone), particularly 15 or fewer amino acid residues in the backbone (e.g., 15 amino acid residues in the backbone), in particular 12 or fewer amino acid residues in the backbone (e.g., 12 amino acid residues in the backbone), such as 11 or fewer amino acid residues in the backbone (e.g., 11 amino acid residues in the backbone).

[0042] In some embodiments, linear peptide comprises 6 or more amino acid residues in the backbone, for example, 7 or more amino acid residues in the backbone (for example, 7 amino acid residues in the backbone), particularly 8 or more amino acid residues in the backbone (for example, 8 amino acid residues in the backbone), particularly 9 or more amino acid residues in the backbone (for example, 9 amino acid residues in the backbone), for example, 10 or more amino acid residues in the backbone (for example, 10 amino acid residues in the backbone).In some embodiments, linear peptide comprises 11 or more amino acid residues in the backbone (for example, 11 amino acid residues in the backbone).

[0043] In some embodiments, the peptide has the sequence: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt.

[0044] In some embodiments, the peptide has the sequence: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof.

[0045] In some embodiments, the peptide has the sequence: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt.

[0046] In some embodiments, the peptide has the sequence: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof.

[0047] In some embodiments, the peptide has the sequence: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt.

[0048] In some embodiments, the peptide has the sequence: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof.

[0049] In some embodiments, the peptide has the sequence: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt.

[0050] In some embodiments, the peptide has the sequence: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof.

[0051] In some embodiments, the peptide has the sequence: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt.

[0052] In some embodiments, the peptide has the sequence: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof.

[0053] In some embodiments, the peptide has the sequence: [ka] (where: X1 represents M or K; X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt.

[0054] In some embodiments, the peptide has the sequence: [ka] (where: X1 represents M or K; X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof.

[0055] In some embodiments, the peptide has the sequence: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt.

[0056] In some embodiments, the peptide has the sequence: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof.

[0057] In some embodiments, the peptide has the sequence: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt.

[0058] In some embodiments, the peptide has the sequence: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof.

[0059] In some embodiments, the peptide has the sequence: [ka] (where: X1 represents M or K; X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt.

[0060] In some embodiments, the peptide has the sequence: [ka] (where: X1 represents M or K; X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof.

[0061] In some embodiments, the peptide has the sequence: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt.

[0062] In some embodiments, the peptide has the sequence: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof.

[0063] In some embodiments, the peptide has the sequence: [ka] (where: X1 represents M or K; X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt.

[0064] In some embodiments, the peptide has the sequence: [ka] (where: X1 represents M or K; X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof.

[0065] In some embodiments, X1 represents M. In other embodiments, X1 represents K.

[0066] 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 certain embodiments, X2 represents G.

[0067] In some embodiments, X3 represents I. In other embodiments, X3 represents L. In further embodiments, X3 represents A. In additional embodiments, X3 represents T. In certain embodiments, X3 represents V.

[0068] In some embodiments, X4 represents E. In further embodiments, X4 represents A.

[0069] As will be appreciated by those skilled in the art, certain amino acid residues may be replaced with other amino acid residues without significantly affecting function (e.g., stability and / or activity). Such substitutions are usually known as conservative substitutions. Typically, conservatively substituted variants maintain at least 50%, e.g., at least 80%, and especially at least 90% (e.g., at least 100%) of the relevant functional capacity of the unsubstituted reference sequence. For example, the functional capacity to increase BDNF, PGC1a, TFEB, and / or phospho-CREB (Ser133), e.g., using the assays described herein (e.g., Example 10). Alternatively, the functional capacity may be measured by measuring the t 1 / 2 , AUC, or C max , especially in the brain 1 / 2 may be also possible.

[0070] A conservatively substituted variant may contain two conservative substitutions, or alternatively, a conservatively substituted variant may contain one conservative substitution.

[0071] In some embodiments, the peptide contains no conservative substitutions.

[0072] Specific conservative substitutions can be determined empirically, but generally suitable substitutions are known, for example as shown in Table 1. Table 1 – Common conservative substitutions [Table 1]

[0073] Thus, in some embodiments, the variant comprises a substitution of X1 at position -2. X1 can be substituted for M, e.g., I, (K), L, R, T, V. Alternatively, X1 can be substituted for K, e.g., E, (M), N, Q, R, T. X1 can be substituted for E, N, Q, R, T, I, L, or V.

[0074] In some embodiments, the variant comprises a substitution of T at position -1, e.g., with A, K, M, N, R, or S, especially A, K, M, N, or R.

[0075] In some embodiments, the variant comprises a substitution of E at position 0, e.g., with A, D, G, K, Q, or V, especially G, K, Q, or V.

[0076] In some embodiments, the variant comprises a substitution of X2 at position 1. X2 can be replaced with P, e.g., H, L, (Q), R, or S, particularly H, L, (Q), or R. Alternatively, X2 can be replaced with D, e.g., A, E, (G), H, N, V, or Y. X2 can be replaced with Q, e.g., E, H, (K), L, (P), or R. X2 can be replaced with K, e.g., E, M, N, (Q), R, T. X2 can be replaced with G, e.g., A, C, (D), E, ​​or R. X2 can be replaced with 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.

[0077] In some embodiments, the variant comprises a substitution of X3 at position 2. X3 can be substituted for I, e.g., F, (L), M, N, or (V). Alternatively, X3 can be substituted for L, e.g., F, H, (I), M, P, Q, R, (V), or W. X3 can be substituted for A, e.g., D, E, G, S, or T, particularly D, E, G, or T. X3 can be substituted for T, e.g., (A), K, M, N, R, or S, particularly (A), K, M, N, or R. X3 can be substituted for V, e.g., D, E, (I), (L), or M. X3 may be replaced by D, E, F, G, H, K, M, N, P, Q, S, or W, in particular D, E, F, G, H, K, M, N, P, Q, or W.

[0078] In some embodiments, the variant comprises a substitution of E at position 3, e.g., with A, D, G, K, Q, or V, especially G, K, Q, or V.

[0079] In some embodiments, the variant comprises a substitution of H at position 4 with, for example, D, L, N, P, Q, R, or Y.

[0080] In some embodiments, the variant comprises a substitution of X4 at position 5. X4 may be substituted for E, such as (A), D, G, K, Q, or V. Alternatively, X4 may be substituted for D, such as H, N, or Y. X4 may be substituted for A, such as D, (E), G, S, or T, particularly D, E, G, or T. X4 may be substituted for G, K, Q, S, T, or V, particularly G, K, Q, T, or V.

[0081] In some embodiments, the variant comprises a substitution of E at position 6, e.g., with A, D, G, K, Q, or V.

[0082] In some embodiments, the variant comprises a substitution of D at position 7, e.g., with A, E, G, H, N, V, or Y.

[0083] In some embodiments, the variant comprises a substitution of V at position 8, for example, with D, E, I, L, or M.

[0084] Suitably, the peptide comprises an amino acid sequence selected from any one of SEQ ID NOs: 1 to 11, 16 to 42, or 49. Such peptides may be in the form of a salt, for example, a pharma- ceutical acceptable salt.

[0085] Preferably, the peptide consists of any one of CLP1 to CLP11, LLP1 to LLP12, CP1 to CP15, or CP22 (as listed in Tables 2 and 3). Such peptides may be in the form of a salt, for example, a pharma- ceutically acceptable salt. More preferably, the peptide consists of CLP1 or a salt thereof, for example, a pharma- ceutically acceptable salt. Table 2 - Overview of lipidated peptides [Table 2] [ka]

[0086] In CLP1, C18DA-γGlu-OEG-OEG- may be C18DA-L-γGlu-OEG-OEG. Alternatively, in CLP1, C18DA-γGlu-OEG-OEG- may be C18DA-D-γGlu-OEG-OEG. Table 3 - Overview of non-lipidated peptides [Table 3] * As described in WO2022029281

[0087] Desirably, the peptides and conservatively substituted variants thereof have improved functional capabilities, such as improved inhibition of BDNF, PGC1a, TFEB, and / or phospho-CREB (Ser133), and / or t1 / 2 , AUC, or C max (In particular, BDNF, PGC1a, TFEB, phospho-CREB (Ser133), t 1 / 2 , AUC, and C max Most preferably, the peptides and conservatively substituted variants thereof exhibit a functional ability to increase, for example, BDNF, PGC1a, TFEB, and / or phospho-CREB (Ser133), and / or tRNA, at least as well as CLP1. 1 / 2 , AUC, or C max (In particular, BDNF, PGC1a, TFEB, phospho-CREB (Ser133), t 1 / 2 , AUC, and C max The functional capacity of the stimuli to increase the level of function (all of the above).

[0088] Desirably, the peptides of the present invention have the following properties: - in vitro stability - lack of fibrillation at pH 6.5 and 7.5, preferably at pH 4.5, pH 6.5, and pH 7.5 (e.g., by the method of Example 5); In vivo stability - t of at least 1 hour, preferably at least 4 hours, especially at least 8 hours 1 / 2 (For example, by the method of Example 9). t indicates one or more (e.g., all) of 1 / 2 is preferably determined in the brain.

[0089] (lipidization) As mentioned above, certain peptides of the present invention are lipidated. Lipidation approaches are reviewed in the literature, including Ostergaard, 1993; Bech, 2018; van Witteloostuijn, 2016:. Kurtzhals, 2023 provides further information on lipidation.

[0090] Although several residues including Cys and Tyr can be used for lipidation, lipidation is conveniently performed at the side chain of a Lys residue. Lipidation is desirably toward the N-terminus of the peptide. In the present invention, the lipidated Lys residue is preferably located at X1 (position -2) or X2 (position 1).

[0091] Lipidation may involve replacement of native amino residues with residues more suitable for lipidation.

[0092] A linking group is typically used to space the lipid chain from the peptide.

[0093] The linker may comprise a γGlu residue, in particular L-γGlu. Alternatively, the linker may comprise (i) L-Asp, L-Glu, or D-Glu, in particular L-Glu or D-Glu, (ii) butanoyl-sulfonamide. The linker may comprise multiple residues (e.g. 2, 3, or 4), e.g. multiple L-γGlu (e.g. 2, 3, or 4), but may conveniently comprise a single residue, e.g. a single L-γGlu.

[0094] The linking group may also contain, for example, 1 to 4, for example, 2 spacers, for example, OEG units. The linking group may contain b-Ala instead of an OEG unit.

[0095] Typical lipid chains include carboxylic acids such as C16, C18, C20 acids, and dicarboxylic acids such as C18DA, C20DA diacids. However, other chain lengths and types can be used in some cases, such as carboxylic acid isosteres or tetrazoles such as sulfonic acids. Preferably, the lipid chain is C16DA, C18DA, or C20DA, particularly C18DA or C20DA, especially C18DA.

[0096] Suitably the peptide is lipidated with C18DA-γGlu-OEG-OEG-, e.g., C18DA-L-γGlu-OEG-OEG or e.g., C18DA-D-γGlu-OEG-OEG.

[0097] Typically, the peptide has a single lipidation.

[0098] The optimal choice of type and location of lipidation may depend on the structure of a particular peptide.

[0099] (Method of preparing peptides) The peptides according to the invention can be prepared by any method known in the art. Thus, the peptides can be prepared by standard peptide preparation techniques, such as solution synthesis or Merrifield-type solid phase synthesis (exemplified in Examples 1 and 2).

[0100] In one embodiment, the peptides according to the invention are synthetically made or produced. Methods for synthetic production of peptides are well known in the art. Detailed descriptions and practical advice for producing synthetic peptides can be found in Synthetic Peptides: A User's Guide (Advances in Molecular Biology), edited by Grant GA, Oxford University Press, 2002 or in Pharmaceutical Formulation: Development of Peptides and Proteins, edited by Frokjaer and Hovgaard, Taylor and Francis, 1999. In one embodiment, the peptides or peptide sequences of the invention are synthetically produced, in particular by the sequence-assisted peptide synthesis (SAPS) method, by solution synthesis or by solid-phase peptide synthesis (SPPS), e.g. Merrifield-type solid-phase synthesis.

[0101] For example, after purification of the linear peptide by reversed-phase HPLC, the linear peptide can be further processed into a cyclic peptide. Techniques for cyclizing peptides and for obtaining cyclic peptides, for example, by using solid supports, are known (exemplified in Example 2).

[0102] In one aspect, the present invention provides a method for producing a lipidated cyclic peptide of the present invention, comprising the steps of: (i) preparing a lipidated linear peptide having an appropriate amino acid sequence; and (ii) then generating a cyclized peptide from the linear peptide. : relates to a method,

[0103] In one aspect, the present invention provides a method for producing a cyclic peptide of the present invention, comprising the steps of: (i) preparing a linear peptide having a suitable amino acid sequence; and (ii) then generating a cyclized peptide from the linear peptide. : relates to a method,

[0104] Suitable amino acid sequences are those which, when cyclized, provide the intended cyclic peptide (e.g., CLP1-CLP11, CP1-CP15 or CP22). Side-chain, head-to-side-chain or tail-to-side-chain cyclized peptides require a linear sequence of the usual N- to C-terminal residue order. However, for example, a backbone cyclized peptide consisting of CP1 may be formed from the linear peptides MTEPIEHEEDV, VMTEPIEHEED, etc.

[0105] A linear peptide is usually only joined by peptide bonds. A cyclized peptide is usually only joined by peptide bonds. A cyclized peptide may be backbone cyclized.

[0106] Synthetic preparation of linear peptides may require or benefit from the presence of side chain protecting groups on some or all residues containing potentially reactive side chains, which may or may not be removed, or may be removed and reintroduced, depending on the particular sequence, prior to the generation of the cyclized peptide, e.g., backbone cyclized peptide. If some side chain protection is present during the generation of the cyclized peptide, e.g., backbone cyclized peptide, it may then be removed to form a deprotected cyclized peptide. In the preparation of non-backbone cyclized peptides, protecting groups may be present at the N- or C-terminus, as appropriate.

[0107] The linear and / or cyclized peptides (or protected versions thereof, where appropriate) may be in the form of a salt, in particular a pharma- ceutically acceptable salt.

[0108] The present invention provides linear peptides or protected versions thereof which, when cyclized, provide the cyclic peptides or protected versions thereof described herein.The present invention provides linear peptides or side-chain protected versions thereof which, when cyclized, provide the cyclic peptides or side-chain protected versions thereof described herein.

[0109] The present invention provides lipidated linear peptides, or protected versions thereof, which when cyclized provide the lipidated cyclic peptides, or protected versions thereof, described herein.The present invention provides lipidated linear peptides, or side-chain protected versions thereof, which when cyclized provide the lipidated cyclic peptides, or side-chain protected versions thereof, described herein.

[0110] Protected cyclic peptides and protected lipidated cyclic peptides also form part of the present invention.

[0111] Amino acid protecting groups are known to those of skill in the art and are discussed, for example, in Isidro-Llobet et al., Chem Rev 2009 109 2455-2504 and Chandrudu et al., Molecules 2013 18(4):4373-4388. Common side chain protections include Arg(Pbf), Asn(Trt), Asp(OtBu), Cys(Trt), Gln(Trt), Glu(OtBu), His(Trt), Lys(Boc), Ser(tBu), Thr(tBu), and Tyr(tBu):

[0112] Intermediates useful in the preparation of peptides (i.e., lipidated cyclic, cyclic, lipidated linear, or linear, and variants of any of these) include such peptides or protected versions thereof covalently attached to a solid support. The covalent attachment to the solid support may be by means of a spacing group or directly through a spacing group.

[0113] (medical use) As shown in the Examples herein, peptides of the invention can promote the clearance of disease-causing aggregates, neuronal survival, and improve mitochondrial and lysosomal function.

[0114] Preferably, the peptides of the present invention (lipidated cyclic, cyclic, lipidated linear, or linear, and variants of any of these) or salts thereof, particularly pharma- ceutically acceptable salts, are capable of increasing BDNF levels, more preferably, BDNF levels are increased by at least 30% between 0 and 24 hours after administration in the assay of Example 10.

[0115] Preferably, the peptides of the present invention (lipidated cyclic, cyclic, lipidated linear, or linear, and variants of any of these) or salts thereof, particularly pharma- ceutically acceptable salts, are capable of increasing phospho-CREB (Ser133) levels. More preferably, phospho-CREB (Ser133) levels are increased by at least 30% between 0 and 24 hours after administration in the assay of Example 10.

[0116] Preferably, the peptides of the present invention (lipidated cyclic, cyclic, lipidated linear, or linear, and variants of any of these) or salts thereof, particularly pharma- ceutically acceptable salts, are capable of increasing PGC1a levels, more preferably, PGC1a levels are increased by at least 30% between 0 and 24 hours after administration in the assay of Example 10.

[0117] Preferably, the peptides of the invention (lipidated cyclic, cyclic, lipidated linear, or linear, and variants of any of these) or salts thereof, particularly pharma- ceutically acceptable salts, are capable of increasing TFEB levels, more preferably, TFEB levels are increased by at least 30% between 0 and 24 hours after administration in the assay of Example 10.

[0118] Preferably, the peptides of the invention (lipidated cyclic, cyclic, lipidated linear, or linear, and variants of any of these) or salts thereof, particularly pharma- ceutically acceptable salts, are capable of reducing NfL levels, more preferably, NfL levels are reduced by at least 10%, especially at least 20%, in the assay of Example 31.

[0119] Neurodegenerative diseases are often associated with a blockade of neurotrophic signaling caused by aggregates of misfolded proteins. In healthy neurons, various signaling pathways initiated by neurotrophic growth factors converge on the activation of the transcription factor CREB, leading to growth, neuronal plasticity, and survival. However, reduced activation of the downstream transcription factor CREB has been observed in several neurodegenerative diseases.

[0120] A hallmark of neurodegenerative diseases is the aggregation of misfolded proteins, and mutations associated with neurodegenerative diseases have been shown to attenuate general clearance mechanisms of misfolded proteins and damaged organelles within the cell.

[0121] The effect of administering the peptide of the present invention can be quantified in various ways.For example, in the context of Huntington's disease, the Unified Huntington's Disease Rating Scale (UHDRS) can be applied as a measure of motor function, cognition, behavioral abnormalities, and functional ability that can be improved (improvement is usually compared to that without treatment).Other Huntington's disease markers include measuring mutant huntingtin in the cerebrospinal fluid (CSF) of subjects, which can be reduced.

[0122] Total functional capacity scores (TFC) may improve.

[0123] In the context of Parkinson's disease, the Unified Huntington's Disease Rating Scale (UPDRS) or the Movement Disorder Society-revised Unified Parkinson's Disease Rating Scale (MDS-UPDRS) can be used to assess both motor and non-motor symptoms associated with Parkinson's disease. Such scales may be reversible.

[0124] In the context of FTD, monitoring PGRN in CSF or plasma may be of interest.

[0125] CSF or blood plasma levels of neurofilament light chain (NfL), a biomarker of neuronal loss, may be decreased.

[0126] Magnetic resonance imaging (MRI) can be used to quantify brain volume, either in the whole brain or in specific regions. Loss of brain volume can be reduced.

[0127] In clinical relevance, efficacy in humans can be monitored using markers of dopaminergic system function, such as PET radiotracers.

[0128] The present invention provides a lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, a variant of any of these, and / or a pharma- ceutically acceptable salt of any of these described herein, for use as a medicament. The present invention also provides CLP1-CLP11, LLP1-LLP12, CP1-CP15, or CP22, or a pharma- ceutically acceptable salt of any of these, for use as a medicament. In particular, the present invention provides CLP1 or a pharma- ceutically acceptable salt of any of these, for use as a medicament.

[0129] In some embodiments, the medicament is for prophylactic use, hi other embodiments, the medicament is for therapeutic use.

[0130] The present invention provides lipidated cyclic peptides, cyclic peptides, lipidated linear peptides, linear peptides, variants of any of these, and / or pharma- ceutically acceptable salts of any of these as described herein for the treatment or prevention of a disease or disorder selected from the group consisting of neurodegenerative diseases, proteinopathies, lysosomal storage diseases, mitochondrial disorders, psychiatric disorders, and other BDNF-related disorders. The present invention also provides lipidated cyclic peptides, cyclic peptides, lipidated linear peptides, linear peptides, variants of any of these, and / or pharma- ceutically acceptable salts of any of these as described herein for the treatment of a disease or disorder selected from the group consisting of neurodegenerative diseases, proteinopathies, lysosomal storage diseases, mitochondrial disorders, psychiatric disorders, and other BDNF-related disorders. Further provided are lipidated cyclic peptides, cyclic peptides, lipidated linear peptides, linear peptides, variants of any of these, and / or pharma- ceutically acceptable salts of any of these as described herein for the prevention of a disease or disorder selected from the group consisting of neurodegenerative diseases, proteinopathies, lysosomal storage diseases, mitochondrial disorders, psychiatric disorders, and other BDNF-related disorders.

[0131] Further provided is the use of the lipidated cyclic peptides, cyclic peptides, lipidated linear peptides, linear peptides, variants of any of these, and / or pharma- ceutically acceptable salts of any of these described herein in the manufacture of a medicament for the treatment or prevention of a disease or disorder selected from the group consisting of neurodegenerative diseases, proteinopathies, lysosomal storage diseases, mitochondrial disorders, psychiatric disorders, and other BDNF-related disorders. Also provided is the use of the lipidated cyclic peptides, cyclic peptides, lipidated linear peptides, linear peptides, variants of any of these, and / or pharma- ceutically acceptable salts of any of these described herein in the manufacture of a medicament for the treatment of a disease or disorder selected from the group consisting of neurodegenerative diseases, proteinopathies, lysosomal storage diseases, mitochondrial disorders, psychiatric disorders, and other BDNF-related disorders. The present invention provides the use of the lipidated cyclic peptides, cyclic peptides, lipidated linear peptides, linear peptides, variants of any of these, and / or pharma- ceutically acceptable salts of any of these described herein in the manufacture of a medicament for the prevention of a disease or disorder selected from the group consisting of neurodegenerative diseases, proteinopathies, lysosomal storage diseases, mitochondrial disorders, psychiatric disorders, and other BDNF-related disorders.

[0132] Provided are methods of treating or preventing a disease or disorder in a subject, wherein the disease or disorder is selected from the group consisting of a neurodegenerative disease, a proteinopathy, a lysosomal storage disease, a mitochondrial dysfunction disorder, a psychiatric disorder, and a BDNF-related disorder, the method comprising administering to the subject a lipidated cyclic peptide, a cyclic peptide, a lipidated linear peptide, a linear peptide, a variant of any of these, and / or a pharma- ceutically acceptable salt of any of these described herein.Also provided are methods of treating a disease or disorder in a subject, wherein the disease or disorder is selected from the group consisting of a neurodegenerative disease, a proteinopathy, a lysosomal storage disease, a mitochondrial dysfunction disorder, a psychiatric disorder, and a BDNF-related disorder, the method comprising administering to the subject a lipidated cyclic peptide, a cyclic peptide, a lipidated linear peptide, a linear peptide, a variant of any of these, and / or a pharma- ceutically acceptable salt of any of these described herein. Further provided is a method of preventing a disease or disorder in a subject, wherein the disease or disorder is selected from the group consisting of a neurodegenerative disease, a proteinopathy, a lysosomal storage disease, a mitochondrial dysfunction disorder, a psychiatric disorder, and a BDNF-related disorder, the method comprising administering to the subject a lipidated cyclic peptide, a cyclic peptide, a lipidated linear peptide, a linear peptide, a variant of any of these, and / or a pharma- ceutical acceptable salt of any of these described herein.

[0133] In one embodiment, the disease or disorder is a neurodegenerative disease, particularly a neurodegenerative disease associated with reduced BDNF, rescue by BDNF, mitochondrial dysfunction, and / or lysosomal dysfunction.

[0134] In one embodiment, the disease or disorder is selected from the group consisting of Huntington's disease, Parkinson's disease, Alzheimer's disease, frontotemporal dementia (especially in subjects with GRN haploinsufficiency), ALS, multiple sclerosis, hereditary ataxia, motor neuron disorder, and vascular dementia. In one embodiment, the disease or disorder is Huntington's disease. In one embodiment, the disease or disorder is Parkinson's disease (PD), for example, in subjects with monoallelic mutations of GBA1 (Stoker, 2018-incorporated by reference for its disclosure of specific mutations associated with PD), where pathogenic mutations include N370S, L444P, R463C, G10S, N426K, R48W, and R257Q. In one embodiment, the disease or disorder is Alzheimer's disease. In one embodiment, the disease or disorder is frontotemporal dementia. In one embodiment, the disease or disorder is frontotemporal dementia in subjects with GRN haploinsufficiency.

[0135] In one embodiment, the disease or disorder is a proteinopathy, particularly a proteinopathy associated with protein aggregation. In one embodiment, the proteinopathy is selected from the group consisting of prion disease, alpha-synucleinopathy, tauopathy, C9orf72-dependent ALS / FTD, dementia with Lewy bodies, dementia with amyloid plaques, Huntington's disease, TDP-43-positive ALS / FTD, and hereditary ataxias.

[0136] In one embodiment, the disease or disorder is a lysosomal storage disease, particularly a lysosomal storage disease associated with lysosomal dysfunction. In one embodiment, the lysosomal storage disease is selected from the group consisting of Niemann-Pick disease and neuronal ceroid lipofuscinosis. The lysosomal storage disease may be, for example, Gaucher disease in subjects with biallelic mutations of GBA1 (Sheth, 2019 - incorporated by reference for its disclosure of specific mutations associated with Gaucher disease), with one study identifying p.Leu483Pro as the most commonly occurring Gaucher disease mutation (62% patients), followed by p.Arg535Cys (7% patients) and RecNcil (7% patients).

[0137] In one embodiment, the disease or disorder is a mitochondrial dysfunction disorder. In one embodiment, the mitochondrial dysfunction disorder is selected from the group consisting of mitochondrial myopathies and Leigh's syndrome.

