An analog peptide compound (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide in the treatment of neurodegenerative disorders

Abstract

The present invention provides new methods of treating or preventing amyotrophic lateral sclerosis (ALS), delaying the onset of ALS-related neurological symptoms, improving survival in subjects with ALS, and reducing ALS-related muscle strength decline in patients in need thereof. The present invention also provides methods of treating or preventing alpha- synucleinopathies or TDP-43 proteinopathies. These methods comprise administering to a subject an effective amount of a mitochondrially-targeted mimetic peptide compound, such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-xylyl)-1-oxopropan-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof.

Description

[0001] Cross-referencing of related patent applications

[0002] This application claims the priority benefit of U.S. Patent Application No. 62 / 878,272, filed July 24, 2019, and U.S. Patent Application No. 63 / 046,292, filed June 30, 2020, the entire contents of which are incorporated herein by reference and are part of this invention. Technical Field

[0003] This invention generally relates to compositions and methods for improving or treating amyotrophic lateral sclerosis (ALS). It also generally relates to compositions and methods for improving or treating other neurodegenerative disorders, such as α-connucleopathies or TDP-43 proteinopathies, including frontotemporal degeneration (FTLD), Parkinson's disease (PD), PD with dementia, Lewy body dementia, or multiple system atrophy. Furthermore, this invention relates to administering an effective amount of a mitochondrial-targeting mimic peptide compound, such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof, to a subject suffering from ALS, α-connucleopathies, or TDP-43 proteinopathies. Background Technology

[0004] The following description is provided to aid the reader's understanding. The information or references provided are not prior art to the compositions and methods disclosed in this invention.

[0005] Neurodegenerative diseases and disorders affect physical activities such as balance, movement, speech, breathing, and / or cardiac function. Neurodegenerative diseases and disorders are often incurable and debilitating, leading to progressive degeneration and / or death of nerve cells. Some examples of neurodegenerative diseases and disorders include: amyotrophic lateral sclerosis (ALS), frontotemporal degeneration (FTLD), Parkinson's disease (PD), PD with dementia, Lewy body dementia, or multiple system atrophy (MSA). Some neurodegenerative diseases can manifest as alpha-comonopathies or TDP-43 proteinopathies.

[0006] Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that causes the death of motor neurons in the brain and spinal cord. This disorder typically develops in middle age and usually leads to paralysis and death within three to five years of diagnosis. Up to 10% of ALS cases are familial, and it is usually inherited in an autosomal dominant pattern. Several pathogenic genes are known, the most common being mutant superoxide dismutase 1 (SOD1) and mutant C9orf72 (i.e., the G4C2 hexanucleotide repeat sequence in the C9orf72 gene). Mutations in the TARDBP gene that modify TAR DNA-binding protein 43 (TDP-43) can also cause familial ALS (see Sreedharan et al., Science (2008), 319(5870): 1668-1672). Currently, there are no effective treatments for ALS. Therefore, there is a need in the field to develop treatment strategies for ALS. Summary of the Invention

[0007] On one hand, the present invention provides a method for treating or preventing amyotrophic lateral sclerosis (ALS) or frontotemporal degeneration (FTLD) in a subject of need, comprising administering to the subject a therapeutically effective amount of a mimic peptide, such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof.

[0008] In some embodiments, the subject is diagnosed with ALS or FTLD. In some embodiments, the ALS is familial ALS. In some embodiments, the familial ALS is caused by TAR DNA-binding protein (TDP-43) modification due to mutations in the superoxide dismutase 1 (SOD1) gene or the TARDBP gene.

[0009] In some embodiments, the mimic peptide is administered daily for 2 weeks or more. In some embodiments, the mimic peptide is administered daily for 12 weeks or more.

[0010] In some embodiments, the treatment or prevention includes treating or preventing one or more signs or symptoms of ALS or FTLD, including muscle weakness, muscle wasting (atrophy), fasciculations, muscle spasms, bradykinesia, poor balance, incoordination, voice quality changes, dysarthria, dysphagia, incomplete eyelid closure, drooling, pseudobulbar mood, premature death, and increased expression of brain transporter-18kDa (TSPO). In some embodiments, the treatment or prevention includes treating or preventing plasma accumulation of neurofilament light chains (NfL). In some embodiments, the treatment or prevention includes demonstrating improved neurite length (e.g., increased length) in treated subjects compared to subjects not treated with the mimic peptide. In some embodiments, the treatment or prevention includes prolonging the lifespan of treated subjects compared to subjects not treated with the mimic peptide. In some embodiments, the treatment or prevention includes protecting the central nervous system (CNS) from axonal damage. In some embodiments, the treatment or prevention includes delaying the progression of neurological symptoms in treated subjects compared to subjects not treated with the mimic peptide.

[0011] In some embodiments, the subject is a human. In some embodiments, the mammalian subject is a human.

[0012] In some embodiments, the mimic peptide is administered orally. In some embodiments, the subject is administered subcutaneously. In some embodiments, the mimic peptide may be administered topically, intranasally, systemically, intravenously, intraperitoneally, intradermally, intraocularly, intrathecally, intraventricularly, via iontophoresis, through mucous membranes, intravitreal cavity, or intramuscularly.

[0013] In some embodiments, the method further includes administering other treatments to the subject, alone, sequentially, or simultaneously. In some embodiments, the other treatments include administering a therapeutic agent. In some embodiments, the therapeutic agent is selected from the group consisting of riluzole. Idaravon Mecaserine, Baclofen stable Danqulin Nonsteroidal anti-inflammatory drugs (NSAIDs) and anticonvulsants (e.g., carbamazepine) or phenytoin Amitriptyline nortriptyline (Pamelor) TM ) and chlorohydroxynordiazepoxide In some embodiments, the therapeutic agent is elamipretide (also known as SS-31 or bendavia). In some embodiments, the combination of the mimic peptide and other treatments has a synergistic effect in the prevention or treatment of ALS or FTLD.

[0014] In some embodiments, the pharmaceutically acceptable salts of the mimic peptide include tartrate, fumarate, citrate, benzoate, succinate, octanoate, lactate, oxalate, phthalate, methanesulfonate, benzenesulfonate, or maleate (in different cases, monohydrochloride, dihydrochloride, or trihydrochloride, respectively). In some embodiments, the pharmaceutically acceptable salts include tartrate, fumarate, monoacetate, diacetate, triacetate, monotrifluoroacetate, ditrifluoroacetate, trifluoroacetate, monohydrochloride, dihydrochloride, trihydrochloride, monotoluenesulfonate, ditoluenesulfonate, or tritoluenesulfonate. In some embodiments, the mimic peptide is formulated as a trihydrochloride, dihydrochloride, or monohydrochloride.

[0015] On one hand, the present invention provides the use of the composition in the preparation of a medicament for the treatment or prevention of amyotrophic lateral sclerosis (ALS) or frontotemporal degeneration (FTLD) in subjects of need, wherein the composition comprises a therapeutically effective amount of a mimic peptide, such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof.