[0138] In one embodiment, the disease or disorder is psychiatric disorder, particularly the psychiatric disorder associated with SorCS2 gene or function, or associated with BDNF or TrkB.In one embodiment, the psychiatric disorder is selected from bipolar disorder, depression, schizophrenia, autism spectrum disorder, anxiety, and ADHD.Preferably, the disease or disorder is depression.

[0139] In one embodiment, the disease or disorder is another BDNF-related disorder. In one embodiment, the BDNF-related disorder is selected from the group consisting of WAGR syndrome (especially BDNF haploinsufficiency), stroke, and epilepsy.

[0140] The term "treatment" or "treating" as used herein includes the control, alleviation, relief, or modulation of a disease or disorder or a symptom thereof.

[0141] The term "prevention" is used herein to mean preventing the symptoms of a disease or disorder in a subject or preventing the recurrence of symptoms of a disease or disorder in an affected subject, and is not limited to the complete prevention of disease.

[0142] Preferably, the subject is a human.

[0143] In some embodiments, the lipidated cyclic peptides, cyclic peptides, lipidated linear peptides, linear peptides, variants of any of these, and / or pharma- ceutically acceptable salts of any of these are intended for therapeutic use, i.e., administration to a subject having a disease, disorder, or disorder. Therapeutic use may be intended to alleviate or relieve symptoms or complications; delay the progression of a disease, disorder, or disorder; cure or eliminate a disease, disorder, or disorder.

[0144] A "treatment effect" or "therapeutic effect" is manifested when there is a change in the condition being treated as measured by the criteria constituting the definition of the terms "treat" and "treatment". There is a "change" in the condition being treated when there is at least a 5% improvement, preferably a 10% improvement, more preferably at least a 25%, even more preferably at least a 50%, such as at least a 75%, and most preferably at least a 100% improvement in one of a number of parameters. The change can be based on an improvement in the severity of the condition being treated in an individual, or a difference in the frequency of the improved condition in a population of individuals treated with the lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, variants of any of these, and / or pharma- ceutically acceptable salts of any of these and a population of individuals not treated with the same.

[0145] Preferably, the lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, variants of any of these, and / or pharma- ceutically acceptable salts of any of these are administered to a subject in need thereof. Preferably, the peptide of the present invention or its pharma- ceutically acceptable salt is administered in a safe and effective amount, i.e., an amount that provides an acceptable balance between desired benefits and undesired side effects. A "safe and effective amount" is intended to include an amount that is effective to achieve a desired effect in treatment and / or prophylaxis. The desired effect is usually clinically meaningful and / or measurable, for example, in the context of (a) preventing a disease, disorder, or disorder from occurring, especially when the subject is predisposed or at risk, but has not yet been diagnosed; (b) inhibiting a disease, disorder, or disorder, i.e., slowing or halting its onset; and / or (c) alleviating a disease, disorder, or disorder, i.e., causing regression of a disease, disorder, or disorder or alleviation of associated symptoms. A safe and effective amount may be an amount that is sufficient to achieve a desired effect when the peptide of the present invention or a pharma- ceutically acceptable salt thereof is administered alone, or alternatively, when it is administered in combination with one or more further active pharmaceutical ingredients, which are either additional peptides of the present invention or pharma-ceutically acceptable salts thereof or different from the peptides of the present invention.

[0146] In one embodiment of the invention, the lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, variants of any of these, and / or pharma- ceutically acceptable salts of any of these are administered at a dose of 1 μg / day to 200 mg / day.

[0147] In one embodiment of the invention, one single dose of peptide is administered, which may comprise 1 μg / kg body weight to 100 mg / kg body weight, for example 1 μg / kg body weight to 10 mg / kg body weight. A preferred dose is about 0.1 mg / kg to about 10 mg / kg, and an especially preferred dose is about 0.1 mg / kg to about 5 mg / kg. The dose according to the invention can be administered once or several times a day. The dose can also be administered at intermittent intervals, or at intervals where the dose is not administered every day. Instead, one or more doses can be administered every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, every week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, or at intervals within these ranges (e.g., every 2-4 weeks or every 4-6 weeks).

[0148] It will be understood that the preferred route of administration will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated, the location within the body of the tissue to be treated, and the peptide of the invention selected.

[0149] In one embodiment of the invention, the route of administration enables the lipidated cyclic peptide, the cyclic peptide, the lipidated linear peptide, the linear peptide, a variant of any of these, and / or a pharma- ceutically acceptable salt of any of these, to cross the blood-brain barrier.

[0150] For systemic treatment according to the present invention, the route of administration can be to introduce the lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, variants of any of these, and / or pharma- ceutically acceptable salts of any of these into the bloodstream to ultimately target the desired site of action. Such a route of administration can be any suitable route, for example, parenteral route, including subcutaneous, intramuscular, intrathecal, intracerebral, intravenous, and intradermal administration. Parenteral administration is any administration route that is not oral / intestinal, in which the drug avoids first-pass degradation in the liver. Thus, parenteral administration includes any injection and infusion, for example, bolus injection or continuous infusion, for example, intravenous, intramuscular, or subcutaneous administration.

[0151] In one embodiment, administration is subcutaneous, for example by injection. In one embodiment, administration is intramuscular, for example by injection. In one embodiment, administration is intradermal, for example by injection. In one embodiment, administration is intravenous, for example by injection.

[0152] Pharmaceutical Composition Although it is possible to administer the lipidated cyclic peptides, cyclic peptides, lipidated linear peptides, linear peptides, variants of any of these, and / or pharmaceutically acceptable salts of any of these of the present invention as "raw" peptides, it is desirable to present them in the form of a pharmaceutical composition.Thus, the present invention further provides a pharmaceutical formulation comprising the lipidated cyclic peptides, cyclic peptides, lipidated linear peptides, linear peptides, variants of any of these, and / or pharmaceutically acceptable salts of any of these of the present invention and a pharmaceutically acceptable carrier.The pharmaceutical composition can be prepared by conventional techniques, for example as described in Remington: The Science and Practice of Pharmacy, 2005, Lippincott, Williams & Wilkins.

[0153] Pharmaceutically acceptable carriers include water. For better stability, the pharmaceutical composition may be dry and extemporaneously reconstituted with water (or, for example, saline).

[0154] A pharma- ceutically acceptable composition for parenteral administration should have a physiologically acceptable pH and should have a physiologically acceptable osmolality.

[0155] The pH of the aqueous composition can be adjusted taking into account the components of the composition and the required administration suitability. The pH is usually at least 4, particularly at least 5, in particular at least 5.5, for example at least 6. The pH is 9 or less, particularly 8.5 or less, in particular 8 or less, for example 7.5 or less. The pH may be 4 to 9, particularly 5 to 8.5, in particular 5.5 to 8, for example 6.5 to 7.4 (for example 6.5 to 7.1).

[0156] For parenteral administration, a physiologically acceptable osmolality is desirable to avoid excessive cell deformation or lysis. By physiologically acceptable osmolality it is usually meant that the solution has an osmolality that is approximately isotonic or mildly hypertonic. Suitably, the composition for administration has an osmolality of 250-750 mOsm / kg, in particular 250-550 mOsm / kg, in particular 270-500 mOsm / kg, for example 270-400 mOsm / kg.

[0157] Other components, such as buffers or stabilizers, may also be present.

[0158] The phrase "pharmaceutical acceptable" is used herein to refer to materials, compositions, dosage forms, and the like, which are, within the scope of sound medical judgment, suitable for use in humans and animals, e.g., in contact with human tissue, without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0159] It will be understood that for pharmaceutical use, the salts of the peptides should be pharma- ceutically acceptable. Suitable pharma-ceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include those in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p.1418. Such pharma-ceutically 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. Pharmaceutically acceptable salts can also be formed with organic bases, such as basic amines, for example, with ammonia, meglumine, tromethamine, piperazine, arginine, choline, diethylamine, benzathine, or lysine. Salts which are not considered to be pharma- ceutical acceptable may still be useful, for example, in the preparation of peptides and their pharma- ceutical acceptable salts and therefore are included within the scope of the invention.

[0160] Certain peptides can form salts with one or more equivalents of an acid or base. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.

[0161] When peptides contain a basic group and a free acid, they can be zwitterionic.

[0162] The pharmaceutical composition of the present invention can be co-administered with one or more other therapeutic agents. The combined administration of two or more agents can be achieved in several different ways. They can be administered together in a single composition, or they can be administered in separate compositions as part of a combined therapy. For example, one can be administered before or separately from the other, after or consecutively with the other, or simultaneously or concurrently with the other.

[0163] The present invention will be further described with reference to the following clauses:

[0164] (Provisions of the present invention) The present invention will be further described with reference to the following clauses: Article A1. SEQUENCE: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt, comprising: Clause A2. The lipidated cyclic peptide, variant, or salt according to clause A1, wherein said peptide is backbone cyclized. Clause A3. A lipidated cyclic peptide, variant, or salt according to clause A2, wherein the peptide is backbone cyclized and all residues of the peptide backbone are connected only by peptide bonds. Clause A4. The lipidated cyclic peptide, variant, or salt according to any one of clauses A1-A3, comprising 25 or fewer amino acid residues in the ring. Clause A5. A lipidated cyclic peptide, variant, or salt according to clause A4 comprising 20 or fewer amino acid residues in the ring, for example comprising 20 amino acid residues in the ring. Clause A6. A lipidated cyclic peptide, variant, or salt according to clause A5 comprising 15 or fewer amino acid residues in the ring, for example comprising 15 amino acid residues in the ring. Clause A7. A lipidated cyclic peptide, variant, or salt according to clause A6 comprising 12 or fewer amino acid residues in the ring, for example comprising 12 amino acid residues in the ring. Clause A8. A lipidated cyclic peptide, variant, or salt according to clause A7 comprising 11 or fewer amino acid residues in the ring. Clause A9. The lipidated cyclic peptide, variant, or salt according to any one of clauses A1-A8, comprising at least 7 amino acid residues in the ring, for example comprising 7 amino acid residues in the ring. Clause A10. The lipidated cyclic peptide, variant, or salt according to clause A9, comprising at least 8 amino acid residues in the ring, for example comprising 8 amino acid residues in the ring. Clause A11. The lipidated cyclic peptide, variant, or salt according to clause A10, comprising at least 9 amino acid residues in the ring, for example comprising 9 amino acid residues in the ring. Clause A12. A lipidated cyclic peptide, variant, or salt according to clause A11, comprising at least 10 amino acid residues in the ring, for example comprising 10 amino acid residues in the ring. Clause A13. A lipidated cyclic peptide, variant, or salt according to clause A12, comprising at least 11 amino acid residues in the ring. Clause A14. A lipidated cyclic peptide, variant, or salt according to clause A1 comprising 11 amino acid residues in the ring. Article A15. SEQUENCE: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article A16. SEQUENCE: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article A17. SEQUENCE: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article A18. SEQUENCE: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article A19. SEQUENCE: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article A20. SEQUENCE: [ka] (where: X1 represents M or K; X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article A21. SEQUENCE: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article A22. SEQUENCE: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article A23. SEQUENCE: [ka] (where: X1 represents M or K; X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article A24. SEQUENCE: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article A25. SEQUENCE: [ka] (where: X1 represents M or K; X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Clause A26. The lipidated cyclic peptide, variant, or salt according to any one of clauses A1 to A25, wherein X1 represents M. Clause A27. The lipidated cyclic peptide, variant, or salt according to any one of clauses A1 to A25, wherein X1 represents K. Clause A28. The lipidated cyclic peptide, variant, or salt according to any one of clauses A1 to A27, wherein X2 represents P. Clause A29. The lipidated cyclic peptide, variant, or salt according to any one of clauses A1 to A27, wherein X2 represents D. Clause A30. The lipidated cyclic peptide, variant, or salt according to any one of clauses A1 to A27, wherein X2 represents Q. Clause A31. The lipidated cyclic peptide, variant, or salt according to any one of clauses A1 to A27, wherein X2 represents K. Clause A32. The lipidated cyclic peptide, variant, or salt according to any one of clauses A1 to A27, wherein X2 represents G. Clause A33. The lipidated cyclic peptide, variant, or salt according to any one of clauses A1 to A32, wherein X3 represents I. Clause A34. The lipidated cyclic peptide, variant, or salt according to any one of clauses A1 to A32, wherein X3 represents L. Clause A35. The lipidated cyclic peptide, variant, or salt according to any one of clauses A1 to A32, wherein X3 represents A. Clause A36. The lipidated cyclic peptide, variant, or salt according to any one of clauses A1 to A32, wherein X3 represents T. Clause A37. The lipidated cyclic peptide, variant, or salt according to any one of clauses A1 to A32, wherein X3 represents V. Clause A38. The lipidated cyclic peptide, variant, or salt according to any one of clauses A1 to A37, wherein X4 represents E. Clause A39. The lipidated cyclic peptide, variant, or salt according to any one of clauses A1 to A37, wherein X4 represents A. Clause A40. A lipidated cyclic peptide, variant or salt according to any one of clauses A13 to A14, comprising any one of the sequences of SEQ ID NOs: 1 to 11 or a salt thereof, or a conservatively substituted variant of said peptide or salt, for example consisting of any one of the sequences of SEQ ID NOs: 1 to 11 or a salt thereof, or a conservatively substituted variant of said peptide or salt. Clause A41. A lipidated cyclic peptide, variant or salt according to any one of clauses A13-A14, comprising, for example consisting of, the sequence of SEQ ID NO: 1 or a salt thereof, or a conservatively substituted variant of said peptide or salt. Clause A42. A variant or a salt thereof according to any one of clauses A1 to A41, comprising two conservative substitutions. Clause A43. A variant according to any one of clauses A1 to A42, or a salt thereof, comprising a substitution of X1 at position -2, for example with E, N, Q, R, T, I, L, or V. Clause A44. A variant or a salt thereof according to any one of clauses A1 to A42, comprising a substitution of T at position -1, for example by A, K, M, N, R or S, especially by A, K, M, N or R. Clause A45. A variant according to any one of clauses A1 to A42, or a salt thereof, comprising a substitution of E at position 0, for example with A, D, G, K, Q or V, especially with G, K, Q or V. Clause A46. A variant or salt thereof according to any one of clauses A1 to A42, comprising a substitution of X2 in position 1, for example by A, , C, E, H, L, M, N, R, S, T, V or Y, in particular by A, E, H, L, M, N, R, T, V or Y. Clause A47. A variant or salt thereof according to any one of clauses A1 to A42, comprising a substitution of X3 at position 2, for example by D, E, F, G, H, K, M, N, P, Q, S or W, in particular by D, E, F, G, H, K, M, N, P, Q or W. Clause A48. A variant according to any one of clauses A1 to A42 or a salt thereof, comprising a substitution of E in position 3, for example by A, D, G, K, Q or V, especially by G, K, Q or V. Clause A49. A variant according to any one of clauses A1 to A42, or a salt thereof, comprising a substitution of H at position 4, for example with D, L, N, P, Q, R, or Y. Clause A50. A variant or salt thereof according to any one of clauses A1 to A42, comprising a substitution of X4 at position 5, for example with G, K, Q, S, T or V, in particular with G, K, Q, T or V. Clause A51. A variant according to any one of clauses A1 to A42, or a salt thereof, comprising a substitution of E at position 6, for example with A, D, G, K, Q, or V. Clause A52. A variant according to any one of clauses A1 to A42, or a salt thereof, comprising a substitution of D at position 7, for example with A, E, G, H, N, V, or Y. Clause A53. A variant according to any one of clauses A1 to A42, or a salt thereof, comprising a substitution of V at position 8, for example replacement with D, E, I, L, or M. Clause A54. A variant according to any one of clauses A42 to A53, or a salt thereof, comprising a substitution of X1 at position -2, for example replacement with E, N, Q, R, T1, L, or V. Clause A55. A variant or a salt thereof according to any one of clauses A42 to A53, comprising a substitution of T at position -1, for example by A, K, M, N, R or S, especially by A, K, M, N or R. Clause A56. A variant according to any one of clauses A42 to A53 or a salt thereof, comprising a substitution of E at position 0, for example by A, D, G, K, Q or V, especially by G, K, Q or V. Clause A57. A variant or a salt thereof according to any one of clauses A42 to A53, comprising a substitution of X2 in position 1, for example by A, C, E, H, L, M, N, R, S, T, V or Y, in particular by A, E, H, L, M, N, R, T, V or Y. Article A58. A variant or a salt thereof according to any one of articles A42 to A53, comprising a substitution of X3 in position 2, for example by D, E, F, G, H, K, M, N, P, Q, S or W, in particular by D, E, F, G, H, K, M, N, P, Q or W. Clause A59. A variant according to any one of clauses A42 to A53, or a salt thereof, comprising a substitution of E in position 3, for example by A, D, G, K, Q or V, especially by G, K, Q or V. Clause A60. A variant or a salt thereof according to any one of clauses A42 to A53, comprising a substitution of H at position 4, for example with D, L, N, P, Q, R, or Y. Clause A61. A variant or a salt thereof according to any one of clauses A42 to A53, comprising a substitution of X4 at position 5, for example by G, K, Q, S, T or V, in particular by G, K, Q, T or V. Clause A62. A variant according to any one of clauses A42 to A53, or a salt thereof, comprising a substitution of E at position 6, for example with A, D, G, K, Q, or V. Clause A63. A variant according to any one of clauses A42 to A53, or a salt thereof, comprising a substitution of D at position 7, for example with A, E, G, H, N, V, or Y. Clause A64. A variant according to any one of clauses A42 to A53, or a salt thereof, comprising a substitution of V at position 8, for example replacement with D, E, I, L, or M. Clause A65. A variant or a salt thereof according to any one of clauses A43 to A53, comprising one conservative substitution. Clause A66. A lipidated cyclic peptide or a salt thereof according to any one of clauses A1 to A41. Clause A67. A lipidated cyclic peptide, variant, or salt according to any one of clauses A1 to A66, comprising a lipidated K residue. Clause A68. The lipidated cyclic peptide, variant, or salt according to clause A67, wherein said lipidated K residue is X2 at position 1. Clause A69. The lipidated cyclic peptide, variant, or salt according to clause A67, wherein said lipidated K residue is X1 at position -2. Clause A70. The lipidated cyclic peptide, variant, or salt of any one of clauses A1-A69, wherein the lipid chain is a C16DA, a C18DA, or a C20DA group. Clause A71. A lipidated cyclic peptide, variant, or salt according to clause A70, wherein said lipid chain is a C18DA group. Clause A72. The lipidated cyclic peptide, variant, or salt of any one of clauses A1-A71, wherein said lipid is linked to a K residue via γGlu. Clause A73. The lipidated cyclic peptide, variant, or salt according to clause A72, wherein said lipid is linked to a K residue via γGlu and one to four OEG groups. Clause A74. The lipidated cyclic peptide, variant, or salt according to clause A73, wherein said lipid is linked to a K residue via γGlu and two OEG groups. Clause A75. The lipidated cyclic peptide, variant, or salt of any one of clauses A1-A69, wherein said lipid is C18DA-γGlu-OEG-OEG-. Clause A76. The lipidated cyclic peptide or salt according to any one of clauses A1 to A69, wherein said lipid is C18DA-γGlu-OEG-OEG-. Clause A77. The lipidated cyclic peptide or salt according to clause A75 or A76, wherein said lipid is C18DA-L-γGlu-OEG-OEG-. Clause A78. The lipidated cyclic peptide or salt according to clause A75 or A76, wherein said lipid is C18DA-D-γGlu-OEG-OEG-. Clause A79. A lipidated cyclic peptide or salt according to clause A1, comprising CLP1 or a salt thereof. Clause A80. The lipidated cyclic peptide or salt according to clause A1, wherein said lipid consists of CLP1 or a salt thereof which is C18DA-L-γGlu-OEG-OEG-. Clause A81. The lipidated cyclic peptide or salt according to clause A1, wherein said lipid consists of CLP1 or a salt thereof, which is C18DA-D-γGlu-OEG-OEG-. Clause A82. A lipidated cyclic peptide or salt according to clause A1, comprising CLP2 or a salt thereof. Clause A83. A lipidated cyclic peptide or salt according to clause A1, comprising CLP3 or a salt thereof. Clause A84. A lipidated cyclic peptide or salt according to clause A1, comprising CLP4 or a salt thereof. Clause A85. A lipidated cyclic peptide or salt according to clause A1, comprising CLP5 or a salt thereof. Clause A86. A lipidated cyclic peptide or salt according to clause A1, comprising CLP6 or a salt thereof. Clause A87. A lipidated cyclic peptide or salt according to clause A1, comprising CLP7 or a salt thereof. Clause A88. A lipidated cyclic peptide or salt according to clause A1, comprising CLP8 or a salt thereof. Clause A89. A lipidated cyclic peptide or salt according to clause A1, comprising CLP9 or a salt thereof. Clause A90. A lipidated cyclic peptide or salt according to clause A1, which comprises CLP10 or a salt thereof. Clause A91. A lipidated cyclic peptide or salt according to clause A1, comprising CLP11 or a salt thereof. Clause A92. The lipidated cyclic peptide, variant or salt according to any one of clauses A1 to A91, wherein said salt is a pharma- ceutically acceptable salt. Clause A93. A lipidated cyclic peptide according to any preceding clause A. Clause A94. A lipidated variant peptide according to any preceding clause A. Clause A95. A pharma- ceutically acceptable salt of a lipidated cyclic peptide according to any preceding Clause A. Clause A96. A pharma- ceutically acceptable salt of a lipidated variant peptide according to any preceding Clause A. Clause A97. A lipidated cyclic peptide according to any one of clauses A1 to A96, which has no side chain modifications. Clause A98. The lipidated cyclic peptide according to any one of clauses A1 to A96, which is unmodified. Article B1. SEQUENCE: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a conservatively substituted variant of said peptide or salt, comprising: Clause B2. A cyclic peptide, variant, or salt according to clause B1, wherein said peptide is backbone cyclized. Clause B3. A cyclic peptide, variant, or salt according to clause B2, wherein the peptide is backbone cyclized and all residues of the peptide backbone are connected only by peptide bonds. Clause B4. A cyclic peptide, variant, or salt according to any one of clauses B1-B3, comprising 25 or fewer amino acid residues in the ring. Clause B5. A cyclic peptide, variant, or salt according to clause B4 comprising 20 or fewer amino acid residues in the ring, for example comprising 20 amino acid residues in the ring. Clause B6. A cyclic peptide, variant, or salt according to clause B5 comprising 15 or fewer amino acid residues in the ring, for example comprising 15 amino acid residues in the ring. Clause B7. A cyclic peptide, variant, or salt according to clause B6 comprising 12 or fewer amino acid residues in the ring, for example comprising 12 amino acid residues in the ring. Clause B8. A cyclic peptide, variant, or salt according to clause B7 comprising 11 or fewer amino acid residues in the ring. Clause B9. The cyclic peptide, variant, or salt according to any one of clauses B1-B8, comprising at least 7 amino acid residues in the ring, for example comprising 7 amino acid residues in the ring. Clause B10. A cyclic peptide, variant, or salt according to clause B9 comprising at least 8 amino acid residues in the ring, for example comprising 8 amino acid residues in the ring. Clause B11. A cyclic peptide, variant, or salt according to clause B10 comprising at least 9 amino acid residues in the ring, for example comprising 9 amino acid residues in the ring. Clause B12. A cyclic peptide, variant, or salt according to clause B11 comprising at least 10 amino acid residues in the ring, for example comprising 10 amino acid residues in the ring. Clause B13. A cyclic peptide, variant or salt according to clause B12 comprising at least 11 amino acid residues in the ring. Clause B14. A cyclic peptide, variant, or salt according to clause B1 comprising 11 amino acid residues in the ring. Article B15. SEQUENCE: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article B16. SEQUENCE: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article B17. SEQUENCE: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article B18. Array: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article B19. SEQUENCE: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article B20. Array: [ka] (where: X1 represents M or K; X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article B21. Array: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article B22. Array: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article B23. Array: [ka] (where: X1 represents M or K; X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article B24. Array: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article B25. Array: [ka] (where: X1 represents M or K; X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Clause B26. The cyclic peptide, variant or salt according to any one of clauses B1 to B25, wherein X1 represents M. Clause B27. The cyclic peptide, variant or salt according to any one of clauses B1 to B25, wherein X1 represents K. Clause B28. The cyclic peptide, variant, or salt according to any one of clauses B1 to B27, wherein X2 represents P. Clause B29. The cyclic peptide, variant, or salt according to any one of clauses B1 to B27, wherein X2 represents D. Clause B30. The cyclic peptide, variant, or salt according to any one of clauses B1 to B27, wherein X2 represents Q. Clause B31. The cyclic peptide, variant or salt according to any one of clauses B1 to B27, wherein X2 represents K. Clause B32. The cyclic peptide, variant, or salt according to any one of clauses B1 to B27, wherein X2 represents G. Clause B33. The cyclic peptide, variant, or salt according to any one of clauses B1 to B32, wherein X3 represents I. Clause B34. The cyclic peptide, variant or salt according to any one of clauses B1 to B32, wherein X3 represents L. Clause B35. The cyclic peptide, variant, or salt according to any one of clauses B1 to B32, wherein X3 represents A. Clause B36. The cyclic peptide, variant, or salt according to any one of clauses B1 to B32, wherein X3 represents T. Clause B37. The cyclic peptide, variant or salt according to any one of clauses B1 to B27 or B29 to B32, wherein X3 represents V. Clause B38. The cyclic peptide, variant, or salt according to any one of clauses B1 to B37, wherein X4 represents E. Clause B39. The cyclic peptide, variant, or salt according to any one of clauses B1 to B37, wherein X4 represents A. Clause B40. The cyclic peptide, variant or salt according to any one of clauses B13 to B14, comprising any one of the sequences of SEQ ID NOs: 1 to 10 and 28 to 39 or a salt thereof, or a conservatively substituted variant of said peptide or salt, for example, consisting of any one of the sequences of SEQ ID NOs: 1 to 10 and 28 to 39 or a salt thereof, or a conservatively substituted variant of said peptide or salt. Clause B41. A cyclic peptide, variant or salt according to any one of clauses B13 to B14, comprising, for example, the sequence of SEQ ID NO: 1 or a salt thereof, or a conservatively substituted variant of said peptide or salt, comprising, for example, the sequence of SEQ ID NO: 1 or a salt thereof, or a conservatively substituted variant of said peptide or salt. Clause B42. A variant or a salt thereof according to any one of clauses B1 to B41, comprising two conservative substitutions. Clause B43. A variant according to any one of clauses B1 to B42, or a salt thereof, comprising a substitution of X1 at position -2, for example by E, N, Q, R, T, I, L or V. Clause B44. A variant or a salt thereof according to any one of clauses B1 to B42, comprising a substitution of T at position -1, for example by A, K, M, N, R or S, especially by A, K, M, N or R. Clause B45. A variant according to any one of clauses B1 to B42 or a salt thereof, comprising a substitution of E at position 0, for example by A, D, G, K, Q or V, especially by G, K, Q or V. Clause B46. A variant or a salt thereof according to any one of clauses B1 to B42, comprising a substitution of X2 in position 1, for example by A, C, E, H, L, M, N, R, S, T, V or Y, in particular by A, E, H, L, M, N, R, T, V or Y. Clause B47. A variant or a salt thereof according to any one of clauses B1 to B42, comprising a substitution of X3 in position 2, for example by D, E, F, G, H, K, M, N, P, Q, S or W, in particular by D, E, F, G, H, K, M, N, P, Q or W. Clause B48. A variant according to any one of clauses B1 to B42 or a salt thereof, comprising a substitution of E in position 3, for example by A, D, G, K, Q or V, especially by G, K, Q or V. Clause B49. A variant according to any one of clauses B1 to B42, or a salt thereof, comprising a substitution of H at position 4, for example by D, L, N, P, Q, R, or Y. Clause B50. A variant or a salt thereof according to any one of clauses B1 to B42, comprising a substitution of X4 in position 5, for example by G, K, Q, S, T or V, in particular by G, K, Q, T or V. Clause B51. A variant according to any one of clauses B1 to B42, or a salt thereof, comprising a substitution of E at position 6, for example with A, D, G, K, Q, or V. Clause B52. A variant according to any one of clauses B1 to B42, or a salt thereof, comprising a substitution of D at position 7, for example with A, E, G, H, N, V, or Y. Clause B53. A variant according to any one of clauses B1 to B42, or a salt thereof, comprising a substitution of V at position 8, for example with D, E, I, L, or M. Article B54. A variant or a salt thereof according to any one of articles B42 to B53, comprising a substitution of X1 at position -2, for example by E, N, Q, R, T, I, L or V. Clause B55. A variant or a salt thereof according to any one of clauses B42 to B53, comprising a substitution of T in position -1, for example by A, K, M, N, R or S, especially by A, K, M, N or R. Article B56. A variant according to any one of articles B42 to B53 or a salt thereof, comprising a substitution of E at position 0, for example by A, D, G, K, Q or V, especially by G, K, Q or V. Article B57. A variant or a salt thereof according to any one of articles B42 to B53, comprising a substitution of X2 in position 1, for example by A, C, E, H, L, M, N, R, S, T, V or Y, in particular by A, E, H, L, M, N, R, T, V or Y. Article B58. A variant or a salt thereof according to any one of articles B42 to B53, comprising a substitution of X3 in position 2, for example by D, E, F, G, H, K, M, N, P, Q, S or W, in particular by D, E, F, G, H, K, M, N, P, Q or W. Clause B59. A variant according to any one of clauses B42 to B53 or a salt thereof, comprising a substitution of E in position 3, for example by A, D, G, K, Q or V, in particular by G, K, Q or V. Clause B60. A variant or a salt thereof according to any one of clauses B42 to B53, comprising a replacement of H at position 4, for example with D, L, N, P, Q, R or Y. Clause B61. A variant or a salt thereof according to any one of clauses B42 to B53, comprising a substitution of X4 in position 5, for example by G, K, Q, S, T or V, in particular by G, K, Q, T or V. Clause B62. A variant according to any one of clauses B42 to B53, or a salt thereof, comprising a substitution of E at position 6, for example by A, D, G, K, Q, or V. Clause B63. A variant according to any one of clauses B42 to B53, or a salt thereof, comprising a substitution of D at position 7, for example by A, E, G, H, N, V, or Y. Clause B64. The variant according to any one of clauses B42 to B53, or a salt thereof, comprising a substitution of V at position 8, for example by D, E, I, L or M. Clause B65. The variant or a salt thereof according to any one of clauses B43 to B53, comprising one conservative substitution. Clause B66. A cyclic peptide or a salt thereof according to any one of clauses B1 to B41. Clause B67. A cyclic peptide or salt according to clause B1 consisting of SEQ ID NO: 1 or a salt thereof. Clause B68. A cyclic peptide or salt according to clause B1 consisting of SEQ ID NO: 2 or a salt thereof. Clause B69. A cyclic peptide or salt according to clause B1 consisting of SEQ ID NO: 3 or a salt thereof. Clause B70. A cyclic peptide or salt according to clause B1 consisting of SEQ ID NO: 4 or a salt thereof. Clause B71. A cyclic peptide or salt according to clause B1 consisting of SEQ ID NO: 5 or a salt thereof. Clause B72. A cyclic peptide or salt according to clause B1 consisting of SEQ ID NO: 6 or a salt thereof. Clause B73. A cyclic peptide or salt according to clause B1 consisting of SEQ ID NO: 7 or a salt thereof. Clause B74. A cyclic peptide or salt according to clause B1 consisting of SEQ ID NO: 8 or a salt thereof. Clause B75. A cyclic peptide or salt according to clause B1 consisting of SEQ ID NO: 9 or a salt thereof. Clause B76. A cyclic peptide or salt according to clause B1 consisting of SEQ ID NO: 10 or a salt thereof. Clause B77. A cyclic peptide or salt according to clause B1, which comprises CP1 or a salt thereof. Clause B78. A cyclic peptide or salt according to clause B1 which comprises CP2 or a salt thereof. Clause B79. A cyclic peptide or salt according to clause B1, which comprises CP3 or a salt thereof. Clause B80. A cyclic peptide or salt according to clause B1 which comprises CP4 or a salt thereof. Clause B81. A cyclic peptide or salt according to clause B1, comprising CP5 or a salt thereof. Clause B82. A cyclic peptide or salt according to clause B1, which comprises CP6 or a salt thereof. Clause B83. A cyclic peptide or salt according to clause B1, which comprises CP7 or a salt thereof. Clause B84. A cyclic peptide or salt according to clause B1, which comprises CP8 or a salt thereof. Clause B85. A cyclic peptide or salt according to clause B1, which comprises CP9 or a salt thereof. Clause B86. A cyclic peptide or salt according to clause B1, which comprises CP10 or a salt thereof. Clause B87. A cyclic peptide or salt according to clause B1, which comprises CP11 or a salt thereof. Clause B88. A cyclic peptide or salt according to clause B1 which comprises CP12 or a salt thereof. Clause B89. The cyclic peptide, variant or salt according to any one of clauses B1 to B98, wherein said salt is a pharma- ceutically acceptable salt. Clause B90. A cyclic peptide according to any preceding clause B. Clause B91. A variant peptide according to any preceding clause B. Clause B92. A pharma- ceutically acceptable salt of a cyclic peptide according to any preceding Clause B. Clause B93. A pharma- ceutically acceptable salt of a variant peptide according to any preceding Clause B. Clause B94. A cyclic peptide according to any one of clauses B1 to B93, which has no side chain modifications. Clause B95. The cyclic peptide according to any one of clauses B1 to B93, which is unmodified. Clause C1. A peptide having 10 or fewer amino acid residues in a ring and the sequence: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt, comprising: Clause C2. The cyclic peptide, variant, or salt according to clause C1, wherein said peptide is backbone cyclized. Clause C3. A cyclic peptide, variant, or salt according to clause C2, wherein said peptide is backbone cyclized and all residues of the peptide backbone are connected only by peptide bonds. Clause C4. The cyclic peptide, variant, or salt according to any one of clauses C1-C3, comprising 6 amino acid residues in the ring. Clause C5. The cyclic peptide, variant, or salt according to any one of clauses C1-C3, comprising 7 amino acid residues in the ring. Clause C6. The cyclic peptide, variant, or salt according to any one of clauses C1-C3, comprising 8 amino acid residues in the ring. Clause C7. The cyclic peptide, variant, or salt according to any one of clauses C1-C3, comprising 9 amino acid residues in the ring. Clause C8. The cyclic peptide, variant, or salt according to any one of clauses C1-C3, comprising 10 amino acid residues in the ring. Article C9. Sequencing: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article C10. SEQUENCE: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article C11. SEQUENCE: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article C12. Sequence: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article C13. Sequence: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article C14. SEQUENCE: [ka] (where: X1 represents M or K; X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article C15. SEQUENCE: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article C16. SEQUENCE: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article C17. Sequence: [ka] (where: X1 represents M or K; X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article C18. Sequence: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Clause C19. The cyclic peptide, variant, or salt according to any one of clauses C1 to C18, wherein X1 represents M. Clause C20. The cyclic peptide, variant, or salt according to any one of clauses C1 to C18, wherein X1 represents K. Clause C21. The cyclic peptide, variant, or salt according to any one of clauses C1 to C20, wherein X2 represents P. Clause C22. The cyclic peptide, variant, or salt according to any one of clauses C1 to C20, wherein X2 represents D. Clause C23. The cyclic peptide, variant, or salt according to any one of clauses C1 to C20, wherein X2 represents Q. Clause C24. The cyclic peptide, variant, or salt according to any one of clauses C1 to C20, wherein X2 represents K. Clause C25. The cyclic peptide, variant, or salt according to any one of clauses C1 to C20, wherein X2 represents G. Clause C26. The cyclic peptide, variant, or salt according to any one of clauses C1 to C25, wherein X3 represents I. Clause C27. The cyclic peptide, variant, or salt according to any one of clauses C1 to C25, wherein X3 represents L. Clause C28. The cyclic peptide, variant, or salt according to any one of clauses C1 to C25, wherein X3 represents A. Clause C29. The cyclic peptide, variant, or salt according to any one of clauses C1 to C25, wherein X3 represents T. Clause C30. The cyclic peptide, variant, or salt according to any one of clauses C1 to C25, wherein X3 represents V. Clause C31. The cyclic peptide, variant, or salt according to any one of clauses C1 to C30, wherein X4 represents E. Clause C32. The cyclic peptide, variant, or salt according to any one of clauses C1 to C30, wherein X4 represents A. Clause C33. A cyclic peptide, variant or salt according to any one of clauses C1 to C32, wherein (i) the sequence of said cyclic peptide is a part of any one of SEQ ID NOs: 1 to 10 and 28 to 39 or a salt thereof, or (ii) a conservatively substituted variant or salt of said peptide. Clause C34. A cyclic peptide, variant or salt according to clause C33, wherein (i) the sequence of said cyclic peptide is a part of SEQ ID NO: 1 or a salt thereof, or (ii) a conservatively substituted variant or salt of said peptide. Clause C35. The cyclic peptide, variant or salt according to any one of clauses C1 to C32, comprising any one of the sequences of SEQ ID NOs: 40 to 42 or a salt thereof, or a conservatively substituted variant of said peptide or salt, for example consisting of any one of the sequences of SEQ ID NOs: 40 to 42 or a salt thereof, or a conservatively substituted variant of said peptide or salt. Clause C36. The variant according to any one of clauses C1 to C35, or a salt thereof, comprising two conservative substitutions. Clause C37. The variant according to any one of clauses C1 to C36, or a salt thereof, comprising a substitution of X1 at position -2, for example with E, N, Q, R, T, I, L, or V. Clause C38. The variant or a salt thereof according to any one of clauses C1 to C36, comprising a substitution of T at position -1, for example by A, K, M, N, R or S, especially by A, K, M, N or R. Clause C39. The variant according to any one of clauses C1 to C36 or a salt thereof, comprising a substitution of E at position 0, for example with A, D, G, K, Q or V, especially with G, K, Q or V. Clause C40. A variant according to any one of clauses C1 to C36, or a salt thereof, comprising a substitution of X2 in position 1, for example by A, C, E, H, L, M, N, R, S, T, V or Y, in particular by A, E, H, L, M, N, R, T, V or Y. Clause C41. The variant or a salt thereof according to any one of clauses C1 to C36, comprising a substitution of X3 at position 2, for example by D, E, F, G, H, K, M, N, P, Q, S or W, in particular by D, E, F, G, H, K, M, N, P, Q or W. Clause C42. The variant according to any one of clauses C1 to C36 or a salt thereof, comprising a substitution of E at position 3, for example with A, D, G, K, Q or V, especially with G, K, Q or V. Clause C43. The variant according to any one of clauses C1 to C36, or a salt thereof, comprising a replacement of H at position 4, for example with D, L, N, P, Q, R, or Y. Clause C44. The variant or a salt thereof according to any one of clauses C1 to C36, comprising a substitution of X4 at position 5, for example by G, K, Q, S, T or V, in particular by G, K, Q, T or V. Clause C45. The variant according to any one of clauses C1 to C36, or a salt thereof, comprising a substitution of E at position 6, for example with A, D, G, K, Q, or V. Clause C46. The variant according to any one of clauses C1 to C36, or a salt thereof, comprising a substitution of D at position 7, for example with A, E, G, H, N, V, or Y. Clause C47. The variant according to any one of clauses C1 to C36, or a salt thereof, comprising a substitution of V at position 8, for example with D, E, I, L, or M. Clause C48. The variant or a salt thereof according to any one of clauses C36 to C47, comprising a substitution of X1 at position -2, for example with E, N, Q, R, T, I, L or V. Clause C49. A variant or a salt thereof according to any one of clauses C36 to C47, comprising a substitution of T at position -1, for example by A, K, M, N, R or S, especially by A, K, M, N or R. Clause C50. A variant according to any one of clauses C36 to C47, or a salt thereof, comprising a substitution of E at position 0, for example with A, D, G, K, Q or V, especially with G, K, Q or V. Clause C51. A variant or a salt thereof according to any one of clauses C36 to C47, comprising a substitution of X2 in position 1, for example by A, C, E, H, L, M, N, R, S, T, V or Y, in particular by A, E, H, L, M, N, R, T, V or Y. Clause C52. A variant or a salt thereof according to any one of clauses C36 to C47, comprising a substitution of X3 at position 2, for example by D, E, F, G, H, K, M, N, P, Q, S or W, in particular by D, E, F, G, H, K, M, N, P, Q or W. Clause C53. A variant according to any one of clauses C36 to C47, or a salt thereof, comprising a substitution of E in position 3, for example with A, D, G, K, Q or V, especially with G, K, Q or V. Clause C54. The variant according to any one of clauses C36 to C47, or a salt thereof, comprising a replacement of H at position 4, for example with D, L, N, P, Q, R, or Y. Clause C55. The variant or a salt thereof according to any one of clauses C36 to C47, comprising a substitution of X4 at position 5, for example by G, K, Q, S, T or V, in particular by G, K, Q, T or V. Clause C56. The variant according to any one of clauses C36 to C47, or a salt thereof, comprising a substitution of E at position 6, for example with A, D, G, K, Q, or V. Clause C57. The variant according to any one of clauses C36 to C47, or a salt thereof, comprising a substitution of D at position 7, for example with A, E, G, H, N, V, or Y. Clause C58. The variant according to any one of clauses C36 to C47, or a salt thereof, comprising a substitution of V at position 8, for example with D, E, I, L, or M. Clause C59. The variant or salt thereof according to any one of clauses C37 to C47, comprising one conservative substitution. Clause C60. A cyclic peptide or a salt thereof according to any one of clauses C1 to C35. Clause C61. A cyclic peptide or salt according to clause C1 consisting of CP13 or a salt thereof. Clause C62. A cyclic peptide or salt according to clause C1 consisting of CP14 or a salt thereof. Clause C63. A cyclic peptide or salt according to clause C1 consisting of CP15 or a salt thereof. Clause C64. The cyclic peptide, variant, or salt according to any one of clauses C1 to C63, wherein said salt is a pharma- ceutically acceptable salt. Clause C65. A cyclic peptide according to any preceding clause C. Clause C66. A variant peptide according to any preceding clause C. Clause C67. A pharma- ceutically acceptable salt of a cyclic peptide according to any preceding Clause C. Clause C68. A pharma- ceutically acceptable salt of a variant peptide according to any preceding Clause C. Clause C69. The cyclic peptide according to any one of clauses C1 to C68, which has no side chain modifications. Clause C70. The cyclic peptide according to any one of clauses C1 to C68, which is unmodified. Article D1. SEQUENCE: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt, comprising: Clause D2. The lipidated linear peptide, variant, or salt according to clause D1, wherein all residues of the peptide backbone are connected only by peptide bonds. Clause D3. The lipidated linear peptide, variant, or salt according to clause D1 or D2 comprising 25 or fewer amino acid residues in the backbone. Clause D4. The lipidated linear peptide, variant, or salt according to clause D3 comprising 20 or fewer amino acid residues in the backbone, for example 20 amino acid residues in the backbone. Clause D5. The lipidated linear peptide, variant, or salt according to clause D4 comprising 15 or fewer amino acid residues in the backbone, for example 15 amino acid residues in the backbone. Clause D6. The lipidated linear peptide, variant, or salt according to clause D5 comprising 12 or fewer amino acid residues in the backbone, for example 12 amino acid residues in the backbone. Clause D7. The lipidated linear peptide, variant, or salt according to clause D6 comprising 11 or fewer amino acid residues in the backbone. Clause D8. The lipidated linear peptide, variant, or salt according to any one of clauses D1-D7, comprising at least 7 amino acid residues in the backbone, such as 7 amino acid residues in the backbone. Clause D9. The lipidated linear peptide, variant, or salt according to clause D8 comprising at least 8 amino acid residues in the backbone, such as 8 amino acid residues in the backbone. Clause D10. The lipidated linear peptide, variant, or salt according to clause D9 comprising at least 9 amino acid residues in the backbone, such as 9 amino acid residues in the backbone. Clause D11. The lipidated linear peptide, variant, or salt according to clause D10, comprising at least 10 amino acid residues in the backbone, for example 10 amino acid residues in the backbone. Clause D12. The lipidated linear peptide, variant, or salt according to clause D11 comprising at least 11 amino acid residues in the backbone. Clause D13. A lipidated linear peptide, variant, or salt according to clause D12 comprising 11 amino acid residues in the backbone. Article D14. Sequencing: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article D15. SEQUENCE: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article D16. SEQUENCE: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article D17. SEQUENCE: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article D18. SEQUENCE: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article D19. Sequencing: [ka] (where: X1 represents M or K; X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article D20. Sequencing: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article D21. SEQUENCE: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article D22. SEQUENCE: [ka] (where: X1 represents M or K; X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article D23. SEQUENCE: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article D24. Sequencing: [ka] (where: X1 represents M or K; X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Clause D25. The lipidated linear peptide, variant, or salt according to any one of clauses D1 to D24, wherein X1 represents M. Clause D26. The lipidated linear peptide, variant, or salt according to any one of clauses D1 to D24, wherein X1 represents K. Clause D27. The lipidated linear peptide, variant, or salt according to any one of clauses D1-D26, wherein X2 represents P. Clause D28. The lipidated linear peptide, variant, or salt according to any one of clauses D1-D26, wherein X2 represents D. Clause D29. The lipidated linear peptide, variant, or salt according to any one of clauses D1-D26, wherein X2 represents Q. Clause D30. The lipidated linear peptide, variant, or salt according to any one of clauses D1-D26, wherein X2 represents K. Clause D31. The lipidated linear peptide, variant, or salt according to any one of clauses D1-D26, wherein X2 represents G. Clause D32. The lipidated linear peptide, variant, or salt according to any one of clauses D1-D31, wherein X3 represents I. Clause D33. The lipidated linear peptide, variant, or salt according to any one of clauses D1-D31, wherein X3 represents L. Clause D34. The lipidated linear peptide, variant, or salt according to any one of clauses D1-D31, wherein X3 represents A. Clause D35. The lipidated linear peptide, variant, or salt according to any one of clauses D1-D31, wherein X3 represents T. Clause D36. The lipidated linear peptide, variant, or salt according to any one of clauses D1-D31, wherein X3 represents V. Clause D37. The lipidated linear peptide, variant, or salt according to any one of clauses D1-D36, wherein X4 represents E. Clause D38. The lipidated linear peptide, variant, or salt according to any one of clauses D1-D36, wherein X4 represents A. Article D39. The lipidated linear peptide, variant or salt according to any one of articles D13 to D14, comprising, for example consisting of, any one of SEQ ID NOs: 1 to 11 or a salt thereof, or a conservatively substituted variant of said peptide or salt. Clause D40. The lipidated linear peptide, variant or salt according to any one of clauses D13 to D14, comprising, e.g. consisting of, the sequence of SEQ ID NO: 1 or a salt thereof, or a conservatively substituted variant of said peptide or salt. Clause D41. The lipidated linear peptide, variant or salt according to any one of clauses D13 to D14, comprising any one of the sequences of LLP1 to LLP12 or a salt thereof, or a conservatively substituted variant of said peptide or salt, for example consisting of any one of the sequences of LLP1 to LLP12 or a salt thereof, or a conservatively substituted variant of said peptide or salt. Clause D42. The variant or a salt thereof according to any one of clauses D1 to D41, which comprises two conservative substitutions. Clause D43. The variant or a salt thereof according to any one of clauses D1 to D42, comprising a substitution of X1 at position -2, for example with E, N, Q, R, T, I, L or V. Clause D44. A variant or a salt thereof according to any one of clauses D1 to D42, comprising a substitution of T at position -1, for example by A, K, M, N, R or S, especially by A, K, M, N or R. Article D45. A variant according to any one of articles D1 to D42 or a salt thereof, comprising a substitution of E at position 0, for example by A, D, G, K, Q or V, especially by G, K, Q or V. Article D46. A variant or a salt thereof according to any one of articles D1 to D42, comprising a substitution of X2 in position 1, for example by A, C, E, H, L, M, N, R, S, T, V or Y, in particular by A, E, H, L, M, N, R, T, V or Y. Article D47. A variant or a salt thereof according to any one of articles D1 to D42, comprising a substitution of X3 in position 2, for example by D, E, F, G, H, K, M, N, P, Q, S or W, in particular by D, E, F, G, H, K, M, N, P, Q or W. Clause D48. A variant according to any one of clauses D1 to D42 or a salt thereof, comprising a substitution of E in position 3, for example by A, D, G, K, Q or V, especially by G, K, Q or V. Clause D49. The variant or a salt thereof according to any one of clauses D1 to D42, comprising a substitution of H at position 4, for example with D, L, N, P, Q, R, or Y. Clause D50. A variant or a salt thereof according to any one of clauses D1 to D42, comprising a substitution of X4 in position 5, for example by G, K, Q, S, T or V, in particular by G, K, Q, T or V. Clause D51. The variant according to any one of clauses D1 to D42, or a salt thereof, comprising a substitution of E at position 6, for example with A, D, G, K, Q, or V. Clause D52. The variant or a salt thereof according to any one of clauses D1 to D42, comprising a substitution of D at position 7, for example with A, E, G, H, N, V, or Y. Clause D53. The variant according to any one of clauses D1 to D42, or a salt thereof, comprising a substitution of V at position 8, for example with D, E, I, L, or M. Article D54. The variant or a salt thereof according to any one of articles D42 to D53, comprising a substitution of X1 at position -2, for example by E, N, Q, R, T, I, L or V. Article D55. A variant or a salt thereof according to any one of articles D42 to D53, comprising a substitution of T at position -1, for example by A, K, M, N, R or S, especially by A, K, M, N or R. Article D56. A variant according to any one of articles D42 to D53 or a salt thereof, comprising a substitution of E at position 0, for example by A, D, G, K, Q or V, especially by G, K, Q or V. Article D57. A variant or a salt thereof according to any one of articles D42 to D53, comprising a substitution of X2 in position 1, for example by A, C, E, H, L, M, N, R, S, T, V or Y, in particular by A, E, H, L, M, N, R, T, V or Y. Article D58. A variant or a salt thereof according to any one of articles D42 to D53, comprising a substitution of X3 in position 2, for example by D, E, F, G, H, K, M, N, P, Q, S or W, in particular by D, E, F, G, H, K, M, N, P, Q or W. Article D59. A variant according to any one of articles D42 to D53 or a salt thereof, comprising a substitution of E in position 3, for example by A, D, G, K, Q or V, especially by G, K, Q or V. Clause D60. The variant or a salt thereof according to any one of clauses D42 to D53, comprising a replacement of H at position 4, for example with D, L, N, P, Q, R, or Y. Article D61. A variant or a salt thereof according to any one of articles D42 to D53, comprising a substitution of X4 in position 5, for example by G, K, Q, S, T or V, in particular by G, K, Q, T or V. Clause D62. The variant according to any one of clauses D42 to D53, or a salt thereof, comprising a substitution of E at position 6, for example with A, D, G, K, Q, or V. Clause D63. The variant according to any one of clauses D42 to D53, or a salt thereof, comprising a substitution of D at position 7, for example with A, E, G, H, N, V, or Y. Clause D64. The variant according to any one of clauses D42 to D53, or a salt thereof, comprising a substitution of V at position 8, for example replacement with D, E, I, L, or M. Clause D65. A variant or a salt thereof according to any one of clauses D43 to D53, which comprises one conservative substitution. Clause D66. A lipidated linear peptide or a salt thereof according to any one of clauses D1 to D41. Clause D67. The lipidated linear peptide, variant, or salt according to any one of clauses D1-D66, comprising a lipidated K residue. Clause D68. The lipidated linear peptide, variant, or salt according to clause D67, wherein said lipidated K residue is X2 at position 1. Clause D69. The lipidated linear peptide, variant, or salt according to clause D67, wherein said lipidated K residue is X1 at position -2. Clause D70. The lipidated linear peptide, variant, or salt according to any one of clauses D1-D69, wherein said lipid chain is a C16DA, a C18DA, or a C20DA group. Clause D71. The lipidated linear peptide, variant, or salt according to clause D70, wherein said lipid chain is a C18DA group. Clause D72. The lipidated linear peptide, variant, or salt of any one of clauses D1-D71, wherein said lipid is linked to a K residue via γGlu. Clause D73. The