[0016] In some embodiments, the subject is diagnosed with ALS or FTLD. In some embodiments, the ALS is familial ALS. In some embodiments, the familial ALS is caused by TAR DNA-binding protein (TDP-43) modification due to mutations in the superoxide dismutase 1 (SOD1) gene or the TARDBP gene.

[0017] In some embodiments, the mimic peptide is intended to be administered daily for 2 weeks or more. In some embodiments, the mimic peptide is intended to be administered daily for 12 weeks or more.

[0018] In some embodiments, the treatment or prevention includes treating or preventing one or more signs or symptoms of ALS or FTLD, including muscle weakness, muscle wasting (atrophy), fasciculations, muscle spasms, bradykinesia, poor balance, incoordination, voice quality changes, dysarthria, dysphagia, incomplete eyelid closure, drooling, pseudobulbar mood, premature death, and increased expression of brain transporter-18kDa (TSPO). In some embodiments, the treatment or prevention includes treating or preventing plasma accumulation of neurofilament light chains (NfL). In some embodiments, the treatment or prevention includes demonstrating improved neurite length (e.g., increased length) in treated subjects compared to subjects not treated with the mimic peptide. In some embodiments, the treatment or prevention includes prolonging the lifespan of treated subjects compared to subjects not treated with the mimic peptide. In some embodiments, the treatment or prevention includes protecting the central nervous system (CNS) from axonal damage. In some embodiments, the treatment or prevention includes delaying the progression of neurological symptom onset in treated subjects compared to subjects not treated with the mimic peptide.

[0019] In some embodiments, the subject is a human. In some embodiments, the mammalian subject is a human.

[0020] In some embodiments, the mimic peptide is formulated for oral administration. In some embodiments, the mimic peptide is formulated for subcutaneous administration. In some embodiments, the mimic peptide is formulated for local, intranasal, systemic, intravenous, peritoneal, intradermal, intraocular, ocular, intrathecal, intraventricular, iontophoresis, mucosal, intravitreal, or intramuscular administration.

[0021] In some embodiments, the mimetic peptide is intended to be used alone, sequentially, or simultaneously with other treatments. In some embodiments, the other treatments include the use of therapeutic agents. In some embodiments, the therapeutic agent is selected from a group including riluzole. Idaravon Mecaserine, Baclofen stable Danqulin Nonsteroidal anti-inflammatory drugs (NSAIDs) and anticonvulsants (e.g., carbamazepine) or phenytoin Amitriptyline nortriptyline (Pamelor) TM ) and chlorohydroxynordiazepoxide In some embodiments, the therapeutic agent is elamipretide (also known as SS-31 or bendavia). In some embodiments, the combination of the mimic peptide and other treatments has a synergistic effect in the prevention or treatment of ALS or FTLD.

[0022] In some embodiments, the pharmaceutically acceptable salts include tartrates, fumarates, citrates, benzoates, succinates, octanoates, lactates, oxalates, phthalates, methanesulfonates, benzenesulfonates, or maleates (in different cases, monohydrochlorides, dihydrochlorides, or trihydrochlorides, respectively). In some embodiments, the pharmaceutically acceptable salts include tartrates, fumarates, monoacetates, diacetates, triacetates, monotrifluoroacetates, ditrifluoroacetates, trifluoroacetates, monohydrochlorides, ditrifluoroacetates, trihydrochlorides, monotoluenesulfonates, ditoluenesulfonates, or tritoluenesulfonates. In some embodiments, the mimetic peptide is formulated as a trihydrochloride, dihydrochloride, or monohydrochloride.

[0023] On one hand, the present invention provides a mimicry peptide for the treatment or prevention of amyotrophic lateral sclerosis (ALS) or frontotemporal degeneration (FTLD) in subjects of need, such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof.

[0024] In some embodiments, the subject is diagnosed with ALS or FTLD. In some embodiments, the ALS is familial ALS. In some embodiments, the familial ALS is caused by TAR DNA-binding protein (TDP-43) modification due to mutations in the superoxide dismutase 1 (SOD1) gene or the TARDBP gene.

[0025] In some embodiments, the mimic peptide is intended to be administered daily for 2 weeks or more. In some embodiments, the mimic peptide is intended to be administered daily for 12 weeks or more.

[0026] In some embodiments, the treatment or prevention includes treating or preventing one or more signs or symptoms of ALS or FTLD, including muscle weakness, muscle wasting (atrophy), fasciculations, muscle spasms, bradykinesia, poor balance, incoordination, voice quality changes, dysarthria, dysphagia, incomplete eyelid closure, drooling, pseudobulbar mood, premature death, and increased expression of brain transporter-18kDa (TSPO). In some embodiments, the treatment or prevention includes treating or preventing plasma accumulation of neurofilament light chains (NfL). In some embodiments, the treatment or prevention includes demonstrating improved neurite length (e.g., increased length) in treated subjects compared to subjects not treated with the mimic peptide. In some embodiments, the treatment or prevention includes prolonging the lifespan of treated subjects compared to subjects not treated with the mimic peptide. In some embodiments, the treatment or prevention includes protecting the central nervous system (CNS) from axonal damage. In some embodiments, the treatment or prevention includes delaying the progression of neurological symptoms in treated subjects compared to subjects not treated with the mimic peptide.

[0027] In some embodiments, the subject is a human. In some embodiments, the mammalian subject is a human.

[0028] In some embodiments, the mimic peptide is formulated for oral administration. In some embodiments, the mimic peptide is formulated for subcutaneous administration. In some embodiments, the mimic peptide is formulated for local, intranasal, systemic, intravenous, peritoneal, intradermal, intraocular, ocular, intrathecal, intraventricular, iontophoresis, mucosal, intravitreal, or intramuscular administration.

[0029] In some embodiments, the mimetic peptide is intended to be used alone, sequentially, or simultaneously with other treatments. In some embodiments, the other treatments include the use of therapeutic agents. In some embodiments, the therapeutic agent is selected from several of the following: riluzole ( Idaravon Mecaserine, Baclofen stable Danqulin Nonsteroidal anti-inflammatory drugs (NSAIDs) and anticonvulsants (e.g., carbamazepine) or phenytoin Amitriptyline nortriptyline (Pamelor) TM ) and chlorohydroxynordiazepoxide In some embodiments, the therapeutic agent is elamipretide (also known as SS-31 or bendavia). In some embodiments, the combination of the mimic peptide and other treatments has a synergistic effect in the prevention or treatment of ALS or FTLD.

[0030] In some embodiments, the pharmaceutically acceptable salts include tartrates, fumarates, citrates, benzoates, succinates, octanoates, lactates, oxalates, phthalates, methanesulfonates, benzenesulfonates, or maleates (in different cases, monohydrochlorides, dihydrochlorides, or trihydrochlorides, respectively). In some embodiments, the pharmaceutically acceptable salts include tartrates, fumarates, monoacetates, diacetates, triacetates, monotrifluoroacetates, ditrifluoroacetates, trifluoroacetates, monohydrochlorides, ditrifluoroacetates, trihydrochlorides, monotoluenesulfonates, ditoluenesulfonates, or tritoluenesulfonates. In some embodiments, the mimetic peptide is formulated as a trihydrochloride, dihydrochloride, or monohydrochloride.