lipidated linear peptide, variant, or salt according to clause D72, wherein said lipid is linked to a K residue via γGlu and one to four OEG groups. Clause D74. The lipidated linear peptide, variant, or salt according to clause D73, wherein said lipid is linked to a K residue via γGlu and two OEG groups. Clause D75. The lipidated linear peptide, variant, or salt of any one of clauses D1-D69, wherein said lipid is C18DA-γGlu-OEG-OEG-. Clause D76. The lipidated linear peptide or salt according to any one of clauses D1 to D69, wherein said lipid is C18DA-γGlu-OEG-OEG-. Clause D77. The lipidated linear peptide or salt according to any of clauses D75 or D76, wherein said lipid is C18DA-L-γGlu-OEG-OEG-. Clause D78. The lipidated linear peptide or salt according to any of clauses D75 or D76, wherein said lipid is C18DA-D-γGlu-OEG-OEG-. Clause D79. The lipidated linear peptide, variant, or salt according to any one of clauses D1 to D78, which is acetylated at the N-terminus. Clause D80. The lipidated linear peptide, variant, or salt according to any one of clauses D1 to D78, which is not modified at the N-terminus. Clause D81. The lipidated linear peptide, variant, or salt according to any one of clauses D1-D80, which is amidated at the C-terminus. Clause D82. The lipidated linear peptide, variant, or salt of any one of clauses D1-D80, which is not modified at the C-terminus. Clause D83. A lipidated linear peptide or salt according to clause D1 consisting of LLP1 or a salt thereof. Clause D84. A lipidated linear peptide or salt according to clause D1 consisting of LLP2 or a salt thereof. Clause D85. A lipidated linear peptide or salt according to clause D1 consisting of LLP3 or a salt thereof. Clause D86. A lipidated linear peptide or salt according to clause D1 consisting of LLP4 or a salt thereof. Clause D87. A lipidated linear peptide or salt according to clause D1 consisting of LLP5 or a salt thereof. Clause D88. A lipidated linear peptide or salt according to clause D1 consisting of LLP6 or a salt thereof. Clause D89. A lipidated linear peptide or salt according to clause D1 consisting of LLP7 or a salt thereof. Clause D90. A lipidated linear peptide or salt according to clause D1 consisting of LLP8 or a salt thereof. Clause D91. A lipidated linear peptide or salt according to clause D1 which consists of LLP9 or a salt thereof. Clause D92. A lipidated linear peptide or salt according to clause D1 consisting of LLP10 or a salt thereof. Clause D93. A lipidated linear peptide or salt according to clause D1 consisting of LLP11 or a salt thereof. Clause D94. A lipidated linear peptide or salt according to clause D1 consisting of LLP12 or a salt thereof. Article D95. The lipidated linear peptide, variant, or salt according to any one of articles D1 to D95, wherein said salt is a pharma-ceutically acceptable salt. Clause D96. A lipidated linear peptide according to any preceding clause D. Clause D97. A lipidated variant peptide according to any preceding clause D. Clause D98. A pharma- ceutically acceptable salt of a lipidated linear peptide according to any preceding Clause D. Clause D99. A pharma- ceutically acceptable salt of a lipidated variant peptide according to any preceding Clause D. Clause D100. The lipidated linear peptide according to any one of clauses D1 to D99, which has no side chain modifications. Clause D101. The lipidated linear peptide according to any one of clauses D1 to D99, which is unmodified. Clause E1. SEQUENCE: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a conservatively substituted variant of said peptide or salt, comprising: Clause E2. A linear peptide, variant, or salt according to clause E1, wherein all residues of the peptide backbone are connected only by peptide bonds. Clause E3. A linear peptide, variant, or salt according to clause E1 or E2 comprising 25 or fewer amino acid residues in the backbone. Clause E4. A linear peptide, variant, or salt according to clause E3 comprising 20 or fewer amino acid residues in the backbone, for example 20 amino acid residues in the backbone. Clause E5. A linear peptide, variant, or salt according to clause E4 comprising 15 or fewer amino acid residues in the backbone, for example 15 amino acid residues in the backbone. Clause E6. A linear peptide, variant, or salt according to clause E5 comprising 12 or fewer amino acid residues in the backbone, for example 12 amino acid residues in the backbone. Clause E7. A linear peptide, variant, or salt according to clause E6 comprising 11 or fewer amino acid residues in the backbone. Clause E8. The linear peptide, variant, or salt of any one of clauses E1-E7 comprising at least 7 amino acid residues in the backbone, such as 7 amino acid residues in the backbone. Clause E9. A linear peptide, variant, or salt according to clause E8 comprising at least 8 amino acid residues in the backbone, for example 8 amino acid residues in the backbone. Clause E10. The linear peptide, variant, or salt according to clause E9 comprising at least 9 amino acid residues in the backbone, for example 9 amino acid residues in the backbone. Clause E11. The linear peptide, variant, or salt according to clause E10 comprising at least 10 amino acid residues in the backbone, for example 10 amino acid residues in the backbone. Clause E12. A linear peptide, variant, or salt according to clause E11 comprising at least 11 amino acid residues in the backbone. Clause E13. A linear peptide, variant, or salt according to clause E12 comprising 11 amino acid residues in the backbone. Article E14. SEQUENCE: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article E15. Sequence: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article E16. SEQUENCE: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article E17. Arrays: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article E18. Array: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article E19. Array: [ka] (where: X1 represents M or K; X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article E20. Array: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article E21. Array: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article E22. Array: [ka] (where: X1 represents M or K; X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article E23. Array: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article E24. Array: [ka] (where: X1 represents M or K; X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Clause E25. The linear peptide, variant, or salt according to any one of clauses E1-E24, wherein X1 represents M. Clause E26. The linear peptide, variant, or salt according to any one of clauses E1-E24, wherein X1 represents K. Clause E27. The linear peptide, variant, or salt according to any one of clauses E1-E25, wherein X2 represents P. Clause E28. The linear peptide, variant, or salt according to any one of clauses E1-E25, wherein X2 represents D. Clause E29. The linear peptide, variant, or salt according to any one of clauses E1-E25, wherein X2 represents Q. Clause E30. The linear peptide, variant, or salt of any one of clauses E1-E25, wherein X2 represents K. Clause E31. The linear peptide, variant, or salt of any one of clauses E1-E25, wherein X2 represents G. Clause E32. The linear peptide, variant, or salt of any one of clauses E1-E31, wherein X3 represents I. Clause E33. The linear peptide, variant, or salt of any one of clauses E1-E31, wherein X3 represents L. Clause E34. The linear peptide, variant, or salt of any one of clauses E1-E31, wherein X3 represents A. Clause E35. The linear peptide, variant, or salt of any one of clauses E1-E31, wherein X3 represents T. Clause E36. The linear peptide, variant, or salt according to any one of clauses E1-E26 or E28-E31, wherein X3 represents V. Clause E37. The linear peptide, variant, or salt according to any one of clauses E1-E36, wherein X4 represents E. Clause E38. The linear peptide, variant, or salt according to any one of clauses E1-E36, wherein X4 represents A. Clause E39. A linear peptide, variant or salt according to any one of clauses E12 to E13, comprising any one of the sequences of SEQ ID NOs: 1 to 10 and 16 to 39 or a salt thereof, or a conservatively substituted variant of said peptide or salt, for example consisting of any one of the sequences of SEQ ID NOs: 1 to 10 and 16 to 39 or a salt thereof, or a conservatively substituted variant of said peptide or salt. Clause E40. A linear peptide, variant or salt according to any one of clauses E12-E13, comprising, e.g. consisting of, the sequence of SEQ ID NO: 1 or a salt thereof, or a conservatively substituted variant of said peptide or salt. Clause E41. The variant or a salt thereof according to any one of clauses E1 to E40, comprising two conservative substitutions. Clause E42. The variant according to any one of clauses E1-E41 or a salt thereof, comprising a substitution of X1 at position -2, for example replacement with E, N, Q, R, T, I, L, or V. Clause E43. The variant or a salt thereof according to any one of clauses E1 to E41, comprising a substitution of T at position -1, for example by A, K, M, N, R or S, especially by A, K, M, N or R. Clause E44. The variant according to any one of clauses E1-E41 or a salt thereof, comprising a substitution of E at position 0, for example with A, D, G, K, Q or V, especially with G, K, Q or V. Clause E45. The variant or a salt thereof according to any one of clauses E1 to E41, comprising a substitution of X2 at position 1, for example by A, C, E, H, L, M, N, R, S, T, V or Y, in particular by A, E, H, L, M, N, R, T, V or Y. Clause E46. The variant or a salt thereof according to any one of clauses E1 to E41, comprising a substitution of X3 at position 2, for example by D, E, F, G, H, K, M, N, P, Q, S or W, in particular by D, E, F, G, H, K, M, N, P, Q or W. Clause E47. The variant according to any one of clauses E1-E41 or a salt thereof, comprising a substitution of E at position 3, for example with A, D, G, K, Q or V, especially with G, K, Q or V. Clause E48. The variant or a salt thereof according to any one of clauses E1-E41, comprising a replacement of H at position 4, for example with D, L, N, P, Q, R, or Y. Clause E49. The variant or a salt thereof according to any one of clauses E1 to E41, comprising a substitution of X4 at position 5, for example with G, K, Q, S, T or V, in particular with G, K, Q, T or V. Clause E50. The variant according to any one of clauses E1-E41 or a salt thereof, comprising a substitution of E at position 6, for example with A, D, G, K, Q, or V. Clause E51. The variant or a salt thereof according to any one of clauses E1-E41, comprising a substitution of D at position 7, for example with A, E, G, H, N, V, or Y. Clause E52. The variant according to any one of clauses E1-E41 or a salt thereof, comprising a substitution of V at position 8, for example with D, E, I, L, or M. Clause E53. The variant or a salt thereof according to any one of clauses E41 to E52, comprising a substitution of X1 at position -2, for example replacement with E, N, Q, R, T, I, L, or V. Clause E54. The variant or a salt thereof according to any one of clauses E41 to E52, comprising a substitution of T at position -1, for example by A, K, M, N, R or S, in particular by A, K, M, N or R. Clause E55. The variant according to any one of clauses E41 to E52 or a salt thereof, comprising a substitution of E at position 0, for example by A, D, G, K, Q or V, especially by G, K, Q or V. Clause E56. The variant or a salt thereof according to any one of clauses E41 to E52, comprising a substitution of X2 at position 1, for example by A, C, E, H, L, M, N, R, S, T, V or Y, in particular by A, E, H, L, M, N, R, T, V or Y. Article E57. The variant or a salt thereof according to any one of articles E41 to E52, comprising a substitution of X3 at position 2, for example by D, E, F, G, H, K, M, N, P, Q, S or W, in particular by D, E, F, G, H, K, M, N, P, Q or W. Article E58. The variant according to any one of articles E41 to E52 or a salt thereof, comprising a substitution of E at position 3, for example by A, D, G, K, Q or V, in particular by G, K, Q or V. Clause E59. The variant or a salt thereof according to any one of clauses E41 to E52, comprising a replacement of H at position 4, for example with D, L, N, P, Q, R, or Y. Clause E60. The variant or a salt thereof according to any one of clauses E41 to E52, comprising a substitution of X4 at position 5, for example by G, K, Q, S, T or V, in particular by G, K, Q, T or V. Clause E61. The variant according to any one of clauses E41 to E52, or a salt thereof, comprising a substitution of E at position 6, for example with A, D, G, K, Q, or V. Clause E62. The variant according to any one of clauses E41 to E52, or a salt thereof, comprising a substitution of D at position 7, for example with A, E, G, H, N, V, or Y. Clause E63. The variant according to any one of clauses E41 to E52, or a salt thereof, comprising a substitution of V at position 8, for example with D, E, I, L, or M. Clause E64. The variant or a salt thereof according to any one of clauses E42 to E52, comprising one conservative substitution. Clause E65. A linear peptide or a salt thereof according to any one of clauses E1 to E40. Clause E66. The linear peptide, variant, or salt of any one of clauses E1-E65, which is acetylated at the N-terminus. Clause E67. A linear peptide, variant or salt according to any one of clauses E1 to E65 which is not modified at the N-terminus. Clause E68. The linear peptide, variant, or salt of any one of clauses E1-E67 which is amidated at the C-terminus. Clause E69. The linear peptide, variant, or salt of any one of clauses E1-E67, which is unmodified at the C-terminus. Clause E70. A linear peptide or salt according to clause E1 consisting of SEQ ID NO:1 or a salt thereof. Clause E71. A linear peptide or salt according to clause E1 consisting of SEQ ID NO:2 or a salt thereof. Clause E72. The linear peptide or salt according to clause E1 consisting of SEQ ID NO:3 or a salt thereof. Clause E73. The linear peptide or salt according to clause E1 consisting of SEQ ID NO: 4 or a salt thereof. Clause E74. The linear peptide or salt according to clause E1 consisting of SEQ ID NO:5 or a salt thereof. Clause E75. The linear peptide or salt according to clause E1 consisting of SEQ ID NO:6 or a salt thereof. Clause E76. The linear peptide or salt according to clause E1 consisting of SEQ ID NO: 7 or a salt thereof. Clause E77. The linear peptide or salt according to clause E1 consisting of SEQ ID NO: 8 or a salt thereof. Clause E78. The linear peptide or salt according to clause E1 consisting of SEQ ID NO: 9 or a salt thereof. Clause E79. The linear peptide or salt according to clause E1 consisting of SEQ ID NO: 10 or a salt thereof. Clause E80. The linear peptide or salt according to clause E1 consisting of SEQ ID NO: 16 or a salt thereof. Clause E81. The linear peptide or salt according to clause E1 consisting of SEQ ID NO: 17 or a salt thereof. Clause E82. The linear peptide or salt according to clause E1 consisting of SEQ ID NO: 18 or a salt thereof. Clause E83. The linear peptide or salt according to clause E1 consisting of SEQ ID NO: 19 or a salt thereof. Clause E84. The linear peptide or salt according to clause E1 consisting of SEQ ID NO: 20 or a salt thereof. Clause E85. The linear peptide or salt according to clause E1 consisting of SEQ ID NO: 21 or a salt thereof. Clause E86. The linear peptide or salt according to clause E1 consisting of SEQ ID NO: 22 or a salt thereof. Clause E87. The linear peptide or salt according to clause E1 consisting of SEQ ID NO: 23 or a salt thereof. Clause E88. The linear peptide or salt according to clause E1 consisting of SEQ ID NO: 24 or a salt thereof. Clause E89. The linear peptide or salt according to clause E1 consisting of SEQ ID NO: 25 or a salt thereof. Clause E90. The linear peptide or salt according to clause E1 consisting of SEQ ID NO: 26 or a salt thereof. Clause E91. The linear peptide or salt according to clause E1 consisting of SEQ ID NO: 27 or a salt thereof. Clause E92. The linear peptide or salt according to clause E1 consisting of SEQ ID NO: 28 or a salt thereof. Clause E93. The linear peptide or salt according to clause E1 consisting of SEQ ID NO: 29 or a salt thereof. Clause E94. The linear peptide or salt according to clause E1 consisting of SEQ ID NO: 30 or a salt thereof. Clause E95. The linear peptide or salt according to clause E1 consisting of SEQ ID NO: 31 or a salt thereof. Clause E96. The linear peptide or salt according to clause E1 consisting of SEQ ID NO: 32 or a salt thereof. Clause E97. The linear peptide or salt according to clause E1 consisting of SEQ ID NO: 33 or a salt thereof. Clause E98. The linear peptide or salt according to clause E1 consisting of SEQ ID NO: 34 or a salt thereof. Clause E99. The linear peptide or salt according to clause E1 consisting of SEQ ID NO: 35 or a salt thereof. Clause E100. The linear peptide or salt according to clause E1 consisting of SEQ ID NO: 36 or a salt thereof. Clause E101. The linear peptide or salt according to clause E1 consisting of SEQ ID NO: 37 or a salt thereof. Clause E102. The linear peptide or salt according to clause E1 consisting of SEQ ID NO: 38 or a salt thereof. Clause E103. The linear peptide, variant, or salt according to any one of clauses E1-E102, wherein said salt is a pharma-ceutically acceptable salt. Clause E104. A linear peptide according to any preceding clause E. Clause E105. A variant peptide according to any preceding clause E. Clause E106. A pharma- ceutically acceptable salt of a linear peptide according to any preceding Clause E. Clause E107. A pharma- ceutically acceptable salt of a variant peptide according to any preceding Clause E. Clause E108. The linear peptide of any one of clauses E1-E107, which has no side chain modifications. Clause E109. The linear peptide of any one of clauses E1-E107, which is unmodified. Clause F1. The scaffold comprising 10 or fewer amino acid residues and the sequence: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt, comprising: Clause F2. A linear peptide, variant, or salt according to clause F1, wherein all residues of the peptide backbone are connected only by peptide bonds. Clause F3. A linear peptide, variant, or salt according to clause F1 or F2 comprising 6 amino acid residues in the backbone. Clause F4. A linear peptide, variant, or salt according to clause F1 or F2 comprising 7 amino acid residues in the backbone. Clause F5. A linear peptide, variant, or salt according to clause F1 or F2 comprising 8 amino acid residues in the backbone. Clause F6. A linear peptide, variant, or salt according to clause F1 or F2 comprising 9 amino acid residues in the backbone. Clause F7. A linear peptide, variant, or salt according to clause F1 or F2 comprising 10 amino acid residues in the backbone. Article F8. SEQUENCE: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article F9. SEQUENCE: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article F10. SEQUENCE: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article F11. Array: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article F12. SEQUENCE: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article F13. Sequencing: [ka] (where: X1 represents M or K; X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article F14. SEQUENCE: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article F15. SEQUENCE: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article F16. SEQUENCE: [ka] (where: X1 represents M or K; X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Article F17. SEQUENCE: [ka] (where: X2 represents P, D, Q, K, and G. X3 stands for I, L, A, T, and V. X4 represents E or A. or a salt thereof, or a conservatively substituted variant of said peptide or salt. Clause F18. A linear peptide, variant, or salt according to any one of clauses F1 to F17, wherein X1 represents M. Clause F19. A linear peptide, variant, or salt according to any one of clauses F1 to F17, wherein X1 represents K. Clause F20. The linear peptide, variant, or salt according to any one of clauses F1 to F19, wherein X2 represents P. Clause F21. The linear peptide, variant, or salt according to any one of clauses F1 to F19, wherein X2 represents D. Clause F22. The linear peptide, variant, or salt according to any one of clauses F1 to F19, wherein X2 represents Q. Clause F23. The linear peptide, variant, or salt according to any one of clauses F1 to F19, wherein X2 represents K. Clause F24. The linear peptide, variant, or salt according to any one of clauses F1 to F19, wherein X2 represents G. Clause F25. The linear peptide, variant, or salt according to any one of clauses F1 to F24, wherein X3 represents I. Clause F26. The linear peptide, variant, or salt according to any one of clauses F1 to F24, wherein X3 represents L. Clause F27. The linear peptide, variant, or salt according to any one of clauses F1 to F24, wherein X3 represents A. Clause F26. The linear peptide, variant, or salt according to any one of clauses F1 to F24, wherein X3 represents T. Clause F29. The linear peptide, variant, or salt according to any one of clauses F1 to F24, wherein X3 represents V. Clause F30. The linear peptide, variant, or salt according to any one of clauses F1 to F29, wherein X4 represents E. Clause F31. The linear peptide, variant, or salt according to any one of clauses F1 to F29, wherein X4 represents A. Clause F32. A linear peptide, variant or salt according to any one of clauses F1 to F31 comprising any one of SEQ ID NOs: 40 to 42 or a salt thereof, or a conservatively substituted variant of said peptide or salt. Clause F33. A linear peptide, variant or salt according to clause F32, consisting of any one of SEQ ID NOs: 40 to 42 or a salt thereof, or a conservatively substituted variant of said peptide or salt. Clause F34. The variant according to any one of clauses F1 to F33, or a salt thereof, which comprises two conservative substitutions. Clause F35. The variant or a salt thereof according to any one of clauses F1 to F34, comprising a substitution of X1 at position -2, for example replacement with E, N, Q, R, T, I, L or V. Clause F36. A variant according to any one of clauses F1 to F34 or a salt thereof, comprising a substitution of T at position -1, for example by A, K, M, N, R or S, especially by A, K, M, N or R. Clause F37. A variant according to any one of clauses F1 to F34, or a salt thereof, comprising a substitution of E at position 0, for example by A, D, G, K, Q or V, especially by G, K, Q or V. Clause F38. A variant according to any one of clauses F1 to F34, or a salt thereof, comprising a substitution of X2 in position 1, for example by A, C, E, H, L, M, N, R, S, T, V or Y, in particular by A, E, H, L, M, N, R, T, V or Y. Clause F39. A variant according to any one of clauses F1 to F34, or a salt thereof, comprising a substitution of X3 in position 2, for example by D, E, F, G, H, K, M, N, P, Q, S or W, in particular by D, E, F, G, H, K, M, N, P, Q or W. Clause F40. A variant according to any one of clauses F1 to F34, or a salt thereof, comprising a substitution of E in position 3, for example by A, D, G, K, Q or V, especially by G, K, Q or V. Clause F41. The variant according to any one of clauses F1 to F34, or a salt thereof, comprising a replacement of H at position 4, for example with D, L, N, P, Q, R, or Y. Clause F42. A variant according to any one of clauses F1 to F34, or a salt thereof, comprising a substitution of X4 in position 5, for example by G, K, Q, S, T or V, in particular by G, K, Q, T or V. Clause F43. The variant according to any one of clauses F1 to F34, or a salt thereof, comprising a substitution of E at position 6, for example with A, D, G, K, Q, or V. Clause F44. The variant according to any one of clauses F1 to F34, or a salt thereof, comprising a substitution of D at position 7, for example with A, E, G, H, N, V, or Y. Clause F45. The variant according to any one of clauses F1 to F34, or a salt thereof, comprising a substitution of V at position 8, for example by D, E, I, L, or M. Clause F46. The variant according to any one of clauses F34 to F45, or a salt thereof, comprising a substitution of X1 in position -2, for example by E, N, Q, R, T, I, L or V. Article F47. A variant or a salt thereof according to any one of articles F34 to F45, comprising a substitution of T in position -1, for example by A, K, M, N, R or S, in particular by A, K, M, N or R. Article F48. A variant according to any one of articles F34 to F45 or a salt thereof, comprising a substitution of E at position 0, for example by A, D, G, K, Q or V, especially by G, K, Q or V. Article F49. A variant or a salt thereof according to any one of articles F34 to F45, comprising a substitution of X2 in position 1, for example by A, C, E, H, L, M, N, R, S, T, V or Y, in particular by A, E, H, L, M, N, R, T, V or Y. Article F50. A variant or a salt thereof according to any one of articles F34 to F45, comprising a substitution of X3 in position 2, for example by D, E, F, G, H, K, M, N, P, Q, S or W, in particular by D, E, F, G, H, K, M, N, P, Q or W. Article F51. A variant according to any one of articles F34 to F45 or a salt thereof, comprising a substitution of E in position 3, for example by A, D, G, K, Q or V, especially by G, K, Q or V. Clause F52. The variant according to any one of clauses F34 to F45, or a salt thereof, comprising a replacement of H at position 4, for example by D, L, N, P, Q, R, or Y. Article F53. A variant according to any one of articles F34 to F45, or a salt thereof, comprising a substitution of X4 in position 5, for example by G, K, Q, S, T or V, in particular by G, K, Q, T or V. Clause F54. The variant according to any one of clauses F34 to F45, or a salt thereof, comprising a substitution of E in position 6, for example by A, D, G, K, Q, or V. Clause F55. The variant according to any one of clauses F34 to F45, or a salt thereof, comprising a substitution of D at position 7, for example by A, E, G, H, N, V, or Y. Clause F56. The variant according to any one of clauses F34 to F45, or a salt thereof, comprising a substitution of V at position 8, for example by D, E, I, L, or M. Clause F57. The variant or a salt thereof according to any one of clauses F35 to F45, comprising one conservative substitution. Clause F58. The linear peptide, variant, or salt according to any one of clauses F1 to F57, which is acetylated at the N-terminus. Clause F59. A linear peptide, variant, or salt according to any one of clauses F1 to F57, which is not modified at the N-terminus. Clause F60. A linear peptide, variant, or salt according to any one of clauses F1 to F59 which is not amidated at the C-terminus. Clause F61. The linear peptide, variant, or salt according to any one of clauses F1 to F59, which is not modified at the C-terminus. Clause F62. A linear peptide or a salt thereof according to any one of clauses F1 to F33. Clause F63. A linear peptide or salt according to clause F1 consisting of SEQ ID NO: 40 or a salt thereof. Clause F64. A linear peptide or salt according to clause F1 consisting of SEQ ID NO: 41 or a salt thereof. Clause F65. A linear peptide or salt according to clause F1 consisting of SEQ ID NO: 42 or a salt thereof. Clause F66. A linear peptide, variant, or salt according to any one of clauses F1 to F65, wherein said salt is a pharma- ceutically acceptable salt. Clause F67. A linear peptide according to any preceding clause F. Clause F68. A variant peptide according to any preceding clause F. Clause F69. A pharma- ceutically acceptable salt of a linear peptide according to any preceding Clause F. Clause F70. A pharma- ceutically acceptable salt of a variant peptide according to any preceding Clause F. Clause F71. The linear peptide of any one of clauses F1 to F70, which has no side chain modifications. Clause F72. The linear peptide of any one of clauses F1 to F70, which is unmodified. Clause G1. A protected cyclic peptide comprising a cyclic peptide according to any one of clauses A1-A98, B1-B95, or C1-C70, wherein at least one reactive amino acid side chain is protected. Clause G2. A protected cyclic peptide according to clause G1, wherein all reactive amino acid side chains are protected. Clause H1. A protected linear peptide comprising a linear peptide according to any one of clauses D1-D101, E1-E109, or F1-F72, wherein at least one reactive group is protected. Clause H2. The protected linear peptide of clause H1, wherein at least one reactive amino acid side chain is protected. Clause H3. A protected linear peptide according to clause H2, wherein all reactive amino acid side chains are protected. Clause H4. The protected linear peptide of any one of clauses H1-H3, wherein said N-terminus is protected. Clause H5. The protected linear peptide of any one of clauses H1-H4, wherein said C-terminus is protected. Clause I1. A linear peptide which when cyclized provides a cyclic peptide according to any one of clauses A1-A98, B1-B95, or C1-C70. Clause J1. A protected linear peptide which, when cyclized, provides a protected cyclic peptide according to either clause G1 or G2. Clause K. Methods of Producing the Peptides Described herein. Clause L1. The lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, variant of any of these, and / or any of these according to any one of clauses A1-A98, B1-B99, C1-C70, D1-D101, E1-E109, or F1-F72, capable of increasing BDNF levels. Clause L2. A lipidated cyclic peptide, a cyclic peptide, a lipidated linear peptide, a linear peptide, a variant of any of these, and / or any of these described in clause J1, capable of increasing BDNF levels by at least 20% between 0 and 24 hours after administration in the assay of Example 10. Clause M1. The lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, variant of any of these, and / or salt of any of these according to any one of clauses A1-A98, B1-B95, C1-C70, D1-D101, E1-E109, or F1-F72, capable of increasing phospho-CREB (Ser133) levels. Clause M2. A lipidated cyclic peptide, a cyclic peptide, a lipidated linear peptide, a linear peptide, a variant of any of these, and / or a salt of any of these, according to clause M1, capable of increasing CREB levels by at least 30% between 0 and 24 hours after administration in the assay of Example 10. Clause N1. The lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, variant of any of these, and / or salt of any of these according to any one of clauses A1-A99, B1-B95, C1-C70, D1-D101, E1-E109, or F1-F72, capable of increasing PGC1a levels. Clause N2. A lipidated cyclic peptide, a cyclic peptide, a lipidated linear peptide, a linear peptide, a variant of any of these, and / or any of these described in clause M1, capable of increasing PGC1a levels by at least 30% between 0 and 24 hours after administration in the assay of Example 10. Clause O1. The lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, variant of any of these, and / or salt of any of these according to any one of clauses A1-A99, B1-B95, C1-C70, D1-D101, E1-E109, or F1-F72, capable of increasing TFEB levels. Clause O2. A lipidated cyclic peptide, a cyclic peptide, a lipidated linear peptide, a linear peptide, a variant of any of these, and / or a salt of any of these, according to clause O1, capable of increasing TFEB levels by at least 30% between 0 and 24 hours after administration in the assay of Example 10. Clause P1. The lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, variant of any of these, and / or salt of any of these according to any one of clauses A1 to A99, B1 to B95, C1 to C70, D1 to D101, E1 to E109, or F1 to F72, capable of reducing NfL levels. Clause P2. A lipidated cyclic peptide, a cyclic peptide, a lipidated linear peptide, a linear peptide, a variant of any of these, and / or a salt of any of these according to clause P1, capable of reducing NfL levels by at least 10% in the assay of Example 31. Clause Q1. A peptide or variant thereof, and / or a salt thereof, according to any of the preceding clauses, having an improved ability to increase BDNF, PGC1a, TFEB, and / or phospho-CREB (Ser133) compared to CPX. Article Q2. Improved t, especially in the brain, compared to CPX 1 / 2 , AUC, or C max 2. The peptide according to any preceding clause, or a variant thereof, and / or a salt thereof, having the formula: Article Q3. Improved t in the brain compared to CPX1 / 2 2. The peptide according to any preceding clause, or a variant thereof, and / or a salt thereof, having the formula: Clause Q4. A peptide or variant thereof, and / or a salt thereof, according to any of the preceding clauses, having the ability to increase BDNF, PGC1a, TFEB, and / or phospho-CREB (Ser133) at least as much as CLP1. Clause Q5. At least as effective as CLP1, especially in the brain 1 / 2 , AUC, or C max 2. The peptide according to any preceding clause, or a variant thereof, and / or a salt thereof, having the formula: Clause Q6. At least as effective as CLP1, especially in the brain 1 / 2 2. The peptide according to any preceding clause, or a variant thereof, and / or a salt thereof, having the formula: Clause Q7. A peptide or variant thereof, and / or a salt thereof, according to any preceding clause, which exhibits (e.g., by the method of Example 5) a lack of fibrillation at pH 6.5 and 7.5, preferably at pH 4.5, pH 6.5, and pH 7.5. Clause Q8. t for at least 1 hour, preferably at least 4 hours, in particular at least 8 hours 1 / 2 Any of the preceding clauses, or variants thereof, and / or salts thereof, which exhibit (for example, by the method of Example 9) Clause Q9. The t in the brain for at least 1 hour, preferably at least 4 hours, in particular at least 8 hours 1 / 2 A peptide according to clause Q8 or a variant thereof, and / or a salt thereof, as shown (for example by the method of Example 9). Clause R1. A pharmaceutical composition comprising a lipidated cyclic peptide, a cyclic peptide, a lipidated linear peptide, a linear peptide, a variant of any of these, and / or a pharma- ceutical acceptable salt of any of these according to any one of clauses A1 to A98, B1 to B95, C1 to C70, D1 to D101, E1 to E109, F1 to F72, L1 or L2, M1 or M2, N1 or N2, O1 or O2, P1 or P2, Q1 to Q9, and a pharma- ceutical composition comprising a pharma- ceutical acceptable carrier or excipient. Clause R2. The pharmaceutical composition according to clause R1 which is a solid. Clause R3. The pharmaceutical composition according to clause R2, which is a liquid. Clause R4. The pharmaceutical composition according to clause R3, wherein said pharma- ceutically acceptable carrier or excipient is water. Clause R5. The pharmaceutical composition according to any one of clauses R1 to R4, which is in unit dose form. Clause R6. The pharmaceutical composition according to clause R5, wherein said unit dosage form contains from 0.005 mg to 100 mg, more preferably from 0.05 mg to 50 mg. Clause R7. A lipidated cyclic peptide, a cyclic peptide, a lipidated linear peptide, a linear peptide, a variant of any of these, and / or a pharma- ceutically acceptable salt of any of these according to any one of clauses A1 to A98, B1 to B95, C1 to C70, D1 to D101, E1 to E109, F1 to F72, L1 or L2, M1 or M2, N1 or N2, O1 or O2, P1 or P2, Q1 to Q9 for use as a medicament. Clause R8. Use of a lipidated cyclic peptide, a cyclic peptide, a lipidated linear peptide, a linear peptide, a variant of any of these, and / or a pharma- ceutical acceptable salt of any of these according to any one of clauses A1 to A98, B1 to B95, C1 to C70, D1 to D101, E1 to E109, F1 to F72, L1 or L2, M1 or M2, N1 or N2, O1 or O2, P1 or P2, Q1 to Q9 in the manufacture of a medicament. Clause R9. The lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, a variant of any of these, and / or a pharma- ceutically acceptable salt of any of these according to any one of clauses A1-A98, B1-B95, C1-C70, D1-D101, E1-E109, F1-F72, L1 or L2, M1 or M2, N1 or N2, O1 or O2, P1 or P2, Q1-Q9 for use in increasing BDNF levels. Clause R10. Use of a lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, a variant of any of these, and / or a pharma- ceutically acceptable salt of any of these according to any one of clauses A1-A98, B1-B95, C1-C70, D1-D101, E1-E109, F1-F72, L1 or L2, M1 or M2, N1 or N2, O1 or O2, P1 or P2, Q1-Q9 in the manufacture of a medicament for increasing BDNF levels. Clause R11. A method of increasing BDNF levels in a subject comprising administering to the subject a lipidated cyclic peptide, a cyclic peptide, a lipidated linear peptide, a linear peptide, a variant of any of these, and / or a pharma- ceutical acceptable salt of any of these according to any one of clauses A1-A98, B1-B95, C1-C70, D1-D101, E1-E109, F1-F72, L1 or L2, M1 or M2, N1 or N2, O1 or O2, P1 or P2, Q1-Q9. Clause R12. The lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, a variant of any of these, and / or a pharma- ceutically acceptable salt of any of these according to any one of clauses A1-A98, B1-B95, C1-C70, D1-D101, E1-E109, F1-F72, L1 or L2, M1 or M2, N1 or N2, O1 or O2, P1 or P2, Q1-Q9 for use in increasing phospho-CREB (Ser133) levels. Clause R13. Use of a lipidated cyclic peptide, a cyclic peptide, a lipidated linear peptide, a linear peptide, a variant of any of these, and / or a pharma- ceutically acceptable salt of any of these according to any one of clauses A1-A98, B1-B95, C1-C70, D1-D101, E1-E109, F1-F72, L1 or L2, M1 or M2, N1 or N2, O1 or O2, P1 or P2, Q1-Q9 in the manufacture of a medicament for increasing phospho-CREB (Ser133) levels. Clause R14. A method of increasing CREB levels in a subject comprising administering to the subject a lipidated cyclic peptide, a cyclic peptide, a lipidated linear peptide, a linear peptide, a variant of any of these, and / or a pharma- ceutical acceptable salt of any of these according to any one of clauses A1-A98, B1-B95, C1-C70, D1-D101, E1-E109, F1-F72, L1 or L2, M1 or M2, N1 or N2, O1 or O2, P1 or P2, Q1-Q9. Clause R15. The lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, a variant of any of these, and / or a pharma- ceutically acceptable salt of any of these according to any one of clauses A1-A98, B1-B95, C1-C70, D1-D101, E1-E109, F1-F72, L1 or L2, M1 or M2, N1 or N2, O1 or O2, P1 or P2, Q1-Q9 for use in increasing PGC1a levels. Clause R16. Use of a lipidated cyclic peptide, a cyclic peptide, a lipidated linear peptide, a linear peptide, a variant of any of these, and / or a pharma- ceutically acceptable salt of any of these according to any one of clauses A1-A98, B1-B95, C1-C70, D1-D101, E1-E109, F1-F72, L1 or L2, M1 or M2, N1 or N2, O1 or O2, P1 or P2, Q1-Q9 in the manufacture of a medicament for increasing PGC1a levels. Article R17. A method of increasing PGC1a levels in a subject comprising administering to the subject a lipidated cyclic peptide, a cyclic peptide, a lipidated linear peptide, a linear peptide, a variant of any of these, and / or a pharma- ceutical acceptable salt of any of these according to any one of articles A1-A98, B1-B95, C1-C70, D1-D101, E1-E109, F1-F72, L1 or L2, M1 or M2, N1 or N2, O1 or O2, P1 or P2, Q1-Q9. Clause R18. The lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, a variant of any of these, and / or a pharma- ceutically acceptable salt of any of these according to any one of clauses A1-A98, B1-B95, C1-C70, D1-D101, E1-E109, F1-F72, L1 or L2, M1 or M2, N1 or N2, O1 or O2, P1 or P2, Q1-Q9 for use in increasing TFEB levels. Clause R19. Use of a lipidated cyclic peptide, a cyclic peptide, a lipidated linear peptide, a linear peptide, a variant of any of these, and / or a pharma- ceutically acceptable salt of any of these according to any one of clauses A1-A98, B1-B95, C1-C70, D1-D101, E1-E109, F1-F72, L1 or L2, M1 or M2, N1 or N2, O1 or O2, P1 or P2, Q1-Q9 in the manufacture of a medicament for increasing TFEB levels. Clause R20. A method of increasing TFEB levels in a subject, comprising administering to the subject a lipidated cyclic peptide, a cyclic peptide, a lipidated linear peptide, a linear peptide, a variant of any of these, and / or a pharma- ceutical acceptable salt of any of these according to any one of clauses A1-A98, B1-B95, C1-C70, D1-D101, E1-E109, F1-F72, L1 or L2, M1 or M2, N1 or N2, O1 or O2, P1 or P2, Q1-Q9. Clause R21. The lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, a variant of any of these, and / or a pharma- ceutically acceptable salt of any of these according to any one of clauses A1-A98, B1-B95, C1-C70, D1-D101, E1-E109, F1-F72, L1 or L2, M1 or M2, N1 or N2, O1 or O2, P1 or P2, Q1-Q9 for use in reducing NfL levels. Clause R22. Use of a lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, a variant of any of these, and / or a pharma- ceutically acceptable salt of any of these according to any one of clauses A1 to A98, B1 to B95, C1 to C70, D1 to D101, E1 to E109, F1 to F72, L1 or L2, M1 or M2, N1 or N2, O1 or O2, P1 or P2, Q1 to Q9 in the manufacture of a medicament for reducing NfL levels. Clause R23. A method of reducing NfL levels in a subject comprising administering to the subject a lipidated cyclic peptide, a cyclic peptide, a lipidated linear peptide, a linear peptide, a variant of any of these, and / or a pharma- ceutical acceptable salt of any of these according to any one of clauses A1-A98, B1-B95, C1-C70, D1-D101, E1-E109, F1-F72, L1 or L2, M1 or M2, N1 or N2, O1 or O2, P1 or P2, Q1-Q9. Clause R24. The lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, a variant of any of these, and / or a pharma- ceutically acceptable salt of any of these according to any one of clauses A1-A98, B1-B95, C1-C70, D1-D101, E1-E109, F1-F72, L1 or L2, M1 or M2, N1 or N2, O1 or O2, P1 or P2, Q1-Q9 for use in the treatment or prevention of a disease or disorder selected from the group consisting of neurodegenerative diseases, proteinopathies, lysosomal storage diseases, mitochondrial disorders, psychiatric disorders, and other BDNF-related disorders. Clause R25. Use of a lipidated cyclic peptide, a cyclic peptide, a lipidated linear peptide, a linear peptide, a variant of any of these, and / or a pharma- ceutically acceptable salt of any of these according to any one of clauses A1-A98, B1-B95, C1-C70, D1-D101, E1-E109, F1-F72, L1 or L2, M1 or M2, N1 or N2, O1 or O2, P1 or P2, Q1-Q9 in the manufacture of a medicament for the treatment or prevention of a disease or disorder selected from the group consisting of neurodegenerative diseases, proteinopathies, lysosomal storage diseases, mitochondrial disorders, psychiatric disorders, and other BDNF-related disorders. Article R26. A method for treating or preventing a disease or disorder selected from the group consisting of neurodegenerative diseases, proteinopathies, lysosomal storage diseases, mitochondrial disorders, psychiatric disorders, and other BDNF-related disorders in a subject, the method comprising administering to the subject a lipidated cyclic peptide, a cyclic peptide, a lipidated linear peptide, a linear peptide, a variant of any of these, and / or a pharma- ceutical acceptable salt of any of these according to any one of articles A1 to A98, B1 to B95, C1 to C70, D1 to D101, E1 to E109, F1 to F72, L1 or L2, M1 or M2, N1 or N2, O1 or O2, P1 or P2, Q1 to Q9. Article R27. A peptide, use or method according to any one of articles R24 to R26 for the treatment or prevention of a neurodegenerative disease, in particular a neurodegenerative disease associated with reduced BDNF, rescue by BDNF, mitochondrial dysfunction and / or lysosomal dysfunction. Clause R28. A peptide, use or method according to any one of clauses R24 to R26 for the treatment or prevention of Huntington's disease, Parkinson's disease, Alzheimer's disease, frontotemporal dementia (especially in subjects with GRN-haploinsufficiency), ALS, multiple sclerosis, hereditary ataxias, motor neuron disorders or vascular dementia. Clause R29. A peptide, use or method according to clause R28 for the treatment or prevention of Huntington's disease. Clause R30. The peptide, use or method according to clause R29, wherein said UHDRS is improved (compared to the absence of treatment). Clause R31. A peptide, use or method according to clause R28 for the treatment or prevention of Parkinson's disease. Clause R32. The peptide, use or method according to clause R31 in a subject having a monoallelic mutation in GBA1. Clause R33. The peptide, use or method according to clause R32 in a subject carrying an N370S, L444P, R463C, G10S, N426K, R48W and / or R257Q mutation. Clause R34. The peptide, use or method according to any one of clauses R31 to R33, wherein said UPDRS is improved (compared to the absence of treatment). Clause R35. The peptide, use or method according to any one of clauses R31 to R34, wherein said MDS-UPDRS is improved (compared to the absence of treatment). Clause R36. A peptide, use or method according to clause R28 for the treatment or prevention of Alzheimer's disease. Clause R37. A peptide, use or method according to clause R28 for the treatment or prevention of frontotemporal dementia, in particular in subjects with GRN-haploinsufficiency. Article R38. A peptide, use or method according to any one of articles R24 to R26 for the treatment or prevention of a proteinopathy, in particular one associated with protein aggregation. Article R39. The peptide, use or method according to any one of articles R24 to R26 for the treatment or prevention of prion disease, alpha-synucleinopathy, tauopathy, C9orf72-dependent ALS / FTD, dementia with Lewy bodies, dementia with amyloid plaques, Huntington's disease, TDP-43 positive ALS / FTD or hereditary ataxia. Article R40. A peptide, use or method according to any one of articles R24 to R26 for the treatment or prevention of lysosomal storage diseases, in particular lysosomal storage diseases associated with lysosomal dysfunction. Clause R41. A peptide, use or method according to clause R40 in a subject with Gaucher disease. Clause R42. A peptide, use or method according to clause R41 in a subject having biallelic mutations of GBA1. Clause R43. The peptide, use or method according to clause R42 in a subject carrying the p.Leu483Pro, p.Arg535Cys, and / or RecNcil mutations. Article R44. A peptide, use or method according to any one of articles R24 to R26 for the treatment or prevention of Niemann-Pick disease and neuronal ceroid lipofuscinosis. Clause R45. A peptide, use or method according to any one of clauses R24 to R26 for the treatment or prevention of a mitochondrial dysfunction disorder. Clause R46. A peptide, use or method according to any one of clauses R24 to R26 for the treatment or prevention of mitochondrial myopathies or Leigh's syndrome. Article R47. A peptide, use or method according to any one of articles R24 to R26 for the treatment or prevention of a psychiatric disorder, in particular a psychiatric disorder associated with the SorCS2 gene or function, or associated with BDNF or TrkB. Article R48. A peptide, use or method according to any one of articles R24 to R26 for the treatment or prevention of bipolar disorder, depression, schizophrenia, autism spectrum disorder, anxiety or ADHD. Article R49. A peptide, use or method according to any one of articles R24 to R26 for the treatment or prevention of depression. Clause R50. A peptide, use or method according to any one of clauses R24 to R26 for the treatment or prevention of another BDNF-related disorder. Article R51. A peptide, use or method according to any one of articles R24 to R26 for the treatment or prevention of WAGR syndrome (in particular BDNF haploinsufficiency), stroke or epilepsy. Clause R52. A peptide, use or method according to any one of clauses R7 to R51 for use in therapy. Clause R53. A peptide, use or method according to any one of clauses R7 to R51 for use in prophylaxis. Clause R54. A peptide, use or method according to any one of clauses R7 to R53 for use in a human subject. Clause R55. The peptide, use or method according to any one of clauses R7 to R54, wherein said lipidated cyclic peptide, cyclic peptide, lipidated linear peptide, linear peptide, variant of any of these, and / or a pharma- ceutically acceptable salt of any of these is provided in the form of a pharmaceutical composition according to any one of clauses R1 to R7. Clause S1. A peptide according to any one of clauses A1 to A98, B1 to B95, C1 to C70, D1 to D101, E1 to E109, F1 to F72, L1 or L2, M1 or M2, N1 or N2, O1 or O2, P1 or P2, Q1 to Q9 or a protected peptide according to any one of clauses G1 and G2, H1 to H5, I1 or J1, which is covalently attached to a solid support.

[0165] The present invention will also be explained in more detail with reference to the following examples, without however being limited thereto, which may be modified without departing from the scope of the invention.

[0166] Moreover, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to a "peptide" includes two or more such peptides, and so forth.

[0167] All publications, patents, and patent applications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety. EXAMPLES

[0168] (Example) (statistics) Significance was assessed using a two-tailed Student's T-test unless otherwise indicated. Error bars indicate * p<0.05, ** p<0.01, *** p<0.001, **** SEM is shown with p<0.0001.

[0169] Example 1: Peptide synthesis Linear peptides were synthesized using standard Fmoc (fluorenylmethyloxycarbonyl) chemistry.

[0170] (Resin preparation:) Fmoc-Pro-OH (0.2 mmol, 1 equiv.) and N,N-diisopropylethylamine (DIPEA) (0.14 mL, 4 equiv.) were added to 2-CTC resin (0.2 mmol, 1.00 equiv., less than 1.05 mmol / g) in dichloromethane (DCM) (10 mL). The mixture was stirred with N2 at 20° C. for 2 h, after which methanol (MeOH) (0.5 mL) was added and stirred with N2 bubbling for an additional 30 min. The resin was washed three times with dimethylformamide (DMF) (15 mL).

[0171] (Deprotection:) Fmoc removal was carried out using 20% ​​piperidine in DMF (15 mL) that was added to the resin and stirred with N2 for 30 min. The resin was washed 4 times with DMF (15 mL) and filtered.

[0172] (Coupling:) Successive amino acid couplings were performed using a solution of 2-(1H-benzotriazol-1-yl)-1,1,3,3 tetramethyluronium hexafluorophosphate (HBTU) (2.85 equiv.), DIPEA (6 equiv.), and Fmoc-protected amino acid (3 equiv.) in DMF (5 mL) that was added to the resin and stirred with N2 at 20° C. for 30 min. The resin was then washed four times with DMF (15 mL). The Fmoc deprotection and coupling steps were repeated for each of the subsequent amino acids until the desired peptide sequence was obtained. The resin was then washed four times with dimethylformamide (DMF) (15 mL). The Fmoc removal and coupling steps were repeated until the desired peptide sequence was obtained. The resulting side-chain protected and resin-bound linear peptide was used directly in the next step.

[0173] The Fmoc-protected amino acid building blocks used were: Fmoc-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Gln(Trt)-OH, FmocGlu(OtBu)-OH, Fmoc-Gly-OH, Fmoc-His(Trt)-OH, Fmoc-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. If nothing else is specified, the natural L-form of the amino acid was used. Addition of lipids to lysine residues was accomplished using orthogonally protected Lys (Dde-Lys(Fmoc)-OH), where Dde is placed on the α-amine while Fmoc is placed on the side chain amine. After coupling of the protected Lys, the Fmoc was first removed and then the lipid was coupled to the resulting exposed amine. The Dde was then removed and the peptide chain was elongated as usual using Fmoc chemistry.

[0174] Example 2: Peptide cleavage, cyclization, and purification After the final amino acid coupling and Fmoc removal, the resin of Example 1 was washed 5 times with DMF, 3 times with MeOH, and dried under vacuum. To generate the cyclic peptide, the peptide resin was then treated with a cleavage cocktail (1% trifluoroacetic acid (TFA) / 99% DCM) (15 mL) for 15 minutes, and the peptide-containing TFA-DCM mixture was collected. The cleavage was repeated three times. For the linear peptides, they were cleaved and deprotected in situ using strong acid (95% TFA). For the cyclic peptides, the peptide (in 1% TFA / 99% DCM) was diluted in DCM (200 mL) with 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU) (2 eq.) and 1-hydroxybenzotriazole hydrate (HOBT) (2 eq.) and DIPEA (6 eq.) to couple the peptide head to the tail. The mixture was stirred for 1 h at 20° C. The cyclization was monitored by LC-MS.

[0175] After stirring, the mixture was washed twice with 1 M hydrochloric acid (HCl) (30 mL) and dried under reduced pressure. 5 mL of cleavage 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 h. The peptide was precipitated with ice-cold tert-butyl methyl ether (40 mL), centrifuged (2 min at 3000 rpm), and washed twice with ice-cold tert-butyl methyl ether (40 mL). The crude peptide was dried under vacuum for 2 h, purified by preparative HPLC, and the target peptide fraction was freeze-dried to give a white solid.

[0176] (Preparative HPLC method:) (System: Gilson GX-281; ​​Column: Gemini, C18, 110 Å, 5 μm or Luna, C18, 100 Å, 10 μm; Gradient: 50 min gradient run time; 0-50 min 7-37% B; Flow rate: 20 mL / min; Column temperature: 30 °C; Diode array: 220 / 254 nm; Solvent A: 0.075% TFA in water; Solvent B: acetonitrile.

[0177] Qualitative analysis of the peptides was performed by HPLC and LCMS (see Figure 1).

[0178] (HPLC: 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 in water; Solvent B: 0.075% TFA in acetonitrile).