[0031] On one hand, the present invention provides a method for treating or preventing α-connuclear disease or TDP-43 proteinopathy in a subject of need, comprising administering to the subject a therapeutically effective amount of a mimic peptide, such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof. In some embodiments, the subject is diagnosed with α-connuclear disease or TDP-43 proteinopathy.

[0032] In some embodiments, the α-commonoprotein disease is Parkinson's disease (PD), PD with dementia, Lewy body dementia, or multiple system atrophy, and the TDP-43 protein disease is amyotrophic lateral sclerosis (ALS) or frontotemporal degeneration (FTLD).

[0033] In some embodiments, the mimic peptide is administered daily for 2 weeks or more. In some embodiments, the mimic peptide is administered daily for 12 weeks or more.

[0034] In some embodiments, the treatment or prevention of α-commonoproteinopathy includes reducing the loss of dopaminergic neurons in the subject compared to an untreated control. In some embodiments, the treatment or prevention of TDP-43 proteinopathy includes improving (e.g., increasing) neurite length in the subject compared to an untreated control.

[0035] In some embodiments, the subject is a human. In some embodiments, the mammalian subject is a human.

[0036] In some embodiments, the mimic peptide is administered orally. In some embodiments, the subject is administered subcutaneously. In some embodiments, the mimic peptide may be administered topically, intranasally, systemically, intravenously, intraperitoneally, intradermally, intraocularly, intrathecally, intraventricularly, via iontophoresis, through mucous membranes, intravitreal cavity, or intramuscularly.

[0037] In some embodiments, the method further includes administering other treatments to the subject, alone, sequentially, or simultaneously. In some embodiments, the other treatments include administering therapeutic agents. In some embodiments, the therapeutic agents include levodopa for treating alpha-connucleoproteinopathy, and the therapeutic agents include selective serotonin reuptake inhibitors (SSRIs) antidepressants for treating TDP-43 proteinopathy. In some embodiments, combinations of mimic peptides and other therapeutic treatments have a synergistic effect in the prevention or treatment of alpha-connucleoproteinopathy or TDP-43 proteinopathy.

[0038] In some embodiments, the pharmaceutically acceptable salts include tartrates, fumarates, citrates, benzoates, succinates, octanoates, lactates, oxalates, phthalates, methanesulfonates, benzenesulfonates, or maleates (in different cases, monohydrochlorides, dihydrochlorides, or trihydrochlorides, respectively). In some embodiments, the pharmaceutically acceptable salts include tartrates, fumarates, monoacetates, diacetates, triacetates, monotrifluoroacetates, ditrifluoroacetates, trifluoroacetates, monohydrochlorides, ditrifluoroacetates, trihydrochlorides, monotoluenesulfonates, ditoluenesulfonates, or tritoluenesulfonates. In some embodiments, the mimetic peptide is formulated as a trihydrochloride, dihydrochloride, or monohydrochloride.

[0039] On one hand, the present invention provides the use of the composition in the preparation of a medicament for treating or preventing α-connucleoproteinopathy or TDP-43 proteinopathy in subjects of need, wherein the composition comprises a therapeutically effective amount of a mimic peptide, such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof.

[0040] In some embodiments, the subject is diagnosed with α-commonoprotein disease or TDP-43 protein disease. In some embodiments, the α-commonoprotein disease is Parkinson's disease (PD), PD with dementia, Lewy body dementia, or multiple system atrophy, and the TDP-43 protein disease is amyotrophic lateral sclerosis (ALS) or frontotemporal degeneration (FTLD).

[0041] In some embodiments, the mimic peptide is intended to be administered daily for 2 weeks or more. In some embodiments, the mimic peptide is intended to be administered daily for 12 weeks or more.

[0042] In some embodiments, the treatment or prevention of α-commonoproteinopathy includes reducing the loss of dopaminergic neurons in the subject compared to an untreated control. In some embodiments, the treatment or prevention of TDP-43 proteinopathy includes improving (e.g., increasing) neurite length in the subject compared to an untreated control.

[0043] In some embodiments, the subject is a human. In some embodiments, the mammalian subject is a human.

[0044] In some embodiments, the mimic peptide is formulated for oral administration. In some embodiments, the mimic peptide is formulated for subcutaneous administration. In some embodiments, the mimic peptide is formulated for local, intranasal, systemic, intravenous, peritoneal, intradermal, intraocular, ocular, intrathecal, intraventricular, iontophoresis, mucosal, intravitreal, or intramuscular administration.

[0045] In some embodiments, the use further includes administering other treatments to the subject, alone, sequentially, or simultaneously. In some embodiments, the other treatments include administering a therapeutic agent. In some embodiments, the therapeutic agent includes levodopa for treating alpha-connucleoproteinopathy, and the therapeutic agent includes a selective serotonin reuptake inhibitor (SSRI) antidepressant for treating TDP-43 proteinopathy.

[0046] In some embodiments, the combination of mimic peptides and other therapeutic treatments has a synergistic effect in the prevention or treatment of α-connucleoproteinopathy or TDP-43 proteinopathy.

[0047] In some embodiments, the pharmaceutically acceptable salts include tartrates, fumarates, citrates, benzoates, succinates, octanoates, lactates, oxalates, phthalates, methanesulfonates, benzenesulfonates, or maleates (in different cases, monohydrochlorides, dihydrochlorides, and trihydrochlorides, respectively). In some embodiments, the pharmaceutically acceptable salts include tartrates, fumarates, monoacetates, diacetates, triacetates, monotrifluoroacetates, ditrifluoroacetates, trifluoroacetates, monohydrochlorides, dihydrochlorides, trihydrochlorides, monotoluenesulfonates, ditoluenesulfonates, or tritoluenesulfonates. In some embodiments, the mimetic peptide is formulated as a trihydrochloride, dihydrochloride, or monohydrochloride.

[0048] On one hand, the present invention provides a mimic peptide for treating or preventing α-connuclear proteinopathy or TDP-43 proteinopathy in subjects of need, such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof.

[0049] In some embodiments, the subject is diagnosed with α-commonoprotein disease or TDP-43 protein disease. In some embodiments, the α-commonoprotein disease is Parkinson's disease (PD), PD with dementia, Lewy body dementia, or multiple system atrophy, and the TDP-43 protein disease is amyotrophic lateral sclerosis (ALS) or frontotemporal degeneration (FTLD).

[0050] In some embodiments, the mimic peptide is intended to be administered daily for 2 weeks or more. In some embodiments, the mimic peptide is intended to be administered daily for 12 weeks or more.

[0051] In some embodiments, the treatment or prevention of α-commonoproteinopathy includes reducing the loss of dopaminergic neurons in the subject compared to an untreated control. In some embodiments, the treatment or prevention of TDP-43 proteinopathy includes improving (e.g., increasing) neurite length in the subject compared to an untreated control.

[0052] In some embodiments, the subject is a human. In some embodiments, the mammalian subject is a human.