[0179] (LCMS method for final product:) (System: Agilent Infinity II 1260 HPLC series; Column: Xbridge C18, 130 Å, 3.5 μm, 2.1 × 30 mm; Detector: Agilent LCMS (G6125C), single quadrupole TIC scan; Scan range: m / z min 100, m / z max 2000, positive mode, electrospray; Gradient: Gradient run time 1 min; 0.00–1.00 min 10–80% B; Column wash and equilibration; 1.00–1.01 80–95% B, 1.01–1.60 min 95% B, 1.60–1.61 min 95–10% B, 1.61–2.00 min 10% B; Flow rate: 1.2 mL / min; Diode array: 215 or 220 nm; column temperature: room temperature; Solvent A: 0.1% TFA in water; Solvent B: 0.075% TFA in acetonitrile.

[0180] (result) A summary of the LC-MS and HPLC purity data is provided in the table below, along with exemplary chromatograms and mass spectra of CLP1 shown in Figures 1A-1C. Table 4 - Summary of peptide HPLC purification and MS characterization [Table 4] TIFF2025506481000117.tif237170TIFF2025506481000118.tif237170TIFF2025506481000119.tif121170 * Monoisotopic

[0181] Example 3: CLP1 treatment leads to an increase in CREB target genes SorCS2 has recently been established to play a key role in BDNF / TrkB signaling by being essential for the activation of downstream kinases (Glerup, 2016). The main mediator of the neurotrophin response to BDNF is attributed to the activation of the transcription factor CREB (Finkbeiner, 1997; Walton, 2000; Benito, 2010; Sakamoto, 2011). CREB activation is well known to improve neuronal survival, synaptogenesis, and growth. A key mediator of this is the production of BDNF itself by CREB (Tao, 1998), thereby establishing a positive feedback loop. Similarly, it has been described that CREB activation induces mitochondrial biogenesis through the upregulation of the master regulator PGC1a (Wu, 2006; Kang, 2017). Indeed, CPX, a cyclized peptidomimetic of the SorCS2 receptor fragment, increases BDNF levels after 4 hours of stimulation in wild-type neurons (WO2022029281). Because CLP1 is a cyclized lipidated peptidomimetic of the SorCS2 receptor fragment that is important for BDNF signaling, we assessed whether CLP1 treatment leads to increased BDNF and PGC1a production in wild-type neurons as a result of CREB activation. The effect of the cyclized and stabilized lipidated peptide CLP1 was compared with that of the cyclized peptide CPX.

[0182] Cortical neurons were isolated from p0 wild-type mice and plated at a density of 200,000 cells per well (24-well trays). After 7 days in vitro, neurons were stimulated with 1 uM CLP1 or CPX in neurobasal A 15 medium and incubated at 37°C and 5% CO2 for 8, 16, or 24 hours. Neurons were then lysed in RIPA lysis buffer containing cOmplete cocktail protease inhibitors. BDNF and PGC1a levels were analyzed by Western blotting normalized to β-actin.

[0183] As shown in Figures 2A and 2B, CLP1 significantly upregulated the assessed CREB downstream target genes BDNF by 180% (p=0.0174) and PGC1a by 611% (p<0.0001) after 24 hours of stimulation. CPX did not increase the levels of either BDNF or PGC1a, likely due to the fact that its effects are induced before the time point of assessment. This indicates an extended signaling of CLP1 compared to CPX.

[0184] Example 4: CLP1 removes soluble mHTT from fibroblasts derived from Huntington's disease patients Autophagy is a process that removes misfolded proteins, aggregates, or damaged organelles. In addition to driving mitochondrial biogenesis, PGC1a has been shown to promote lysosomal biogenesis through regulation of TFEB (master regulator of lysosomal biogenesis) (Ghosh, 2015; Lynch, 2020). As a cause of PGC1a upregulation and TFEB control, we assessed CLP1-induced reduction of mHTT (mutant huntingtin) protein expressed from the disease-causing gene in HD. To compare efficacy, we also included CPX (WO2022029281), which has previously been shown to reduce mutant HTT levels. Patient-derived fibroblasts GM04476 (from Coriell Biobank) were seeded at 30,000–50,000 cells per well in 96-well plates. The next day, cells were treated with 1 uM CLP1 or CPX and incubated at 37°C and 5% CO2 for 24 hours. Afterwards, cells were lysed with RIPA lysis buffer containing cOmplete cocktail protease inhibitors. Total huntingtin levels were analyzed by antibody mab2166 (Sigma-Aldrich) and mutant huntingtin levels were measured by an antibody that detects only the mutant allele (MW1 ab) by Western blotting. These levels were normalized to β-actin. As shown in Figure 3A and Figure 3B, both CLP1 and CPX reduced the levels of mutant huntingtin by 50% (p=0.0048) and 75% (p=0.0209), respectively, while they reduced the total levels of huntingtin (mutated and healthy alleles) by ~65% (p=0.0036) for CLP1 and 75% (p=0.0056) for CPX. This indicates that CLP1 specifically induces degradation of mutant huntingtin protein over healthy huntingtin protein, and that the potency of CLP1 is increased compared to CPX, thereby providing a valuable opportunity as a therapeutic agent for HD patients.

[0185] Example 5: Chemical and physical stability of CLP1 To better understand the chemical basis of CLP1 stability and degradation, the chemical and physical stability of CLP1 in three buffer systems was evaluated. Solutions of CLP1 were prepared in three buffer systems with different pH values ​​and the samples were incubated at 40°C without stirring. Chemical stability was evaluated by UPLC-UV on the day of preparation (t0) and after 2 weeks of incubation (t14). Physical stability was evaluated by Thioflavin T (ThT) assay over 4 days with stirring at 40°C.

[0186] For each assay, samples were dissolved to a peptide concentration of 1 mg / mL in either 25% acetonitrile (ACN) (for analytical standard solutions) or in one of three buffer systems (50 mM sodium acetate buffer, pH 4.5 (22.5 mM sodium acetate + 27.5 mM glacial acetic acid); 50 mM L-histidine buffer, pH 6.5; 50 mM sodium phosphate buffer, pH 7.5 (40.6 mM Na2HPO4 + 9.4 mM NaH2PO4)). All buffers were prepared in 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 before UPLC-UV measurement. For physical stability tests, samples were filtered through a 0.22 um cellulose filter (13φ, Frisenette) before preparing the ThT assay.

[0187] (UPLC-UV method for chemical stability assay:) Column: Kinetex 1.7 μm C18 100 Å 150 × 2.1 mm from Phenomenex; Mobile phase A: ultrapure water + 0.1% TFA; Mobile phase B: acetonitrile + 0.1% TFA; Injection volume: 2 μL of CLP1; Flow rate: 0.3 mL / min, Detection wavelength: 220

[0188] (gradient:) [Table 5]

[0189] (Plate reader settings for ThT assay:) Excitation wavelength: 450 nm; dichroic filter: 465 nm; emission wavelength: 486 nm; focal height: 3.5 mm; gain: 1000; number of cycles: 1000; cycle time: 360 sec; number of flashes per well: 20; shaking: 300 rpm, 5 sec on, 5 sec off between cycles; temperature: 40°C.

[0190] The results (Figures 4A-C) show that maximum degradation was seen at pH 4.5 for CLP1 (9% AUC decrease). CLP1 showed similarly good chemical stability at pH 6.5 and 7.5 (1% AUC decrease). Physical stability was assessed by ThT assay to evaluate fibrillation behavior over 96 h. CLP1 showed no fibrillation in any buffer system, indicating good physical stability (Figures 4D-G). Each line represents an individual replicate.

[0191] Example 6: CLP1 free fraction and stability An important aspect of drug development is pharmacokinetics, including absorption, distribution, metabolism, and excretion (ADME). The stability of CLP1 was evaluated in both human and mouse plasma samples and mouse brain homogenate samples. CLP1 is stabilized by two amino acid substitutions compared to CPX, so CPX was included as a reference in these stability assays. The stability of CLP1 was also evaluated in liver S9 fractions from mouse, dog, rat, human, and monkey. Brain binding (free fraction) in both mouse and human brain homogenates was also evaluated.

[0192] (Plasma stability) Frozen mouse or human plasma was thawed in a 37°C water bath before use. Plasma was centrifuged at 4000 rpm for 5 min to remove clots (if any). Mouse or human plasma was incubated with 2 uM CLP1 or CPX, or 2 uM propantheline bromide (positive control for degradation) and left at 37°C in a water bath. At each time point, stop solution (200 ng / mL tolbutamide and 200 ng / mL labetalol in MeOH) was added to precipitate the proteins, and after mixing and centrifugation, the supernatant was used for LCMS analysis. As shown by Figures 5A and 5B, CLP1 and CPX have half-lives (t 1 / 2), indicating high plasma stability. % remaining = 100 x (PAR at specified incubation time / PAR at TO time), where PAR is the peak area ratio of analyte to internal standard (IS) and half-life is t 1 / 2 = 0.693k.

[0193] (Mouse Brain Stability) Frozen mouse brain homogenates were thawed in a 37°C water bath before use. Mouse brain homogenates were incubated with 1 uM CLP1 or CPX or 2 uM 7-ethoxycoumarin (positive control for degradation) and left in a water bath at 37°C. At each time point, stop solution (200 ng / mL tolbutamide and 200 ng / mL labetalol in MeOH) was added to precipitate the proteins, and after mixing and centrifugation, the supernatant was used for LCMS analysis. As shown by Figure 5C, CLP1 has a half-life (t ) of 40.7 hours compared to 28.9 hours for CPX. 1 / 2), indicating high brain stability of CLP1, which is an improvement when compared with CPX.

[0194] Example 7: Metabolic stability of CLP1 in liver fractions Because the majority of drug metabolism occurs in the liver, hepatic in vitro preparations can serve as models to assess the metabolic stability of drugs. To investigate metabolic stability, S9 fractions, which contain a mixture of unfractionated microsomes and cytosols that contain a wide variety of drug-metabolizing enzymes, are often used. Hepatic S9 fractions are commonly used as the preferred test system for in vitro ADME.

[0195] (Stability of liver S9) CLP1 was added to a final concentration of 1 uM to human liver S9, CD-1 mouse liver S9, Sprague-Dawley rat liver S9, Beagle dog liver S9, and Cynomolgus monkey liver S9 solutions (1 mg protein / mL) in 100 mM potassium phosphate buffer. 7-Ethoxycoumarin (1 uM) was used as a positive control for clearance. The reaction was started by adding a cofactor regenerating system containing nicotinamide adenine dinucleotide phosphate (NADP) (1.3 mM), glucose 6-phosphate (G6P) (3.3 mM), glucose 6-phosphate dehydrogenase (G6PDH) (0.4 U / mL), uridine diphosphate glucuronic acid (UDPGA) (2.5 mM), 3'-phosphoadenosine-5'-phosphosulfate (PAPS) (0.1 mM), glutathione (GSH) (5 mM), MgCl2 (3.3 mM) in 100 mM phosphate buffer. The reaction was run for different time points between 0 and 2 h and then terminated using stop solution. After shaking and centrifugation of the plate, the supernatant was used for LCMS analysis. As shown in Figure 6A (intrinsic clearance rate) and Figure 6C (% remaining), CLP1 has a very low clearance of <2.4 μL / min / mg in all species and a half-life (t 1 / 2). 1 / 2 was calculated as follows: T 1 / 2=Ln2 / k e =0.693 / k e。The intrinsic clearance was calculated as follows: CLint(S9)=0.693 / T1 / 2 / mg S9 protein / mL, where T1 / 2 is the half-life and CL is the intrinsic clearance, indicating high metabolic stability. The 7-ethoxycoumarin control is shown in Figure 6B (percent intrinsic clearance) and Figure 6D (% remaining).

[0196] Example 8: Brain-free fraction of CLP1 Measurement of the total concentration of a drug in the brain has limited correlation with its pharmacodynamic readout. To obtain a better correlation, the drug concentration in the brain must be corrected for the proportion of unbound and bound drug. Therefore, the brain-free fraction of CLP1 in both human and mouse brain homogenates was evaluated. On the day of the experiment, brain homogenates were thawed by running them under cold tap water. CLP1 and a control compound (propranolol) were dissolved in H2O to obtain a 10 mM stock solution in DMSO. A working solution (400 uM) was prepared by diluting 10 uL of the stock solution with 240 uL of H2O.

[0197] (Ultracentrifugation Procedure:) (Buffer preparation) Basic solutions were made by dissolving 14.2 g / L Na2HPO4 and 8.77 g / L NaCl in deionized water. Acidic solutions were made by dissolving 15.6 g / L NaH2PO4·2H2O and 8.77 g / L NaCl in deionized water. The basic ones were titrated to pH 7.4 ± 0.1 with the acidic solutions. Mouse brains were homogenized in buffer and loaded with CLP1 (2 uM) and a control compound (propanol, 2 uM) prepared by diluting 6 uL of working solution with 1194 uL of blank matrix (no compound). The DMSO concentration of the compound stock solution in the final solution was 0.5.

[0198] To prepare time zero (T0) samples that would be used to measure the remaining material, 30 uL of loading matrix was transferred to a sample collection plate (n=2). Samples were immediately added to 30 uL of buffer to obtain a final volume of 60 uL with a plasma:buffer volume ratio (1:1, v:v) in each well. 480 uL of stop solution containing 60 uL of 4% H3PO4 in H2O and an internal standard was added. These were then stored at 2-8 °C until further processing along with the other samples. To prepare protein-free samples (referred to as F samples) that would be used to measure the unbound material, 400 uL aliquots of pre-incubated brain homogenates containing either CLP1 or a control compound were transferred to ultracentrifuge tubes (n=2) and subjected to ultracentrifugation at 37 °C, 47000 × g (115000 rpm) for 2 h to generate F samples. At the end of ultracentrifugation, a 30 uL sample was taken from the second layer of the supernatant (below the top layer) of the F sample. To prepare the samples that would be used for the unbound and residual measurements (referred to as T samples), simultaneously with the ultracentrifugation, the remaining aliquots (n=1) of the preincubated spiked plasma were placed in the same incubator and continued to incubate at 37°C for 2 hours. The samples were transferred to a new 96-well plate. To each sample, an equal volume of the opposite blank matrix (buffer or plasma) was added to reach a final volume of 60 uL with a volume ratio of plasma:buffer of 1:1 (v:v) in each well. To all samples, 60 uL of 4% H3PO4 in H2O and 480 uL of stop solution containing internal standards were added, respectively. The mixtures were vortexed and centrifuged at 4000 rpm for approximately 20 minutes. Afterwards, 100 uL aliquots of the supernatant of all samples were removed for LC-MS / MS analysis.

[0199] % Unbound, % Undiluted Unbound, % Undiluted Bound, and % Remaining were calculated by the following formula: % Unbound (free fraction) = 100. *F / T4.5; where F is the analyte concentration or analyte / internal standard peak area ratio of the protein-free sample after ultracentrifugation, and T4.5 is the analyte concentration or analyte / internal standard peak area ratio in the matrix after 4.5 hours of incubation. As shown in Figure 7A and B, CLP1 has a free fraction of 19% in mouse brain homogenates and 11% in human brain homogenates.

[0200] Example 9: Pharmacokinetics of CLP1 The pharmacokinetics of CLP1 in wild-type mice was evaluated. Ten-fold serial dilutions of CLP1 (2 mg / kg, 0.2 mg / kg, and 0.02 mg / kg) were injected subcutaneously (SC) into wild-type mice (male C57BL / 6J) in 4.38 mM L-His, 140 mM NaCl, 0.2% Tween-20, and 1500 IU hyaluronidase (pH 6.15). Both plasma, whole brain, and cerebrospinal fluid concentrations were determined by LC-MS / MS at different time points from 1 to 24 h.

[0201] (Plasma Processing Procedure:) Aliquots of 40 uL of unknown samples, calibration standards, quality controls, dilution quality controls, single blanks, and double blanks were added to a 96-well plate. Each sample (except double blanks) was quenched with 160 uL of IS1 (internal standards in MeOH: labetalol, tolbutamide, verapamil, dexamethasone, glyburide, and celecoxib, each at 100 ng / mL) (double blank samples were quenched with 160 uL of MeOH), after which the mixtures were vortex mixed at 800 rpm for 10 minutes and centrifuged at 3220 g (4000 rpm) at 4° C. for 15 minutes. 50 uL of the supernatant was transferred to another clean 96-well plate and centrifuged at 3220 g for 5 minutes at 4° C., after which the supernatant was directly injected for LC-MS / MS analysis.

[0202] (Brain Processing Procedure:) Tissue homogenates were prepared by homogenizing tissues in 5 volumes (w:v) of cold homogenization solution (MeOH / 15 mM PBS (1:2, v:v)). Aliquots of 40 uL of unknown samples, calibration standards, quality controls, diluted quality controls, single blanks, and duplicate blanks were added to a 96-well plate; then, 40 uL of male C57BL / 6J mouse plasma (EDTA-K2) was added and vortex-mixed thoroughly (at least 5 min) on a vortexer. Each sample (except duplicate blanks) was quenched with 320 uL of IS1, respectively (duplicate blank samples were quenched with 320 uL of MeOH), after which the mixtures were vortex-mixed at 800 rpm for 10 min and centrifuged at 3220 g (4000 rpm) for 15 min at 4°C. 50 uL of the supernatant was transferred to another clean 96-well plate and centrifuged at 3220 g for 5 min at 4° C., after which the supernatant was directly injected for LC-MS / MS analysis. The process was performed on ice.

[0203] (CSF Processing Procedure:) An equal volume of plasma was added to the CSF samples and blank matrix, mixed well, and proteins were precipitated using 1.5 mL tubes. 20uL aliquots of calibration standards, quality control and dilution quality control, single blank, and double blank samples were added to 1.5mL tubes; each sample (except double blank) was quenched with 400uL IS1 respectively (double blank was quenched with 400uL MeOH), then the mixture was vortexed thoroughly (at least 15 seconds) and centrifuged at 12000xg, 4°C for 15 minutes; all mixed unknown samples were quenched with 20x IS1, then the mixture was vortexed thoroughly (at least 15 seconds) and centrifuged at 12000xg, 4°C for 15 minutes; 50uL aliquots of supernatant were transferred to 96-well plates and centrifuged at 3220xg, 4°C for 5 minutes, then the supernatant was directly injected for LC-MS / MS analysis. Processing was performed on wet ice. Treatments were performed in low binding EP tubes and low binding 96-well plates.

[0204] Figures 8A-8C show the measured concentrations of CLP1 at different time points. The PK parameters of CLP1 are listed below. These results show that CLP1 reaches the brain and CSF after SC injection. Furthermore, CLP1 shows stable levels in the brain for at least 24 hours at both 0.2 mg / kg and 2 mg / kg. In contrast, CPX at 13 mg / kg has previously been shown to be cleared from the brain 1 hour after subcutaneous injection (WO2022029281). Thus, CLP1 shows an excellent stability profile in the brain after subcutaneous delivery.

[0205] The parameters were calculated using WinNonlin software, where the maximum observed concentration is Cmax, T 1 / 2(time)=ln(2) / λz. The definition of λz (Lambda_z) is the first-order rate constant (estimated by linear regression of time vs. log concentration) associated with the terminal (log-linear) part of the curve. AUC 0-t was calculated using the linear / log trapezoidal method. A linear function was used for fitting before Tmax and a log function was used for fitting after Tmax. (plasma) [Table 6] (brain) [Table 7] (CSF) [Table 8]

[0206] Example 10: In vivo efficacy of CLP1 in wild-type mice Previous examples have shown that CLP1 reaches the brain (at measurable levels) after SC administration when injected at both 2 mg / kg and 0.2 mg / kg. The ability of CLP1 to increase downstream targets of CREB after a single dose injection was assessed.

[0207] (single dose administration) Wild-type mice were subcutaneously injected with 0.2 mg / kg CLP1 in 4.38 mM L-His, 140 mM NaCl, 0.2% Tween-20, and 1500 IU hyaluronidase (pH 6.15). Mice were sacrificed at 2-8 hours post-injection. Striatal tissue was isolated and tissue was lysed using a TissueLyser in RIPA lysis buffer containing cOmplete and phosSTOP. Levels of BDNF, PGC1a, and TFEB, a master regulator of lysosomes, were examined by Western blotting. All proteins were normalized to β-actin levels. As shown in Figure 9A-C, CLP1 had a strong tendency to increase BDNF levels 4 hours after SC delivery (p-value 0.06), while it significantly increased both PGC1a and TFEB at 2-4 and 2-8 hours after injection, respectively. Post hoc analysis using two-way ANOVA revealed a significant time-dependent effect on BDNF levels, as well as an overall significant effect of treatment with CLP1 on PGC1a and TFEB levels.Thus, CLP1 demonstrated target engagement in vivo in the striatum of wild-type mice after a single dose SC administration.

[0208] (Daily treatment (7 days)) In another study, we evaluated whether continuous daily administration (SC) of CLP1 or CPX leads to increased levels of CREB target genes. Furthermore, since TFEB has been shown to drive the expression of the lysosomal protein GRN (Tanaka, 2013), we evaluated the efficacy of CLP1 or CPX to increase GRN levels. Heterozygous loss-of-function mutations in the GRN gene are associated with the neurodegenerative disease frontotemporal dementia (FTD), in which the mutations cause lysosomal dysfunction. Therefore, increasing the levels of GRN is considered a therapeutic approach in FTD.

[0209] Wild-type mice were subcutaneously injected once daily with 0.2 mg / kg or 2 mg / kg CLP1 or 13 mg / kg CPX in 4.38 mM L-His, 140 mM NaCl, 0.2% Tween-20, and 1500 IU hyaluronidase (pH 6.15). Mice were sacrificed on day 8, 24 hours after the last injection. Striatal tissue was isolated and tissue was lysed using a TissueLyser in RIPA lysis buffer containing cOmplete and phosSTOP. BDNF, PGC1a, and GRN levels were verified by Western blotting. All proteins were normalized to β-actin levels.

[0210] As shown in Figures 10A-C, CLP1 and CPX significantly increased both PGC1a and GRN at both 0.2 mg / kg and 2 mg / kg doses after daily injections for 7 days. Interestingly, BDNF levels were only significantly and to a greater extent than CPX with the 0.2 mg / kg dose of CLP1, whereas no significant effect was observed with the 2 mg / kg dose of CLP1. This indicates the therapeutic value of CLP1 in FTD patients carrying heterozygous GRN mutations as well as other neurodegenerative disorders.

[0211] Example 11: CLP1 improves behavior in the R6 / 2 mouse model of Huntington's disease Central to the pathobiology of Huntington's disease is the loss of BDNF transport in the cortico-striatal circuitry, which leads to the death of striatal neurons (Strand, 2007; Zuccato, 2007; Conforti, 2013). A daily dosing scheme of 0.2 mg / kg was chosen for treatment of the R6 / 2 mouse model of Huntington's disease for the entire duration of the experiment.

[0212] The aim of the study was to measure the effect of CLP1 during exercise testing in R6 / 2 (B6CBA-R6 / 2(CAG 120+ / -5) mice with Huntington's disease, and the main parameters of life span in the treatment groups according to the Kaplan-Meier scale. CPX (13 mg / kg) was included to compare efficacy. Twenty R6 / 2 mice (B6CBA-R6 / 2(CAG 120+ / -5)) at 5 weeks of age and 10 age-matched WT littermates were used for the experiment. The animals were kept in a standard temperature (22 ± 1 °C) and dimmed environment (lights on from 7 am to 8 pm) with free access to food and water. Dosing was continued from 5 weeks of age until 25 weeks (endpoint) with 4.38 mM L-His, 140 mM NaCl, 0.2% Tween-20, and 1500 IU hyaluronidase (pH The mice were administered daily subcutaneous (SC) injections of CLP1 or CPX during the first 6 weeks of treatment (6.15). In addition to motor behavioral tests (clasping and rotarod), each mouse was weighed weekly.

[0213] (Rotarod measurement) Mice were tested at 4 weeks of age (baseline), 6 weeks of age, 9 weeks of age, and 12 weeks of age for two consecutive days during the day. Each daily session included a 5-minute training trial at 4 RPM on the rotarod apparatus (AccuScan Instruments, Columbus, USA). One hour later, animals were subjected to three consecutive 6-minute acceleration trials, varying speed from 0 to 40 RPM over 360 seconds, with at least 30 minutes between trials. The latency to fall off the rod was recorded. Mice remaining on the rod longer than 360 seconds were removed and the time was scored as 360 seconds.

[0214] (Clasping) Mice were tested during the day at 4 weeks of age (baseline), 6 weeks, 9 weeks, and 12 weeks of age. Mice were suspended by their tails from a height of 50 cm for 30 seconds, and a limb clasping response was defined as withdrawal of any limb toward the trunk for longer than 1 second. Each test session consisted of three trials with a clasping score ranging from 0 to 4, where 0 represents an absence of clasping, 1 represents withdrawal of any one limb, 2 represents withdrawal of any two limbs, 3 represents withdrawal of any three limbs, and 4 represents withdrawal of all four limbs. Limb clasping response scores were averaged for each test session for each animal.

[0215] FIG. 11A shows a schematic of the study in R6 / 2 mice. As shown in FIG. 11B, neither CLP1 nor CPX had any effect on the body weight of the mice. However, CLP1 significantly improved clasping at 9 and 14 weeks of age, whereas CPX treatment only improved at 9 weeks of age (FIG. 11B). Rotarod performance (latency to fall) is shown in 11D. CLP1 and CPX extended the mean survival time of treated R6 / 2 mice by 8 days for CLP1 and 3 days for CPX, and the median survival was extended by 13 days for both CLP1 and CPX (FIG. 11E and FIG. 11F). These results indicate the beneficial effect of CLP1 in this challenging mouse model of Huntington's disease.

[0216] Example 12: CLP1 improves behavior in a mouse model of Parkinson's disease (MPTP model) Many neurodegenerative diseases exhibit mitochondrial dysfunction, energy failure, and oxidative stress as a consequence (Sawa, 2001; Oliveira, 2007; Chaturvedi, 2013; Naia, 2017; Pinho, 2020). A mouse model of mitochondrial dysfunction is the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model, which has been used as a Parkinson's disease (PD) model because the neurotoxic effects of MPTP result in specific damage in dopaminergic neurons of the substantia nigra pars compacta and striatum, two areas that are heavily affected in PD. Injection of MPTP results in the production of the neurotoxin MPP+, which disrupts complex I of the electron transport chain (a component of mitochondrial metabolism) and causes the permanent symptoms of PD.

[0217] A PD animal model was established by intraperitoneal injection of MPTP in C57BL / 6 mice, and the ameliorative effects of CLP1 at doses of 0.2 mg / kg and 2 mg / kg on MPTP-induced hypoactivity and decreased number of neurons in the substania nigra compact were detected.

[0218] A total of 48 animals were randomly divided into four groups. Animals were kept on a 12-hour light / dark (6 am / 6 pm) cycle. Animals were allowed to acclimate for one week before testing. Two days prior to MPTP administration, mice were administered CLP1 (2 mg / kg or 0.2 mg / kg) subcutaneously in 4.38 mM L-His, 140 mM NaCl, 0.2% Tween-20, and 1500 IU hyaluronidase (pH 6.15). The other groups received buffer only. Mice were treated once daily by subcutaneous administration throughout the entire experiment. On day 0, mice in group 1 were further injected once daily with a SC dose of saline throughout the remainder of the experiment. Mice in groups 2-4 were injected once daily with a SC dose of MPTP (30 mg / kg / day) throughout the remainder of the experiment. The total study period was 10 days.

[0219] A battery of endpoint assays was performed including body weight, total distance traveled, vertical counts, grip strength, and immunostaining for tyrosine hydroxylase. A schematic diagram of behavioral testing and treatments is shown in Figure 12A.

[0220] (Behavioral Tests) On the 9th day of the test, 6 hours after MPTP injection, the animals were placed in an open field to detect changes in motor behavior (main indicators: total distance traveled and vertical count) within 10 minutes. On the 10th day of the test, 6 hours after MPTP injection, for grip strength measurement, the mice were made to grasp the metal grid of the grip strength meter with their forelimbs and their tails were gently pulled backwards until they could no longer grasp the grid. The average grip strength observed in 10 trials was recorded and calculated.

[0221] (Tissue Sampling and Immunostaining) After the study was completed, brain tissue was collected. Six brains from each group were perfusion-fixed for immunostaining of tyrosine hydroxylase. Coronal sections of mouse brain tissue were embedded in paraffin using standard histological methods: 3 slide sections (4 um thick, 50 um apart) were cut per mouse. Slides were deparaffinized and dehydrated in 3% aqueous hydrogen peroxide at room temperature. Antigen retrieval citrate buffer (pH 6.0) was used. To avoid non-specific staining, sections were then incubated in blocking serum (DAKO#X0909) for 15 minutes at room temperature, followed by the use of primary tyrosine hydroxylase (TH) antibody (Abcam#ab112) at 1:400 dilution for 1 hour. A secondary goat polyclonal antibody conjugated to HRP (DAKO#K4003) was then added. For neuronal image analysis, TH-stained sections were used and scanned with a Leica Aperio CS2 scanner. The images were opened in HALO and the TH-positive neurons in the SNpc of both sides were counted. The number of positive cells was expressed as the average of three brain sections. Statistics were performed using one-way ANOVA (or Kruskal-Wallis test).

[0222] In this study, the body weight of animals after MPTP injection initially decreased and gradually increased during the study, but MPTP significantly changed the body weight at the end point compared to untreated mice (sham), and CLP1-treated mice showed no significant body weight change at the end point compared to the sham group (Figure 12D). The open field test and grip strength test showed that the travel distance, vertical count, and grip strength of the model group were significantly decreased compared to the control group. Treatment with 2 mg / kg CLP1 significantly increased the travel distance and vertical count in the open field test compared to the model group (Figure 12B), while both 0.2 mg / kg and 2 mg / kg treatments significantly increased the grip strength compared to the MPTP-untreated group (Figure 12C).

[0223] As an index of dopaminergic neuron survival, tyrosine hydroxylase (TH)+ neurons were counted in the substantia nigra pars compacta (SNpc). The MPTP-untreated group showed a significant decrease in neurons after MPTP injection. Administration of 0.2 mg / kg CLP1 significantly increased TH+ neurons compared to the model group, indicating an increase in the level of live dopaminergic neurons (Figures 13A and 13B).

[0224] This indicates the potential use of CLP1 as a therapeutic approach for Parkinson's disease and other neurodegenerative diseases involving mitochondrial dysfunction.

[0225] Example 13: CLP1 clears human α-synuclein PFFs, reduces their diffusion, and prevents dopaminergic neuron loss in injected wild-type rats. Because CLP1 was able to increase expression of TFEB, a master regulator of lysosomal proteins, and induce autophagy, we evaluated the therapeutic efficacy of CLP1 in a PD rat model in which human α-synuclein preformed fibrils were injected to induce α-synuclein pathology. The amygdala was chosen as the injection site for several reasons: (1) it is the most commonly affected region in human PD patients and, in some cases, the only affected structure in the entire brain in incident Lewy body cases (Beach, 2009; Beach, 2010; Adler, 2016), suggesting that PD often begins in this structure; (2) the amygdala is the second CNS structure affected following initial olfactory bulb initiation; (3) the amygdala has an extensive input-output connectome that makes this brain region suitable for examining transneuronal spread; and (4) the amygdala has monosynaptic connections to the olfactory bulb and other important brainstem structures that are all severely affected in PD.

[0226] (Rats and injections) Considering that age is the greatest risk factor for human PD, older experimental animals may provide the most significant and reliable findings. Therefore, older wild-type rats (14 months old at the time of injection) were used in the experiments because, similar to patients, age is an important factor for α-synuclein aggregation and its complete propagation to the heart, stomach, and skin.

[0227] Injections into rats were performed using a 10ul Hamilton syringe (25-gauge needle). 9ug of α-synuclein fibrils (preformed fibrils, PFFs) were distributed bilaterally (3ul of 1ug / ul PFFs in each location) into the basolateral and central amygdala nuclei localized by standardized stereotaxic coordinates (ML -4.45, AP -2.4, DVcentral -7.95, DVbasolateral,1 -8.6, DVbasolateral,2 -9.15). Stereotaxic coordinates were based on the Paxinos and Watson rat brain atlas and three pilot trials. For each group, a control group received an intracerebral injection of saline. Rats were treated with daily SC injections of CLP1 (0.2 mg / kg) in 4.38 mM L-His, 140 mM NaCl, 0.2% Tween-20, and 1500 IU hyaluronidase (pH 6.15) for 32 days. The experimental procedure is outlined in Figure 14A.

[0228] (Tissue collection and immunohistochemistry) 24 hours after the last dose, rats were sedated and transcardially perfused with PBS and phosphate-buffered 4% formaldehyde. Brains were sampled to examine intracerebral propagation of α-syn pathology. Additionally, one brain (n=1) was evaluated for tyrosine hydroxylase (TH) levels to assess dopaminergic neuronal loss. Tissues were processed and cut. Sections (4 um thick, 10 μm thick for skin) from several subjects (3–6 subjects depending on section size) were randomized and mounted on a single tissue slide. Tissue sections were deparaffinized and stained for PFF inclusions or TH.

[0229] (Quantitative assessment of immune reactivity) Images were collected from 4 um thick sections using an Olympus VS120 automated slide scanning microscope. Quantification of immunoreactive density in brain tissue was performed. Rat brains were perfusion fixed and stained for PFF to determine diffusion. PFF positive neurons were counted in the amygdala region, both ipsilateral, at the injection site, and contralateral to assess diffusion. In addition, PFF positive neurons were counted in the substantia nigra pars compacta (SNpc). The injection site and brain region are shown in Figure 14B.

[0230] Representative photographs of both the SNpc and amygdala are shown in Figure 14C and Figure 14D for both ipsilateral and contralateral sites. The number of inclusions is shown in Figure 14E. Striatal dopaminergic staining (TH-staining) is shown in Figure 14F. CLP1 significantly reduced the number of inclusions in the ipsilateral SN and contralateral amygdala, while also tending to reduce inclusions in the ipsilateral amygdala. Furthermore, CLP1 preserved dopaminergic terminals in the striatum intact compared to non-CLP1 treated rats showing a complete loss of dopamine signaling in the striatum. This demonstrates the effect of CLP1 on both diffusion and clearance of a-synuclein, a central aspect of PD treatment where the therapeutic effect is to prevent denervation and cell loss of striatal dopamine terminals. Furthermore, this highlights the possibility of using clinically validated biomarkers of the dopaminergic system, e.g., specific PET radiotracers, as clinical biomarkers of efficacy in humans.

[0231] Example 14: FSL rats BDNF has been linked to depression, as postmortem samples from patients with mood disorders show reduced BDNF levels, particularly in the hippocampus and amygdala brain regions (Dwivedi, 2003; Thompson, 2011; Guilloux, 2012). Furthermore, antidepressants have been shown to induce BDNF expression or act on targets of the BDNF pathway (Chen, 2001; Casarotto, 2021).

[0232] Therefore, we evaluated the therapeutic potential of CLP1 in the Flinders Susceptible Line (FSL), a rat model of depression characterized by reduced locomotor activity, reduced body weight, increased REM sleep, and reduced hippocampal BDNF levels accompanied by cognitive (learning) impairment (Shiromani, 1988; Shiromani, 1991; Overstreet, 1993). Flinders Resistant Line (FRL) rats were used as control (healthy) rats. Rats were treated with daily SC injections of ketamine (10 mg / kg) as a positive control, CLP1 (administered at 0.2 mg / kg or 2 mg / kg), or CPX (administered at 13 mg / kg) in 4.38 mM L-His, 140 mM NaCl, 0.2% Tween-20, and 1500 IU hyaluronidase (pH 6.15) for 8 days.

[0233] (Molecular analysis of BDNF levels) Each rat was anesthetized with pentobarbital, then sacrificed by cervical dislocation, and striatal, hippocampal, and cortical tissues were dissected and flash frozen in floating nitrogen. Tissue samples were dissolved in RIPA buffer containing cOmplete protease inhibitor cocktail in a TissueLyser, and BDNF levels were examined by Western blotting. Hippocampal BDNF levels are shown in Figure 15. As expected, FSL rats showed significantly lower BDNF levels than wild-type control rats (FRL, p=0.041). Rats treated with both doses of CLP1 showed increased hippocampal BDNF levels, but 2 mg / kg completely restored these to normal levels (p=0.0147). CPX appeared to have a more limited effect compared to vehicle, but this was not significant. This indicates the potential therapeutic value of CLP1 in restoring BDNF levels in patients suffering from depression.

[0234] Example 15: CLP1 increases wakefulness in a rat model of depression (Wistar Kyoto) We assessed the therapeutic potential of CLP1 in the Wistar Kyoto (WKY) rat model of depression, characterized by increased anxiety and depression-like behaviors, which has been shown to display abnormal sleep-wake characteristics often associated with depression, including EEG- and EMG-measurable parameters such as decreased wakefulness and increased REM and non-REM sleep (nREM) (Dugovic, 2000).

[0235] EEG and EMG were evaluated in WKY rats treated with 0.2 mg / kg or 2 mg / kg CLP1 after a single injection in 4.38 mM L-His, 140 mM NaCl, 0.2% Tween-20, and 1500 IU hyaluronidase (pH 6.15). The N-methyl-D-aspartate receptor antagonist ketamine (10 mg / kg) was used as a positive control. All rats received all treatments 2 h after the onset of the light phase in a pseudorandomized crossover design with a minimum of 3 days between treatments. Rats were individually placed in recording boxes and sleep-wake behavior was recorded for 24 h. EEG / EMG signals were amplified, analog-filtered (0.5–100 Hz), digitally processed (500 Hz), and then digitally filtered (EEG: 0.5–100 Hz and EMG: 70–100 Hz). EEG / EMG recordings were semi-automatically scored using SleepSign as 10-s periods of wakefulness, non-REM sleep (NREM), or REM sleep. Sleep stages were defined as follows: [Table 9]

[0236] EEG and EMG recordings at 0–3 and 11–12 hours post-administration are shown in Figure 16; all other time points were excluded as no differences were observed between treated and control rats. As expected, ketamine increased wakefulness at the expense of REM and NREM sleep at 0–3 hours post-administration (Figure 16A, Figure 16C, and Figure 16E). A similar trend was seen for ketamine at 11–12 hours post-administration (where the dark phase onset begins and thus the time point at which rodents become active). CLP1 similarly increased wakefulness and decreased REM and NREM sleep at 11–12 hours post-administration (Figure 16B, Figure 16D, and Figure 16F). This indicates the potential therapeutic effect of CLP1 for patients suffering from mood disorders such as depression.

[0237] Example 16 Brain and Plasma Stability of CLP1 Mutants The various mutants CLP2 to CLP10 and LLP1 to LLP10 prepared in Examples 1 and 2 were examined: - Mutants CLP2 to CLP6 are cyclic sequences and are characterized by up to two residue substitutions at positions 4 and / or 5 compared to CLP1. - Mutants CLP7 to CLP10 are cyclic sequences and are characterized by (i) different lipidation positions and (ii) up to two additional residue substitutions at positions 1 and / or 5 compared to CLP1. - Variants LLP1 to LLP6 are linear sequences and are characterized by up to two residue substitutions at positions 4 and / or 5 compared to CLP1. - Variants LLP7 to LLP10 are linear sequences and are characterized by (i) different lipidation positions and (ii) up to two additional residue substitutions at positions 1 and / or 5 compared to CLP1.

[0238] These mutants were tested for their stability in both mouse brain homogenates and plasma, similar to the procedures in Example 6.

[0239] As shown in Figures 17A and 17B, both the cyclic and linear cyclic peptides showed high stability in mouse plasma. The linear lipidated peptides LLP1-LLP10 showed a shorter half-life in brain homogenates than CLP1 (Figure 16C). Stability data for the cyclic lipidated peptides CLP2-CLP10 are shown in Figure 16D. Several cyclic lipidated peptides showed good stability, with CLP4, CLP5, and CLP6 exceeding the stability of CLP1.

[0240] Example 17: Effects of Mutants on CREB Target Genes The mutants CLP2-CLP10 and LLP1-LLP10 were tested for their ability to increase the CREB target genes BDNF and PGC1a. The assay was performed according to Example 3. The results are shown in Figures 18A-D. With regard to both BDNF and PGC1a expression, the most potent peptide was CLP compared to LLP. CLP10 performed better by both increasing BDNF the most and increasing PGC1a to a relatively high extent.

[0241] Example 18: CLP10 removes soluble mHTT from fibroblasts derived from Huntington's disease patients The efficacy of CLP10 in removing mutant huntingtin from patient-derived fibroblasts was evaluated in a manner similar to that described in Example 4. As shown in Figure 19A, CLP10 significantly reduced mHTT. Total HTT levels were not significantly reduced (Figure 19B).

[0242] Example 19: Pharmacokinetics of selected novel candidates The mutants CLP4, CLP5, CLP9, and CLP10, together with the reference CLP1, were selected for pharmacokinetic (PK) studies in mice. The PK studies were performed as described in Example 9.

[0243] As shown in Figures 20A-D, all novel mutants exhibited good half-life, bioavailability, and C-terminal sequence in both plasma and mouse brain after SC injection. max The values ​​were shown.

[0244] Example 20: In vivo efficacy of selected candidate compounds in wild-type mice The mutants CLP4, CLP5, CLP9, and CLP10 were evaluated for their ability to increase downstream targets of CREB after daily continuous administration (SC) to wild-type mice. This was performed similarly to the method described in Example 10. BDNF and PGC1a levels were examined by Western blotting. In addition to this, TrkB levels were evaluated to see if any changes occurred in the BDNF receptor system. CLP1 was the only peptide that significantly increased striatal BDNF levels (Figure 21B). However, all of these peptides increased PGC1a levels (Figure 21B). CLP1, together with CLP4, significantly increased TrkB levels, while no significant effect was observed for the other peptides (Figure 21C). Importantly, this indicates that none of the peptides reduced TrkB, the BDNF receptor that is important for maintaining BDNF / TrkB signaling, and interestingly, CLP1 was indeed found to enhance this system at both the ligand and receptor levels.

[0245] Example 21: Physical stability of CLP10 The physical stability of CLP10 was evaluated in the same three buffer systems as in Example 5. CLP10 did not show fibrillation in buffers at pH 6.5 and 7.5 (Figures 22B and 22C). However, CLP10 showed fibrillation at pH 4.5 (Figure 22A).

[0246] Example 22: Brain-free fraction of CLP10 The brain-free fraction of CLP10 was evaluated in mouse and human homogenates as in Example 10. In this experiment, CLP10 showed similar brain-free fractions of ∼9% in both mouse and human brain homogenates (Figures 23A and 23B).

[0247] Example 23: Pharmacokinetics of CLP10 The pharmacokinetics of CLP10 in wild-type mice was evaluated. Ten-fold serial dilutions of CLP10 (2 mg / kg, 0.2 mg / kg, and 0.02 mg / kg) were injected SC into wild-type mice (male C57BL / 6J) in 4.38 mM L-His, 140 mM NaCl, 0.2% Tween-20, and 1500 IU hyaluronidase (pH 6.15). Both plasma, whole brain, and cerebrospinal fluid concentrations were determined by LC-MS / MS at different time points from 1 to 24 hours. The procedures for plasma and brain processing were as described in Example 9.

[0248] Figure 24A (plasma) and Figure 24B (brain) show the measured concentrations of CLP10 at different time points. The concentration of CLP10 in CSF was below the lower limit of detection, therefore no results were obtained for CSF samples. CLP10 was measurable in the brain after 2 mg / kg administration, indicating that CLP10 reaches the brain and CSF after SC injection, but to a slightly lower extent than CLP1, as it was not measurable at 0.2 mg / kg. The PK parameters of CLP10 are listed below. (plasma) [Table 10] (brain) [Table 11]

[0249] Example 24: Lipidated mutants increase BDNF in vivo In further experiments, the in vivo potency of both the cyclic lipidated variant CLP11 and the linear variants LLP11 and LLP12 was examined. - Mutant CLP11 is a circular sequence and is characterized by two residue substitutions at positions 4 and 5 compared to CLP1, which correspond to a reversion from CLP1 to the native SorCS2 residues at these positions. - Mutant LLP11 is a linear sequence and is characterized by two residue substitutions at positions 4 and 5 compared to CLP1, which correspond to a reversion from CLP1 to the native SorCS2 residues at these positions. -Mutant LLP12 is a linear sequence characterized by (i) two residue substitutions at positions 4 and 5 compared to CLP1 (corresponding to a reversion from CLP1 to the native SorCS2 residues at these positions) and (ii) the inclusion of four additional residues from the native SorCS2 sequence between positions 1 and 2 of CLP1.

[0250] Experiments were performed using single subcutaneous doses of LLP11 (21 mg / kg), LLP12 (26 mg / kg), and CLP11 (21 mg / kg) administered to wild-type mice in 4.38 mM L-His, 140 mM NaCl, 0.2% Tween-20, and 1500 IU hyaluronidase (pH 6.15) as in Example 10, followed by measurement of BDNF. Time points of 4 and 8 hours were selected.

[0251] As shown in FIG. 25, all peptides produced a statistically significant increase in BDNF levels at both 4 and 8 hours.

[0252] Example 25: Identification of minimal active sequences In further experiments, we investigated the in vitro potency of a set of peptide mutants based on the native SorCS2 sequence. The goal of this in vitro potency assay was to identify the minimal sequence within the native SorCS2 sequence that had activity. The mutants included the cyclic peptides CP13-CP17. -Mutant CP13 is a non-lipidated cyclic sequence characterized by two residue substitutions at positions 4 and 5 compared to CLP1 (corresponding to a reversion from CLP1 to the native SorCS2 residues at these positions), accompanied by truncations of the N-terminal M and the C-terminal V. - Mutant CP14 is a non-lipidated cyclic sequence characterized by two residue substitutions at positions 4 and 5 compared to CLP1 (corresponding to a reversion from CLP1 to the native SorCS2 residues at these positions), accompanied by truncation of the N-terminal M and C-terminal DV. -Mutant CP15 is a non-lipidated cyclic sequence characterized by two residue substitutions at positions 4 and 5 compared to CLP1 (corresponding to a reversion from CLP1 to native SorCS2 residues at these positions), accompanied by a truncation of the N-terminal MT and C-terminal DV. -Mutant CP16 is a non-lipidated circular sequence characterized by two residue substitutions at positions 4 and 5 compared to CLP1 (corresponding to a reversion from CLP1 to native SorCS2 residues at these positions), accompanied by a truncation of the N-terminal MT and the C-terminal EDV. - Mutant CP17 is a non-lipidated cyclic sequence characterized by two residue substitutions at positions 4 and 5 compared to CLP1 (corresponding to a reversion from CLP1 to the native SorCS2 residues at these positions), accompanied by a truncation of the N-terminal MTE and the C-terminal EDV.

[0253] These mutants were tested for their ability to increase BDNF levels in primary neurons, and the experiment was performed as in Example 3, using a final concentration of 1 uM of each peptide and stimulated for 6 hours. CPX was included for comparison.

[0254] As shown in Figure 26, CP13, CP14, and CP15 significantly increased BDNF levels, whereas there was a trend for CP16 (p=0.563) and not for CP17. Excessive truncation of peptides derived from the native SorCS2 sequence reduced activity, with a length of 5 amino acids completely abolishing activity.

[0255] Example 26: Brain and plasma stability of cyclic non-lipidated variants As in Example 16, we analyzed a set of novel peptide variants with differences in the position of amino acids or amino acid substitutions around the "QI" site of CLP1 - a position stabilized compared to the native SorCS2 fragment. However, these were "naked" peptides without added lipidation. All of the novel variants were in cyclic form (cyclic peptides, CPs). These variants were tested for their stability in both mouse brain homogenate and plasma, similar to the procedure in Example 6. As shown in Figure 27B, all of these cyclic peptides showed high stability in mouse plasma. CPs with Q→P aa-substituted CLP1 sequences showed low stability in brain homogenate (CP1-CP4). This indicates that adding proline to the sequence reduces stability in mouse brain homogenate.

[0256] Example 27: In vivo efficacy of non-lipidated cyclic peptides The efficacy of the ex vivo brain stable mutants to increase CREB target genes in vivo was tested. Experiments were performed similar to Example 10 using a single subcutaneous dose of CP5-12 (13 mg / kg) administered to wild type mice in 4.38 mM L-His, 140 mM NaCl, 0.2% Tween-20, and 1500 IU hyaluronidase (pH 6.15), after which levels of BDNF, TFEB, and PGC1a were measured. The 4 hour time point was chosen.

[0257] As shown in Figure 28A, CP6, CP7, and CP10 significantly increased TFEB. CP5, CP7, and CP9 increased BDNF (Figure 28B). CP5, CP6, CP7, CP8, and CP10 significantly increased PGC1a levels (Figure 29C). In summary, peptides C5-C7 and C10 showed improvements in two of the three CREB-regulated proteins, while C7 significantly increased all three protein levels.

[0258] Example 28: Identification of amino acids important for activity In further experiments, the in vitro potency of the cyclic mutants CP18-CP22 was examined. - Mutant CP18 is a circular sequence and is characterized by four residue substitutions at positions 4 and 5 compared to CLP1 (corresponding to a reversion of CLP1 to native SorCS2 residues at these positions) and at positions 6 and 8 compared to CLP1 (an E→D residue substitution). - Mutant CP19 is a circular sequence and is characterized by four residue substitutions compared to CLP1 at positions 4 and 5 (corresponding to a reversion of CLP1 to native SorCS2 residues at these positions) and at positions 3 and 6 (E→D residue substitutions) compared to CLP1. - Mutant CP20 is a circular sequence and is characterized by three residue substitutions at positions 4 and 5 compared to CLP1 (corresponding to a reversion of CLP1 to native SorCS2 residues at these positions) and at position 3 compared to CLP1 (an E→A residue substitution). - Mutant CP21 is a circular sequence and is characterized by three residue substitutions at positions 4 and 5 compared to CLP1 (corresponding to a reversion of CLP1 to native SorCS2 residues at these positions) and at position 6 compared to CLP1 (an E→A residue substitution). - Mutant CP22 is a circular sequence and is characterized by three residue substitutions at positions 4 and 5 compared to CLP1 (corresponding to a reversion of CLP1 to native SorCS2 residues at these positions) and at position 8 compared to CLP1 (an E→A residue substitution).

[0259] To treat primary neurons, the experiment was carried out as in Example 3, using a final concentration of 1 uM of each peptide. Neurons were treated for a total of 6 hours. CPX was included as a comparison. As shown in Figure 29, none of the peptides significantly increased BDNF levels, but CP22 showed a tendency to increase BDNF levels (p=0.13).

[0260] Example 29: Evaluation of Different Lipidations for Activity In further experiments, the in vitro potency of the cyclic lipidated mutants CLP12-CLP15 was examined. - Mutant CLP12 is a cyclic sequence and is characterized by three E→D residue substitutions at positions 3, 6 and 8 compared to CLP1. - The mutant CLP13 is a cyclic sequence and is characterized by a C18-γGlu-OEG-OEG-lipid in which the diacid group on C18 has been removed compared to CLP1. - The mutant CLP14 is a cyclic sequence characterized by a C14DA-γGlu-OEG-OEG lipid whose chain length is shortened to C14 compared to CLP1. - Mutant CLP15 is a circular sequence and is characterized by a cholesterol-OEG-OEG-lipid substitution compared to CLP1.