[0053] In some embodiments, the mimic peptide is formulated for oral administration. In some embodiments, the mimic peptide is formulated for subcutaneous administration. In some embodiments, the mimic peptide is formulated for local, intranasal, systemic, intravenous, peritoneal, intradermal, intraocular, ocular, intrathecal, intraventricular, iontophoresis, mucosal, intravitreal, or intramuscular administration.

[0054] In some embodiments, the mimic peptide is intended to be used alone, sequentially, or simultaneously with other treatments. In some embodiments, the other treatments include the use of therapeutic agents. In some embodiments, the therapeutic agents include levodopa for treating alpha-connucleopathies, and the therapeutic agents include selective serotonin reuptake inhibitors (SSRIs) antidepressants for treating TDP-43 proteinopathy. In some embodiments, the combination of the mimic peptide and other therapeutic treatments has a synergistic effect in the prevention or treatment of alpha-connucleopathies or TDP-43 proteinopathy.

[0055] In some embodiments, the pharmaceutically acceptable salts include tartrates, fumarates, citrates, benzoates, succinates, octanoates, lactates, oxalates, phthalates, methanesulfonates, benzenesulfonates, or maleates (in different cases, monohydrochlorides, dihydrochlorides, and trihydrochlorides, respectively). In some embodiments, the pharmaceutically acceptable salts include tartrates, fumarates, monoacetates, diacetates, triacetates, monotrifluoroacetates, ditrifluoroacetates, trifluoroacetates, monohydrochlorides, dihydrochlorides, trihydrochlorides, monotoluenesulfonates, ditoluenesulfonates, or tritoluenesulfonates. In some embodiments, the mimetic peptide is formulated as a trihydrochloride, dihydrochloride, or monohydrochloride. Attached Figure Description

[0056] Figure 1A-1D Systemic administration of (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide, or pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates and / or solvates thereof, can delay the onset of neurological disease symptoms and prolong the lifespan of male SOD1 G93A transgenic mice. Figure 1A and 1B This is a graph showing the progression of neurological symptoms in male and female SOD1 G93A mice, which were treated with (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide trihydrochloride (Ia) at doses of 0.5 mg / kg or 5.0 mg / kg, compared to a vector-treated control group. Figure 1C and 1D Kaplan-Meier survival curves for the lifespan of male and female SOD1 G93A mice compared to the vector-treated control group. These mice were treated with (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide trihydrochloride (Ia) at doses of 0.5 mg / kg or 5.0 mg / kg. *(Ia)@5.0 mg / kg, p<0.05.

[0057] Figure 2A-2BSystemic administration of (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide trihydrochloride (Ia) attenuated grip strength loss in male SOD1 G93A transgenic mice. Figure 2A and 2B The grip strength graphs were determined at baseline (week 8) and at the end of life for each animal treated with 0.5 mg / kg or 5.0 mg / kg (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (Formula I) compared with the control group treated with the carrier.

[0058] Figures 3A-3B Systemic administration of (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide trihydrochloride (Ia) reduced the accumulation of neurofilament light chains (NfL) in the plasma of male SOD1 G93A transgenic mice. Figure 3A and 3B This is a graph showing the plasma NfL levels in male and female SOD1 G93A mice after 10 weeks of administration of (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethyl)-1-oxopropyl-2-yl)-5-guanidinopentamide and a carrier control.

[0059] Figure 4 This is a graph showing the correlation between plasma neurofilament levels and animal survival in male SOD1 G93A transgenic mice. The graph depicts the plasma NfL level of each male mouse in this study as a function of their age at the time of humane termination of life.

[0060] Figure 5AThis is a graph comparing drug accumulation in the brains of Sprague Dawley rats over 36 hours, where rats were subcutaneously injected with (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide trihydrochloride (Ia) or elamipretide at a rate of 5 mg / kg. n = 4 at each time point.

[0061] Figure 5B This is a graph comparing respiratory control rates of mitochondrial respiration in brain homogenates prepared from Sprague Dawley rats, compared to untreated and sham-operated groups, in which rats were treated with (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide trihydrochloride (Ia) at a rate of 5 mg / kg. **p<0.01, one-way ANOVA.

[0062] Figure 6A This is an image of immunostained dopaminergic neurons in C57BL / 6 mice treated with A53T mutant α-synuclein virus particles, compared to the untreated group and the group not injected with A53T mutant α-synuclein virus particles. The mice were treated with 0.5 mg / kg or 5 mg / kg of (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide trihydrochloride (Ia). A = A53T AAV, no drug; B1 = A53T AAV, compound Ia 0.5 mg / kg; B2 = A53TAAV, compound Ia 5.0 mg / kg; C1 = no virus, compound Ia 0.5 mg / kg; C2 = no virus, compound Ia 5.0 mg / kg.

[0063] Figure 6B yes Figure 6A The bar chart shows the data obtained from the experiments mentioned above. A = A53T AAV, no drug; B1 = A53TAAV, compound Ia 0.5 mg / kg; B2 = A53T AAV, compound Ia 5.0 mg / kg; C1 = no virus, compound Ia 0.5 mg / kg; C2 = no virus, compound Ia 5.0 mg / kg. **p<0.01 with group A; ***p<0.001 with group A; OOp<0.001 compared to groups C1 and C2.

[0064] Figure 6C yes Figure 6A and 6B Bar chart showing plasma neurofilament analysis data of C57BL / 6 mice in each animal group after injection of A53T mutant α-synuclein virus particles. A = A53T AAV, no drug; B1 = A53T AAV, compound Ia 0.5 mg / kg; B2 = A53T AAV, compound Ia 5.0 mg / kg; C1 = no virus, compound Ia 0.5 mg / kg; C2 = no virus, compound Ia 5.0 mg / kg.

[0065] Figure 7 It is used to study the effects of different concentrations of compound Ia on prp-TDP-43. A315T - Bar chart of mean neurite length per cell for the effect of UeGFP on cortical and spinal motor neurons. ***p<0.001 with vector; ****p<0.0001 with vector. Detailed Implementation

[0066] It should be understood that, in order to provide a substantial understanding of the technology of the present invention, certain aspects, modes, embodiments, variations, and features of the present invention are described below with varying degrees of detail. Some terms used in this specification are defined as follows. Unless otherwise defined, all technical and scientific terms used in this invention generally have the same meaning as known to one of ordinary skill in the art to which this invention pertains.

[0067] In carrying out the techniques of this invention, many conventional techniques from molecular biology, protein biochemistry, cell biology, immunology, microbiology, and recombinant DNA were used. These techniques are well known and explained in the following references: *Modern Molecular Biology Laboratory Manual*, Volumes I-III, edited by Ausubel (1997); Sambrook et al., *Molecular Cloning: A Laboratory Manual* (2nd edition) (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1989); *DNA Cloning: A Practical Approach*, Volumes I and II, edited by Glover (1985); *Oligonucleotide Synthesis*, edited by Gait (1984); *Nucleic Acid Hybridization*, edited by Hames and Higgins (1985); *Transcription and Translation*. Hames and Higgins (eds.) (1984); Animal Cell Culture, Freshney (ed.) (1986); Immobilized Cells and Enzymes (IRL Press, 1986); Perbal, Practical Guide to Molecular Cloning series, Journal of Enzymological Methods (Academic Press Ltd., 1984); Gene Transfer Vectors for Mammalian Cells, Miller and Calos (eds.), Cold Spring Harbor Laboratory, New York, 1987); and Enzymological Methods, Volumes 154 and 155, edited by Wu and Grossman and edited by Wu, respectively.