[0261] To treat primary neurons, experiments were performed as in Example 3 using a final concentration of 1 uM of each peptide, but neurons were treated for 24 hours. As shown in Figure 30, none of the peptides significantly increased BDNF levels under the conditions tested.

[0262] Example 30: CLP1 increases GRN and rescues lysosomal defects in a GRN heterozygous mouse model of FTD CLP1 induces lysosomal biogenesis in vivo through upregulation of TFEB and subsequent transcription of lysosomal proteins such as GRN (Example 10). This provides a therapeutic rationale for using CLP1 in FTD patients with GRN haploinsufficiency. To further evaluate the therapeutic effect of CLP1 within this patient subgroup, we treated GRN heterozygous mice for 7 days and assessed both GRN levels and the lysosomal marker LAMP1 and the autophagosomal cargo protein P62. GRN haploinsufficiency leads to lysosomal dysfunction and accumulation of the lysosomal protein LAMP1 in FTD-TDP patients with GRN mutations (Gotzl, 2014). Furthermore, increased levels of P62 have been observed in FTD patient-derived fibroblasts (Aoki, 2017) and CSF of FTD patients (Rubino, 2022) as a sign of defective autophagy.

[0263] GRN heterozygous (+ / -) mice were generated by Jackson Laboratory by crossing B6(Cg)-Grntm1.1Aidi / J (PGRN KO) mice with C57BL / J wild-type mice. GRN+ / - mice (9-11 weeks old) were subcutaneously injected once daily with 0.2 mg / kg CLP1 in 4.38 mM L-His, 140 mM NaCl, 0.2% Tween-20, and 1500 IU hyaluronidase (pH 6.15). Wild-type mice were used as controls. Twelve to sixteen mice were included in each condition (n=12-16). Mice were sacrificed on day 8, 24 hours after the last injection. Cortical tissue was isolated and tissue was lysed using a TissueLyser in RIPA lysis buffer containing cOmplete and phosSTOP. The levels of GRN, p62, and LAMP1 were verified by Western blotting. All proteins were normalized to β-actin levels.

[0264] As shown in Figures 31A-C, GRN heterozygous (+ / -) mice showed a 50% reduction in GRN levels, and treatment with CLP1 significantly increased GRN levels by approximately 50% compared to vehicle-treated GRN+ / - mice (p=0.0093). Similarly, GRN heterozygous mice showed increased levels of both LAMP1 (62%) and p62 (20%), as shown in Figures 31B and 31C, respectively. Treatment with CLP1 normalized p62 levels (p=0.1156), while showing a trend toward a 40% reduction in LAMP1 levels (p=0.0268). This indicates the therapeutic potential of increasing GRN levels by CLP1, thereby resulting in a more functional lysosomal network that normalizes levels of lysosomal proteins.

[0265] Example 31: CLP1 rescues the behavioral phenotype of Huntington's disease model zQ175 The aim of this study was to measure the long-term effects of CPX and CLP1 on the zQ175DN (zQ175DN KI, B6J.zQ175DN KI with ~CAG 190) mouse model of Huntington's disease (HD) (Menalled et al., 2003) using locomotor testing and home cage analysis (HCA). zQ175 mice express a mutant mouse / human chimeric protein in the brain that is similar to normal endogenous huntingtin protein. This creates a slow-progression model that mimics human disease progression with high mHTT levels at end-stage (>1 year). Locomotor output parameters were correlated with functional and behavioral data generated from HCA.

[0266] (animal) A total of 60 zQ175DN mice (zQ175DN KI, B6J.zQ175DN KI with ~CAG 190) and 20 age-matched wild-type (WT) littermates aged 2 months were received from the CHDI Foundation and used in the experiments. All mice were housed in a temperature (22 ± 1 °C) and humidity (30–50%) controlled environment with a regular light-dark cycle (8:00–20:00). Clean bedding covering the cage floor was provided and changed as frequently as necessary to maintain dry bedding. This basic environment was enriched with the addition of a play tunnel or igloo and wooden nesting material. Food and water were available ad libitum to the mice in their home cages.

[0267] (Exam and Group Information) Experimental animals were divided into four groups: WT+vehicle, zQ175+vehicle, zQ175+CPX (13 mg / kg), and zQ175+CLP1 (0.2 mg / kg), with 20 mice per group (n=20).

[0268] Treatment was administered once daily via the subcutaneous (SC) route beginning at 3 months of age and continuing until 12 months of age. After injection, the injection site was monitored for irritation.

[0269] Body weight was measured weekly from 3 months of age until the end of the study. Behavioral tests (rotarod and beam tests) and HCA were performed at 3 months (before treatment), 6 months, 9 months, and 12 months of age.

[0270] (Rotarod) Mice were tested at 3 months (before treatment), 6 months, 9 months, and 12 months of age for two consecutive days during the day. Each daily session included a 5-minute training trial at 4 RPM on the rotarod apparatus (AccuScan Instruments, Columbus, USA). One hour later, animals were tested on three consecutive 6-minute acceleration trials, varying speed from 0 to 40 RPM over 360 seconds with at least 30 minutes between trials. The latency to fall off the rod was recorded. Mice remaining on the rod for longer than 360 seconds were removed and the time was scored as 360 seconds.

[0271] (Beam test) Mice were tested during the day at 3 months (before treatment), 6 months, 9 months, and 12 months of age. The horizontal beam test was adapted from the procedure described in Fleming, 2004. Motor performance was measured using a novel beam test adapted from the traditional beam walking test. The beam was constructed of Plexiglas and had four sections (25 cm each, 1 m in total length), each section having a different width. The beam started at 3.5 cm wide and gradually narrowed to 0.5 cm in 1 cm increments. A downward-projecting shelf (1 cm wide) was positioned 1 cm below the top surface of the beam. Animals were trained to traverse the length of the beam starting from the widest section and ending at the narrowest and most difficult section. The narrow end of the beam was directly connected to the animal's home cage. Animals received 2 days of training before testing, and all training was performed without a mesh grid. On the first day, animals received two supportive trials. This trial involved placing the animal on the beam and placing the home cage in close proximity to the animal. This encourages forward movement along the beam. After two assisted trials, the animals were able to traverse the full length of the beam unassisted. Training day 1 ended after all animals had completed the full length of the beam five times unassisted. On training day 2, animals were required to complete five trials. To further increase the difficulty, on the day of testing, a mesh grid of corresponding width (1 cm square) was placed on the beam surface with a gap of ~1 cm between the grid and the beam surface. The downward-projecting shelf provided a support or "crutch" for the animals to use when the limb slipped on the grid, allowing deficits to be assessed longitudinally so that the mice would not have to use compensatory motor strategies to complete the task. Animals were videotaped while traversing the grid-surface beam for a total of five trials.

[0272] The videotapes were viewed in slow motion and assessed by an investigator blinded to the treatment groups for errors, number of steps taken by each animal, and crossing time over five trials. An error was counted if, during forward movement, a paw (fore or hind) slipped off the grid and was visible between the grid and the beam surface. An individual animal could slip up to four times per step. By scoring each paw slip individually, the severity of the error could be measured. For example, an animal that had three paws slip off the grid during one step received an error score of 3, whereas an animal that had only one paw slip off the grid during one step received an error score of 1 for that step. No slips were counted if the animal was not moving forward or if the animal's head was pointing to the left or right of the beam. Step errors and crossing times were measured and averaged over all five trials for WT and zQ175 mice.

[0273] (Home cage analysis) 2.5-month-old zQ175 and WT mice were placed in home cages with N=4 / cage as random groups. For this monitoring, an RFID chip was introduced into each animal. Home cage monitoring was performed at 3 months (before treatment), 6 months, 9 months, and 12 months of age in 48-hour shifts. All groups of mice (n=8 per group, n=4 per sex) were home cage monitored with ActualHCA™ device for 48 hours per cage. The following parameters were measured: movement time, isolation time, periphery time, time in the core zone, climbing time, drinking time, movement speed, movement distance, isolation / separation distance, periphery distance, distance in the core zone, and body temperature. First, the parameter measurements were processed using HCA software, and then the data was visualized using Matlab software (USA).

[0274] (Tissue collection) Mice were sacrificed at the end of the study for tissue sample collection. Mice were first deeply anesthetized with a terminal dose of Zoletil, and cerebrospinal fluid (CSF) was collected from the cisterna magna into Eppendorf microtubes, frozen on dry ice, and stored at -80°C. Blood samples were collected by cardiac puncture. Whole blood was collected into heparin tubes, and plasma was separated by centrifugation (3000 rpm, 15 min) at 4°C. Separated plasma was collected into Eppendorf microtubes, frozen on dry ice, and stored at -80°C.

[0275] (Measuring neuronal 4PlexA in CSF) The concentrations of glial fibrillary acidic protein (GFAP), tubulin-associated unit (tau), neurofilament light chain protein (Nf-L), and ubiquitin C-terminal hydrolase L1 (UCH-L1) in CSF were determined using a Simoa Neuronal 4PlexA assay (cat# 102153, Quanterix). Paramagnetic carboxylated beads (Quanterix Corp, Boston, MA, USA) were coated with mouse anti-GFAP, tau, Nf-L, or UCH-L1 antibodies and incubated with samples and biotinylated mouse anti-GFAP, tau, Nf-L, or UCH-L1 antibodies for 35 min in a Simoa instrument (Quanterix). The average enzyme counts per bead (AEB) of the samples were interpolated to the calibrator curve constructed by AEB measurements.

[0276] (result) Wild-type mice gained weight throughout the study, but none of the zQ175 mice gained weight. No significant differences were observed between treated and vehicle-treated zQ175 mice (FIG. 32A), indicating that treatment does not affect body weight in this HD model.

[0277] The latency to fall from the rotarod generally decreased in all groups with increasing age (FIG. 32B). The latency to fall in vehicle-treated zQ175 tended to be lower compared to that of WT controls. At 12 months of age, the latency to fall in CLP1 and CPX-treated groups tended to be higher compared to the vehicle-treated group, but this was not statistically significant. However, this indicates a potential effect of both CLP1 and CPX on motor function.

[0278] The number of errors made during the crossing (beam test, FIG. 32C) increased with age from 9 months onwards. The number of errors made by vehicle-treated and CPX-treated zQ175 mice increased sharply from 9 to 12 months of age and was significantly higher compared to WT mice. The number of errors in CLP1-treated zQ175 mice was not significantly different from WT at 12 months of age, indicating a complete rescue in this behavioral assessment. This test is highly sensitive to indicate cortico-striatal function, a circuit underlying motor coordination and performance. This indicates a strong rescue of cortico-striatal pathology by CLP1 in HD disease and may be relevant in other disorders.

[0279] Using multiple parameters measured in the home cage analysis (HCA), a principal component analysis (PCA) was constructed (Figure 32D), and to provide a global overview of HCA, groups were classified into WT-like or knock-in (KI)-like phenotypes based on hierarchical dendrogram analysis (Figure 32E).

[0280] Based on PCA, no striking patterns were observed until 12 months of age, at which time vehicle-treated zQ175 mice were clearly distinguished from both WT and CPX- and CLP1-treated zQ175 mice. In PCA, CLP1-treated zQ175 mice clustered above WT mice, exhibiting identical behavior to WT mice, while CPX-treated zQ175 mice clustered closely with WT mice, suggesting nearly identical behavior. Similarly, at 12 months of age, CPX- and CLP1-treated zQ175 mice clustered with WT controls as a WT-like phenotype in hierarchical dendrogram analysis (p=0.01). Individual behavioral parameters of both CPX- and CLP1-treated mice versus WT and zQ175 vehicle groups are shown in Figure 32F and Figure 32G. Taken together, treatment with CPX and CLP1 in HD mice completely rescued the phenotype measured across 12 different behavioral parameters in HCA, demonstrating a strong therapeutic effect of both CPX and CLP1 in this HD mouse model.

[0281] Finally, the concentration of Nf-L in the CSF was measured (Figure 32H). NfL was significantly elevated in the zQ175 group compared to the WT control group. However, NfL concentrations in the treated groups tended to be lower compared to zQ175 with vehicle treatment. NfL is a clinically proven biomarker of CSF in HD patients. This indicates the possibility of using NfL as a biomarker in humans to evaluate the efficacy of CLP1 and CPX. No significant effect was observed on other markers of GFAP, tau, and UCH-L1 (data not shown).

[0282] Example 32: CLP1 increases GBA in human iPSC-derived dopaminergic neurons GBA1 encodes a lysosomal protein important for the key functions of lysosomes: lipid degradation and cell membrane turnover. Monoallelic mutations in GBA1 are found in 5–20% of sporadic PD cases, making it the most common (known) genetic risk factor for PD. Mutations within GBA1 increase the risk of developing PD by 20–30 fold (Stoker et al., 2018). Furthermore, biallelic mutations in the GBA1 gene are known to cause the lysosomal disorder Gaucher disease (GD). Interestingly, GBA1 mutations result in protein variants of GCase (the protein product of the GBA1 gene) that are more prone to degradation, loss of activity, or mis-transport leading to depletion of GCase in the lysosomal compartment (Do et al., 2019).

[0283] TFEB has been shown to not only promote GBA1 expression but also enhance GCase folding and trafficking (Song et al., 2013). Therefore, we evaluated whether treatment with CLP1 could increase GCase levels as a potential therapeutic approach for both GD and PD.

[0284] To assess this, human induced pluripotent stem cells (DANi001-C) were reprogrammed and cultured according to a previous protocol (Chen, 2020). Culture was continued for 95 days, resulting in differentiation of hIPSCs into midbrain dopaminergic neurons. On day 95, six of the neuronal organoids were treated with either vehicle or CLP1 (n=6) for 4 hours and then lysed in RIPA buffer. Levels of TFEB and GBA were verified by Western blotting with β-actin as a loading control.

[0285] As shown in Figure 33A, stimulation with CLP1 increased TFEB by 125% (p=0.02) and GCase levels by 25% (p=0.013) in Figure 33B. Taken together, this establishes that CLP1 does indeed exhibit biological activity in human dopaminergic neurons, particularly those affected in PD, in addition to enhancing its therapeutic potential in PD patients with GBA1 mutations and those suffering from GD.

[0286] Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", are understood to imply the inclusion of a stated integer, step, group of integers, or group of steps, but not the exclusion of any other integer, step, group of integers, or group of steps.

[0287] This application, which forms part of the description and claims, may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form of products, compositions, processes, or uses and may include, by way of example and without limitation, the following claims:

[0288] (References list) [Table 12] TIFF2025506481000128.tif242170TIFF2025506481000129.tif241170TIFF2025506481000130.tif93170

Claims

1. array: 【Chemistry 1】 (where: X 2 represents P, D, Q, K, and G, X 3 stands for I, L, A, T, V, X 4 represents E and A) a lipidated cyclic peptide or a salt thereof, or a conservatively substituted variant of said peptide or said salt, comprising: array: 【Chemistry 2】 (where: X 2 represents P, D, Q, K, and G, X 3 stands for I, L, A, T, V, X 4 represents E and A, where X 2 If represents P, then X 3 is something other than V) a cyclic peptide or a salt thereof, or a conservatively substituted variant of said peptide or said salt, comprising: Contains 10 or fewer amino acid residues in the ring and has the sequence: 【Transformation 3】 (where: X 2 represents P, D, Q, K, and G, X 3 stands for I, L, A, T, V, X 4 represents E and A) a cyclic peptide or a salt thereof, or a conservatively substituted variant of said peptide or said salt, comprising: array: 【Chemistry 4】 (where: X 2 represents P, D, Q, K, and G, X 3 stands for I, L, A, T, V, X 4 represents E and A) a lipidated linear peptide or a salt thereof, or a conservatively substituted variant of said peptide or said salt, comprising: array: 【Transformation 5】 (where: X 2 represents P, D, Q, K, and G, X 3 stands for I, L, A, T, V, X 4 represents E and A, where X 2 If represents P, then X 3 is something other than V) or a conservatively substituted variant of said peptide or said salt; Contains 10 or fewer amino acid residues in the backbone and has the sequence: 【Transformation 6】 (where: X 2 represents P, D, Q, K, and G, X 3 stands for I, L, A, T, V, X 4 represents E and A) or a salt thereof, or a conservatively substituted variant of said peptide or said salt, comprising:

2. array: 【Transformation 7】 (where: X 2 represents P, D, Q, K, and G, X 3 stands for I, L, A, T, V, X 4 represents E and A) 2. The lipidated cyclic peptide or salt thereof according to claim 1, or a conservatively substituted variant of said peptide or salt thereof, comprising:

3. array: 【Transformation 8】 (where: X 2 represents P, D, Q, K, and G, X 3 stands for I, L, A, T, V, X 4 represents E and A) 3. The lipidated cyclic peptide or salt thereof according to claim 2, wherein the peptide comprises 15 or fewer amino acid residues in the ring, is backbone cyclized, and all residues of the peptide backbone are connected only by peptide bonds.

4. 4. The lipidated cyclic peptide of claim 3, wherein the lipid is C18DA-γGlu-OEG-OEG-. 【Request Item 5】 【Table 1】 3. The lipidated cyclic peptide or salt thereof according to claim 2, wherein the cyclic peptide is backbone cyclized and all residues of the peptide backbone are connected only by peptide bonds.

6. formula: 【Chemistry 9】 The peptide CLP1 is represented by: 【Chemistry 10】 (where, ＊ 6. The lipidated cyclic peptide or a salt thereof according to claim 5, wherein the peptide is backbone cyclized and all residues of the peptide backbone are connected only by peptide bonds.

7. Peptide CLP1: 【Chemistry 11】 (where, ＊ 7. The lipidated cyclic peptide or a salt thereof according to claim 6, wherein the peptide is backbone cyclized and all residues of the peptide backbone are connected only by peptide bonds.

8. Peptide CLP1: 【Chemistry 12】 (where, ＊ 7. The lipidated cyclic peptide or a salt thereof according to claim 6, wherein the peptide is backbone cyclized and all residues of the peptide backbone are connected only by peptide bonds.

9. Peptide CLP10: 【Chemistry 13】 (where, ＊ 6. The lipidated cyclic peptide or a salt thereof according to claim 5, wherein the peptide is backbone cyclized and all residues of the peptide backbone are connected only by peptide bonds.

10. Peptide CLP10: 【Chemistry 14】 (where, ＊ 10. The lipidated cyclic peptide or a salt thereof according to claim 9, wherein the peptide is backbone cyclized and all residues of the peptide backbone are connected only by peptide bonds.

11. Peptide CLP10: 【Chemistry 15】 (where, ＊ 10. The lipidated cyclic peptide or a salt thereof according to claim 9, wherein the peptide is backbone cyclized and all residues of the peptide backbone are connected only by peptide bonds.

12. array: 【Chemistry 16】 (where: X 2 represents P, D, Q, K, and G, X 3 stands for I, L, A, T, V, X 4 represents E and A, where X 2 If represents P, then X 3 is something other than V) 2. The cyclic peptide or salt thereof according to claim 1, or a conservatively substituted variant of said peptide or salt, comprising:

13. array: 【Chemistry 17】 (where: X 2 represents P, D, Q, K, and G, X 3 stands for I, L, A, T, V, X 4 represents E and A, where X 2 If represents P, then X 3 is something other than V) 13. The cyclic peptide or salt thereof according to claim 12, wherein the peptide contains 15 or fewer amino acid residues in the ring, is backbone cyclized, and all residues of the peptide backbone are connected only by peptide bonds. 【Request Item 14】 【Table 2】 13. The cyclic peptide or salt thereof according to claim 12, wherein the peptide is backbone cyclized and all residues of the peptide backbone are connected only by peptide bonds.

15. Contains 10 or fewer amino acid residues in the ring and has the sequence: [Chemistry 18] (where: X 2 represents P, D, Q, K, and G, X 3 stands for I, L, A, T, V, X 4 represents E and A) 2. The cyclic peptide or salt thereof according to claim 1, or a conservatively substituted variant of said peptide or said salt, comprising:

16. array: 【Chemistry 19】 (where: X 2 represents P, D, Q, K, and G, X 3 stands for I, L, A, T, V, X 4 represents E and A) 16. The cyclic peptide or salt thereof according to claim 15, comprising: wherein the peptide is backbone cyclized and all residues of the peptide backbone are connected only by peptide bonds. 【Request Item 17】 【Table 3】 16. The cyclic peptide or salt thereof according to claim 15, wherein the peptide is backbone cyclized and all residues of the peptide backbone are connected only by peptide bonds.

18. array: 【Chemistry 20】 (where: X 2 represents P, D, Q, K, and G, X 3 stands for I, L, A, T, V, X 4 represents E and A) 2. The lipidated linear peptide or salt thereof of claim 1, or a conservatively substituted variant of said peptide or salt thereof, comprising:

19. array: 【Chemistry 21】 (where: X 2 represents P, D, Q, K, and G, X 3 stands for I, L, A, T, V, X 4 represents E and A) 19. The lipidated linear peptide or salt thereof according to claim 18, comprising:

20. 20. The lipidated linear peptide of claim 19, wherein the lipid is C18DA-γGlu-OEG-OEG-. 【Request Item 21】 【Table 4】 19. The lipidated linear peptide or salt thereof according to claim 18, wherein all residues of the backbone of the peptide are connected only by peptide bonds.

22. array: 【Chemistry 22】 (where: X 2 represents P, D, Q, K, and G, X 3 stands for I, L, A, T, V, X 4 represents E and A, where X 2 If represents P, then X 3 is something other than V) 2. The linear peptide or salt thereof according to claim 1, or a conservatively substituted variant of said peptide or said salt, comprising:

23. array: 【Chemistry 23】 (where: X 2 represents P, D, Q, K, and G, X 3 stands for I, L, A, T, V, X 4 represents E and A, where X 2 If represents P, then X 3 is something other than V) 23. The linear peptide or salt thereof according to claim 22, comprising: wherein the peptide comprises 15 or fewer amino acid residues, and all residues in the backbone of the peptide are connected only by peptide bonds.

24. array: 【Chemistry 24】 23. The linear peptide or salt thereof according to claim 22, (where (i): X 2 represents P, D, Q, K, and G, X 3 stands for I, L, A, T, V, X 4 represents E and A, the linear peptide comprises 10 or more amino acid residues in the backbone; and / or where (ii): X 2 represents P, D, Q, K, and G, X 3 represents I, L, A, and V, X 4 represents E, A; or X 2 represents P, D, Q, K, and G, X 3 stands for I, L, A, T, V, X 4 represents E) A linear peptide or a salt thereof, wherein all residues of the peptide backbone are connected only by peptide bonds.

25. Contains 10 or fewer amino acid residues in the backbone and has the sequence: 【Chemistry 25】 (where: X 2 represents P, D, Q, K, and G, X 3 stands for I, L, A, T, V, X 4 represents E and A) 2. The linear peptide or salt thereof according to claim 1, or a conservatively substituted variant of said peptide or said salt, comprising:

26. array: 【Chemistry 26】 (where: X 2 represents P, D, Q, K, and G, X 3 stands for I, L, A, T, V, X 4 represents E and A) 26. The linear peptide or salt thereof according to claim 25, comprising: wherein all residues of the backbone of the peptide are connected only by peptide bonds.

27. array: 【Chemistry 27】 26. The linear peptide or salt thereof according to claim 25, (where (i): X 2 represents P, D, Q, K, and G, X 3 stands for I, L, A, T, V, X 4 represents E and A, the linear peptide comprises 10 or more amino acid residues in the backbone; and / or where (ii): X 2 represents P, D, Q, K, and G, X 3 represents I, L, A, and V, X 4 represents E, A; or X 2 represents P, D, Q, K, and G, X 3 stands for I, L, A, T, V, X 4 represents E) A linear peptide or a salt thereof, wherein all residues of the peptide backbone are connected only by peptide bonds.

28. 28. Use of a peptide according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament.

29. 29. Use according to claim 28 in the manufacture of a medicament for the treatment or prevention of Alzheimer's disease, Huntington's disease, Parkinson's disease, frontotemporal dementia, or depression.

30. 30. Use according to claim 29 in the manufacture of a medicament for the treatment or prevention of Huntington's disease.

31. 30. Use according to claim 29 in the manufacture of a medicament for the treatment or prevention of Parkinson's disease.

32. 18. A protected cyclic peptide or a salt thereof, comprising the lipidated or non-lipidated cyclic peptide of any one of claims 1 to 17, wherein at least one reactive group (e.g., an amino acid side chain) is protected.

33. 28. A protected linear peptide or a salt thereof comprising the lipidated or non-lipidated linear peptide of any one of claims 18 to 27, wherein at least one reactive group is protected.

34. 18. A linear peptide or a salt thereof which, when cyclized, provides the lipidated or non-lipidated cyclic peptide of any one of claims 1 to 17.

35. 33. A protected linear peptide or a salt thereof which, when cyclized, provides the protected cyclic peptide of claim 32.

36. 27. The lipidated cyclic peptide of any one of claims 1 to 11, the cyclic peptide of any one of claims 12 to 17, the lipidated linear peptide of any one of claims 18 to 21, the linear peptide of any one of claims 22 to 27, or a protected version thereof, which is covalently attached to a solid support.

37. A method for producing a lipidated cyclic peptide according to any one of claims 1 to 11, comprising: (i) preparing a lipidated linear peptide having the appropriate amino acid sequence (optionally protected); and (ii) then generating a cyclized peptide (optionally protected) from the linear peptide (optionally protected); and (iii) a step of deprotecting the compound, if necessary. The method comprising:

38. A method for producing the cyclic peptide of any one of claims 12 to 17, comprising: (i) preparing a linear peptide having the appropriate amino acid sequence (optionally protected); and (ii) then generating a cyclized peptide (optionally protected) from the linear peptide (optionally protected); and (iii) a step of deprotecting the compound, if necessary. The method comprising:

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