[0068] definition

[0069] In this specification and the appended claims, unless otherwise expressly stated, the singular forms “a,” “an,” and “the” also include plural references. For example, the term “cell” includes a combination of two or more cells.

[0070] In this invention, “administering” a drug, pharmacology, therapeutic agent, peptide, or peptide mimicry to a subject includes any route of introducing or delivering a compound to the subject to achieve the intended function. Administration can be by any route, such as oral. It can be administered subcutaneously. It can be administered intravenously. It can be administered intraocularly. It can be administered systemically. Alternatively, it can be administered topically, intranasally, intraperitoneally, intradermally, ocularly, intrathecally, intraventricularly, via iontophoresis, through mucous membranes, intravitreal cavity, or intramuscularly. Administration includes self-administration and administration by another person.

[0071] In this invention, the term "amino acid" includes both natural and non-natural amino acids. Unless otherwise specified, the term "amino acid" includes isolated amino acid molecules (i.e., molecules that simultaneously include an amino-linked hydrogen and a carbonyl carbon-linked hydroxyl group) and amino acid residues (i.e., molecules in which one or two amino-linked hydrogens or one carbonyl carbon-linked hydroxyl group have been removed). The amino group can be α-amino, β-amino, etc. For example, the term "amino acid alanine" refers to isolated alanine H-Ala-OH, but can also refer to any alanine residue H-Ala-, -Ala-OH, or -Ala-. Unless otherwise stated, all amino acids found in the compounds described in this invention can be D or L configurations. D-configured amino acids can be written with "D" added before the amino acid abbreviation. For example, "D-Arg" represents D-configured arginine. The term "amino acid" includes its salts, including pharmaceutically acceptable salts. Any amino acid can be protected or deprotected. Protecting groups can be attached to an amino group (e.g., α-amino), a main-chain carboxyl group, or any functional group on the side chain. For example, phenylalanine protected by a benzyloxycarbonyl (Z) group on the α-amino group can be represented as Z-Phe-OH.

[0072] Except for the N-terminal amino acid, all amino acid abbreviations in this invention (e.g., Phe) represent the -NH-C(R)(R′)-CO- structure, where R and R′ are hydrogen or the side chain of the amino acid (e.g., for Phe, R = benzyl, R' = H). Thus, phenylalanine is H-Phe-OH. The name "OH" in these amino acids or peptides (e.g., Lys-Val-Leu-OH) indicates that the C-terminus is a free acid. For example, the name "NH2" in Phe-D-Arg-Phe-Lys-NH2 indicates that the C-terminus of the protected peptide fragment is an amidation. Furthermore, certain R and R' that are individually or in combination as cyclic structures may include functional groups that require protection during liquid-phase or solid-phase synthesis.

[0073] If an amino acid has an isomer, unless otherwise explicitly stated as D-form (e.g., D-Arg), it indicates the L-form of the amino acid. It is worth noting that many D- and L-form amino acid residues are commercially available. For example, D-Arg is a commercially available D-amino acid.

[0074] The capital letter "D" used with the abbreviation for amino acids refers to D-type amino acid residues.

[0075] The term "DMT" refers to 2,6-di(methyl)tyrosine (e.g., 2,6-dimethyl-L-tyrosine; CAS 123715-02-6).

[0076] In this invention, the phrase “delayed onset” means that, in a statistical sample, the onset of one or more symptoms, symptoms, conditions or indications of impairment, symptom, or indication is delayed, hindered or caused by the absence of treatment in the treated sample compared to an untreated control sample.

[0077] In this invention, the term "effective amount" refers to an amount sufficient to achieve the desired therapeutic and / or preventative effect, for example, a level capable of partially or completely improving one or more symptoms of ALS, α-connucleopathies, or TDP-43 proteinopathies. In therapeutic or preventative applications, in some embodiments, the amount of composition administered to a subject depends on the type, extent, and severity of the disease, as well as individual-specific circumstances such as overall health status, age, sex, weight, and drug resistance. Those skilled in the art will be able to determine an appropriate dosage based on these and other factors. The composition may also be used in combination with one or more other therapeutic compounds. In the method described in this invention, a mitochondrial-targeted mimic peptide, such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (I), or a pharmaceutically acceptable salt thereof (e.g., (Ia), such as tartrate, fumaric acid), may be administered to a subject with one or more signs, symptoms, or risk factors of ALS or FTLD. Salts, citrates, benzoates, succinates, octanoates, lactates, oxalates, phthalates, methanesulfonates, benzenesulfonates, or maleates (in different cases, monohydrochlorides, dihydrochlorides, and trihydrochlorides), monoacetates (i.e., salts containing one acetic acid group), diacetates (i.e., salts containing two acetic acid groups), triacetates (i.e., salts containing three acetic acid groups), monotrifluoroacetates (i.e., salts containing one trifluoroacetate moiety), ditrifluoroacetates (i.e., salts containing two trifluoroacetate moiety), trifluoroacetates, etc. Acetates (i.e., salts containing three trifluoroacetate moieties), monohydrochlorides (i.e., salts containing one chloride ion, such as those composed of one hydrochloric acid or believed to be composed of one hydrochloric acid; "monohydrochloride"), dihydrochlorides (i.e., salts containing two chloride ions, such as those composed of two hydrochloric acid ions or believed to be composed of two hydrochloric acid ions; "dihydrochloride"), trihydrochlorides (i.e., salts containing three chloride ions, such as those composed of three hydrochloric acid ions or believed to be composed of three hydrochloric acid ions; "trihydrochloride"), monotoluenesulfonates (i.e., salts containing one toluenesulfonate moieties), dihydrochlorides... Toluenesulfonate (i.e., a salt containing two toluenesulfonate portions) or tritoluenesulfonate (i.e., a salt containing three toluenesulfonate portions), the signs, symptoms or risk factors including but not limited to muscle weakness, muscle wasting (atrophy), fasciculations, muscle spasms, bradykinesia, poor balance, incoordination, voice quality changes, dysarthria, dysphagia, incomplete eyelid closure, drooling, pseudobulbar mood, premature death, elevated expression levels of brain transporter-18kDa (TSPO) and accumulation of neurofilament light chains (NfL) in plasma.

[0078] In this invention, the term "hydrate" refers to a compound related to water. The number of water molecules contained in a hydrate may (or may not) be in proportion to the number of compound molecules in the hydrate.

[0079] In this invention, the term "mimic peptide" refers to a small peptide-like polymer containing two or more amino acids but also containing non-peptide-like modifications. Mimic peptides can be formed by modifying existing peptides or by designing similar molecules that mimic peptide functions.

[0080] In this invention, the terms "pharmaceutical-grade carrier" and "carrier" refer to diluents, adjuvants, excipients, or transporters used for administering or preparing medications. Non-limiting examples of such pharmaceutical-grade carriers include liquids, such as water, saline, and oil; and solids, such as gum arabic, gelatin, starch paste, talc, keratin, colloidal silica, urea, etc. Furthermore, adjuvants, stabilizers, thickeners, lubricants, flavoring agents, and coloring agents may be used. Other examples of pharmaceutical-grade carriers are described in EWMartin's *Remington's Complete Book of Pharmacy*, which is incorporated herein by reference in its entirety.

[0081] In this invention, "prevention" or "preventing" of a disorder or condition refers to reducing the occurrence of a disorder or condition in a treated sample compared to an untreated control sample, or delaying the onset of one or more symptoms of a disorder or condition compared to an untreated control sample. In this invention, prevention of ALS, α-connucleoproteinopathy, or TDP-43 proteinopathy includes preventing or delaying the onset of symptoms of ALS, α-connucleoproteinopathy, or TDP-43 proteinopathy. In this invention, prevention of ALS, α-connucleoproteinopathy, or TDP-43 proteinopathy also includes preventing or delaying the recurrence of one or more signs or symptoms of ALS, α-connucleoproteinopathy, or TDP-43 proteinopathy.

[0082] In this invention, the terms "subject" and "patient" are used interchangeably.

[0083] In terms of therapeutic use or administration, the terms "separate" or "separately" refer to the administration of two active ingredients via different routes, formulations, and / or pharmaceutical compositions.

[0084] The term "simultaneous" therapeutic application refers to the simultaneous or substantially simultaneous administration of at least two active ingredients. In some embodiments, simultaneous administration includes, but is not limited to, administration of a single composition or formulation comprising at least one active ingredient, co-administration of at least two separate active ingredients via the same route, and co-administration of at least two separate active ingredients via different routes.

[0085] In this invention, the term "sequential" therapeutic application refers to the application of at least two active ingredients at different times, via the same or different routes of administration. More specifically, sequential application means applying one active ingredient completely before applying another or other active ingredients. Therefore, one active ingredient may be applied over several minutes, hours, or days before applying other active ingredients. In this case, simultaneous treatment is not performed.

[0086] In this invention, the term "subject" refers to a live animal. In various embodiments, the subject is a mammal. In some embodiments, the subject is a non-human mammal, including but not limited to mice, rats, hamsters, guinea pigs, rabbits, sheep, goats, cats, dogs, pigs, miniature pigs, horses, cattle, or non-human primates. In some embodiments, the subject is a human.

[0087] In this invention, the term "solvent" refers to a compound (e.g., a peptide or peptide mimic) bound to a solvent, typically via a solvent decomposition reaction. This physical binding may involve hydrogen bonds. Common solvents include water, methanol, ethanol, isopropanol, acetic acid, ethyl acetate, acetone, hexane, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), diethyl ether, etc.

[0088] In this invention, the term "tautomer" refers to a compound whose structure is interchangeable with that of a particular compound, and in which the hydrogen atoms and electron shifts differ. Thus, the two structures can reach equilibrium through the movement of π electrons and one atom (typically H). For example, enols and ketones are tautomers because they can be rapidly converted by acid or base treatment. The tautomer form may be related to obtaining optimal chemical reactivity and biological activity of the target compound.

[0089] In this invention, "synergistic therapeutic effect" refers to a therapeutic effect greater than additive and exceeding the effect of individual administration of the drugs produced by a combination of at least two agents. For example, low doses of one or more agents can be used to treat ALS, α-connucleopathies, or TDP-43 proteinopathies, thereby improving therapeutic efficacy and reducing side effects.

[0090] In this invention, the terms “treating” or “treatment” or “alleviation” refer to treatment in which the purpose is to reduce, alleviate or slow the progression or development of a target pathological state or disorder, and / or reverse its progression. According to the method of the present invention, after receiving a therapeutic dose of a mitochondrial-targeting mimic peptide, for example, (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (I), or a pharmaceutically acceptable salt thereof (e.g., (Ia), for example, tartrate, fumarate, citrate, benzoate, succinate, octanoate, lactate, oxalate, phthalate, methanesulfonate, benzenesulfonate or maleate (in different cases, monohydrochloride, dihydrochloride, trihydrochloride, respectively), monoacetate, diacetate, triacetate, monotrifluoroacetate, ditrifluoroacetate, trifluoroacetate, monohydrochloride, dihydrochloride, trihydrochloride, monotoluenesulfonate). If a subject exhibits an observable and / or measurable reduction or complete disappearance of one or more signs and symptoms of ALS, α-connucleopathia, or TDP-43 proteinopathy, then the subject has been successfully treated for ALS, α-connucleopathia, or TDP-43 proteinopathy. For example, in ALS, such signs or symptoms include, but are not limited to, muscle weakness, muscle wasting (atrophy), fasciculations, muscle spasms, bradykinesia, poor balance, incoordination, voice changes, dysarthria, dysphagia, incomplete eyelid closure, drooling, pseudobulbar mood, premature death, increased expression levels of brain transporter-18kDa (TSPO), and accumulation of neurofilament light chains (NfL) in plasma. In some embodiments, the treatment refers to delaying the onset of ALS neurological symptoms (assessed using the neurological function score described in this invention).

[0091] It should be understood that the various disease treatment or prevention modalities described in this invention are "substantially" and include all or less all treatments or preventions in which certain biological or medically relevant results are achieved.

[0092] In this invention, the terms "(R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentamide" and "(D-Arg-DMT-NH((S))-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl" are used interchangeably with respect to the use of the term "(R)-2-amino-N-((S)-1-( ... "(1S)-1-[(1S)-1-{[(1S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl]carbamoyl}-2-(4-hydroxy-2,6-dimethyl)ethyl]-5-iminocarbamoyl", "compound 7a" and "7a" refer to the same mitochondrial-targeting mimic peptide compound that is interchangeable in this invention, and refer to the compound of formula (I):

[0093]

[0094] (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)

[0095] (Pentyl)amino)-3-(4-hydroxy-2,6-dimethyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide.

[0096] The terms “(R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide” and “(2R)-2-amino-N-[(1S)-1-{[(1S)-5-amino-1-(3-benzyl-1,2,4-)- ... "(Oxadiazol-5-yl)pentyl]carbamoyl}-2-(4-hydroxy-2,6-dimethyl)ethyl]-5-iminocarbamoyl", "(D-Arg-DMT-NH((S))-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentan-1-yl)", "Compound 7a" and "7a (as shown in the figure below)" should include its pharmaceutically acceptable salt form, such as the trihydrochloride of formula (Ia):

[0097]

[0098] Amyotrophic Lateral Sclerosis (ALS)

[0099] Amyotrophic lateral sclerosis (ALS; also known as Lou Gehrig's disease) is a progressive neuromuscular disease characterized by weakness, muscle wasting, fasciculations, and increased reflexes. Currently, approximately 30,000 Americans have this disease. The annual incidence is 1-2 cases per 100,000 people. This disease is common in middle-aged people, with a higher incidence in men than women. ALS is characterized by adult-onset, idiopathic, progressive degeneration of the anterior horn cells and upper and lower motor neurons, leading to progressive muscle weakness, wasting, and fasciculations. Atrophy of the anterior horn cells and replacement of large motor neurons by fibrillary astrocytes (glial proliferation) cause hardening of the affected anterior and lateral columns of the spinal cord, hence the name "lateral sclerosis." Typical signs or symptoms of ALS include muscle weakness, muscle wasting (atrophy), fasciculations, muscle spasms, bradykinesia, poor balance, incoordination, voice changes, dysarthria, dysphagia, incomplete eyelid closure, drooling, pseudobulbar mood, and premature death.

[0100] Up to 10% of ALS cases are familial, typically inherited in an autosomal dominant pattern. Several pathogenic genes are known, the most common in both familial (fALS) and sporadic (sALS) ALS being mutant superoxide dismutase 1 (SOD1) and mutant C9orf72 (i.e., the G4C2 hexanucleotide repeat sequence in the C9orf72 gene). Several other genes are also known to be causes of typical ALS, although these genes are less prevalent than mutant SOD1; these include mutant FUS (sarcoma fusion), mutant TARDBP leading to modification of TAR DNA-binding protein 43 (TDP-43), and optic nerve proteins.

[0101] Clinical presentation varies depending on the area of ​​neurological damage and the progression of pathological changes. ALS typically presents as insidious, progressive, asymmetric muscle weakness and atrophy, accompanied by neurological signs, particularly fasciculations and hyperreflexia. It usually manifests as agility or gait problems due to muscle weakness. Difficulty speaking or swallowing is the initial symptom of the medullary form. Over months or years, ALS patients develop severe, progressive muscle weakness along with other symptoms caused by the loss of function of upper and lower motor neurons. However, sphincter control, sensory function, intelligence, and skin integrity are preserved. Patients become completely disabled and usually require respiratory support and a gastrostomy. Death usually occurs within five years of diagnosis due to respiratory failure or cachexia. The diagnosis of ALS is clinical, characterized by progressive weakness, atrophy, fasciculations, and hyperreflexia affecting multiple areas of the body. Early differential diagnoses may include musculoskeletal, neurological, or generalized conditions. The etiology of the disease is unknown. Current management includes aggressive, individualized relief of symptoms and complications. There is currently no cure for ALS.

[0102] Currently, the only drug labeled for the treatment of ALS is riluzole. And Idaho The U.S. Food and Drug Administration is considering at least one other drug (mecaserine). Different symptom treatments may be used, including baclofen. stable Danqulin Nonsteroidal anti-inflammatory drugs (NSAIDs) and anticonvulsants, such as carbamazepine (Tegretol) or phenytoin. Amitriptyline nortriptyline (Pamelor) TM ) and chlorohydroxynordiazepoxide

[0103] Neurofilament light chains (NfL)

[0104] Biomarkers reflecting the characteristics of ALS are valuable not only for disease diagnostic algorithms but also for identifying homogeneous patient subgroups. They can also help track disease progression and treatment response. Neurofilaments (NFs) have been extensively studied in various neurological disorders and can be used as markers of acute and chronic neuronal damage (Bacioglu et al., Neuron, 91:56-66 (2016)). Neurofilaments are 10 nm intermediate filaments in neurons, composed of hybrids of different subunits, neurofilament light chains (NfLs), neurofilament medium chains (NfMs), and neurofilament heavy chains (NfHs) (Lee, Annals of Neuroscience, 19:187-217 (1996)). Neurofilament light chains (NfLs) are specific to neuronal cells and detach into cerebrospinal fluid (CSF). Low concentrations of neurofilament light chains (NfLs) can be detected in peripheral blood. CSF, serum, and plasma NfL levels have been shown to be useful for differentiating ALS patients from healthy controls with high sensitivity and specificity, and are associated with disease progression or survival in ALS patients (Lu et al., Journal of Neurology, June 2015; 84(22):2247-57). In a mouse model of ALS with SOD1, degeneration of motor cell origin has been shown to be accompanied by a gradual increase in blood NF levels, which can capture treatment response (Lu et al., PLoS ONE, 7:e40998 (2012); Boylan et al., Journal of Neurochemistry, 111:1182-1191 (2009)).

[0105] α-Conucleoproteinosis

[0106] Alpha-synucleinopathies, or alpha-synucleinopathies, are neurodegenerative diseases characterized by the abnormal accumulation of alpha-synuclein in neurons, nerve fibers, or glial cells. These diseases are also associated with the loss of dopaminergic neurons in the substantia nigra. These diseases include Parkinson's disease (PD), PD with dementia, Lewy body dementia, or multiple system atrophy. The neuropathological diagnosis of alpha-synucleinopathies is based on the detection of alterations in alpha-synuclein in tissues and the recording of the neuroanatomical distribution of these alterations in the brain.

[0107] TDP-43 protein disease

[0108] TAR-DNA binding protein 43 (TDP-43) protein disorders include ALS and frontotemporal degeneration (FTLD). FTLD refers to a group of clinically, genetically, and neuropathologically heterogeneous neurodegenerative disorders and is the third most common form of dementia after Alzheimer's disease (AD) and Lewy body dementia. Current research standards classify FTLD into three clinical syndromes: frontotemporal dementia, primary progressive nonfluency aphasia, and lexical dementia. Frontotemporal dementia is the most common clinical form, mainly manifested as changes in personality and behavior, while primary progressive nonfluency aphasia and lexical dementia are mainly manifested as language dysfunction. In addition, patients may experience motor abnormalities, such as Parkinson's disease and motor neuron disease.

[0109] The term frontotemporal degeneration reflects the significant atrophy of the frontal and temporal lobes found in these patients through neuropathological examination. A characteristic feature of most FTLD brains is the formation of abnormal protein inclusion bodies in neurons and glial cells. TAR-DNA binding protein 43 (TDP-43) has been identified as a disease protein in FTLD. Mutant TDP-43 has been found to inhibit neurite growth, and overexpression of both wild-type (WT) and mutant TDP43 leads to motor neuron toxicity.

[0110] Mitochondrial-targeting mimic peptides

[0111] In some embodiments, the present invention provides compounds of formula (II), or pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, and / or solvates thereof:

[0112]

[0113] in

[0114] AA1 is selected from

[0115] AA2 is selected from

[0116] R 1 Selected from

[0117] R 2a Selected from

[0118] R 2b It is H or Me;

[0119] R 3 and R 4 Selected from H and (C1-C6) alkyl groups, respectively;

[0120] R 5 and R 6 It is an independent H, methyl, ethyl, propyl, cyclopropyl, or cyclobutyl; or R 5 and R 6 Together with the N atoms they bind to, they form 4-6 membered heterocyclic groups;

[0121] R 7 Selected from H, (C1-C6)alkyl, cycloalkyl, and aromatic groups;

[0122] R 8 and R 9 Selected from H, (C1-C6)alkyl, cycloalkyl, and aryl groups respectively; or R 8 and R 9 Together with the N atoms they bind to, they form 4-6 membered heterocyclic groups;

[0123] n is 1, 2, or 3;

[0124] X is selected from as well as

[0125] * indicates X and R 1 The points that are connected.

[0126] In some embodiments, AA1 is In some embodiments, AA1 is In some embodiments, AA1 is

[0127] In some embodiments, AA1 is In some embodiments, AA1 is

[0128] In some embodiments, AA2 is In some embodiments, AA2 is

[0129] In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes

[0130] In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes

[0131] In some embodiments, R 1 yes

[0132] In some embodiments, R 1 yes

[0133] In some embodiments, R 2a yes In some embodiments, R 2a yes

[0134] In some embodiments, R 2a yes In some embodiments, R 2a yes In some embodiments, R 2a yes

[0135] In some embodiments, R 2a yes

[0136] In some embodiments, R 2a yes

[0137] In some embodiments, R 2a yes

[0138] In some embodiments, R 2b It is H. In some embodiments, R 2b It is a methyl group.

[0139] In some embodiments, R 3 It is H. In some embodiments, R 3 It is a (C1-C6) alkyl group. In some embodiments, R 3 It is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl. In some embodiments, R 3It is a methyl group. In some embodiments, R 3 It is an ethyl group.

[0140] In some embodiments, R 4 It is H. In some embodiments, R 4 It is a (C1-C6) alkyl group. In some embodiments, R 4 It is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl. In some embodiments, R 4 It is a methyl group. In some embodiments, R 4 It is an ethyl group.

[0141] In some embodiments, R 3 and R 4 Same. In some embodiments, R 3 and R 4 different.

[0142] In some embodiments, R 5 It is H. In some embodiments, R 5 It is a methyl group.

[0143] In some embodiments, R 6 It is H. In some embodiments, R 6 It is a methyl group.

[0144] In some embodiments, R 5 and R 6 Same. In some embodiments, R 5 and R 6 different.

[0145] In some embodiments, R 5 and R 6 Together with the N atoms they are bonded to, they form 4-6 membered heterocyclic groups. In some embodiments, the heterocyclic group is a 4-6 membered heterocyclic group. In some embodiments, the heterocyclic group is an aza-butyl, pyrrolidinyl, or piperidinyl group.

[0146] In some embodiments, R 7 It is H. In some embodiments, R 7 It is a (C1-C6) alkyl group. In some embodiments, R 7 It is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl. In some embodiments, R 7 It is a methyl group.

[0147] In some embodiments, R 7 It is a cycloalkyl group. In some embodiments, R 7 It is cyclopropyl, cyclobutyl, cyclopropyl, or cyclohexyl. In some embodiments, R 7It is an aromatic group. In some embodiments, R 7 It is a phenyl group.

[0148] In some embodiments, R 8 It is H. In some embodiments, R 8 It is a (C1-C6) alkyl group. In some embodiments, R 8 It is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl. In some embodiments, R 8 It is a methyl group.

[0149] In some embodiments, R 8 It is a cycloalkyl group. In some embodiments, R 8 It is cyclopropyl, cyclobutyl, cyclopropyl, or cyclohexyl. In some embodiments, R 8 It is an aromatic group. In some embodiments, R 8 It is a phenyl group.

[0150] In some embodiments, R 9 It is H. In some embodiments, R 9 It is a (C1-C6) alkyl group. In some embodiments, R 9 It is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl. In some embodiments, R 9 It is a methyl group.

[0151] In some embodiments, R 9 It is a cycloalkyl group. In some embodiments, R 9 It is cyclopropyl, cyclobutyl, cyclopropyl, or cyclohexyl. In some embodiments, R 9 It is an aromatic group. In some embodiments, R 9 It is a phenyl group.

[0152] In some embodiments, R 8 and R 9 Same. In some embodiments, R 8 and R 9 different.

[0153] In some embodiments, R 8 and R 9 Together with the N atoms they are bonded to, they form 4-6 membered heterocyclic groups. In some embodiments, the heterocyclic group is a 4-6 membered heterocyclic group. In some embodiments, the heterocyclic group is an aza-butyl, pyrrolidinyl, or piperidinyl group.

[0154] In some embodiments, X is In some embodiments, X is In some embodiments, X is In some embodiments, X is In some embodiments, X is In some embodiments, X is

[0155] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0156] The chiral center of the mimic peptide disclosed in this invention can be the R- or S-configuration, which will be discussed in detail below.

[0157] Chiral / stereochemical considerations

[0158] The mimetic peptides described in this invention may include one or more asymmetric centers and therefore may exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described in this invention may be in the form of a single enantiomer, diastereomer, or geometric isomer, or in the form of a mixture of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. Isomers can be separated from the mixture by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis. For example, see Jacques et al., Enantiomers, Racemates, and Resolution (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, New York, 1962); and Wilen, Resolving Agents and Optical Resolution Tables, p. 268 (edited by Eliel, University of Notre Dame Press, Notre Dame, Indiana, 1972). Furthermore, the mimetic peptides also include the compounds described in this invention, either as independent isomers substantially free of other isomers, or as mixtures of various isomers.

[0159] R (D represents amino acid) or S (L represents amino acid)

[0160] In this invention, the pure enantiomeric mimic peptide is substantially free of other enantiomers or stereoisomers of the compound (i.e., enantiomer excess). In other words, the “S” type compound is substantially free of the “R” type compound, and therefore is an “R” type enantiomer excess. With regard to amino acids (typically described using “D” and “L” enantiomers), it should be understood that for “D”-amino acids, the configuration is “R”, and for “L”-amino acids, the configuration is “S”. In some embodiments, “substantially free” means: (i) containing less than 2% of an equal fraction of the “S” type “R” type compound; or (ii) containing less than 2% of an equal fraction of the “R” type “S” type compound. The terms "enantiomerically pure" or "pure enantiomers" indicate that a compound contains greater than 90 wt% (by weight), greater than 91 wt%, greater than 92 wt%, greater than 93 wt%, greater than 94 wt%, greater than 95 wt%, greater than 96 wt%, greater than 97 wt% (by weight), greater than 98 wt%, greater than 99 wt%, greater than 99.5 wt%, or greater than 99.9 wt% of enantiomers. In some embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0161] In some embodiments of the present invention, the enantiomerically pure compound may be present together with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure "R" type compound may comprise about 90% excipients and 10% enantiomerically pure "R" type compound. In some embodiments, the enantiomerically pure "R" type compound in such compositions may comprise at least about 95 wt% of an "R" type compound and up to about 5 wt% of an "S" type compound (by total weight of the compound). For example, a pharmaceutical composition comprising an enantiomerically pure "S" type compound may comprise about 90% excipients and 10% enantiomerically pure "S" type compound. In some embodiments, the enantiomerically pure "S" type compound in such compositions may comprise at least about 95 wt% of an "S" type compound and up to about 5 wt% of an "R" type compound (by total weight of the compound). In some embodiments, the active ingredient may be formulated with very little excipient or carrier or without excipient or carrier.

[0162] The nomenclature used to define the peptide compounds described in this invention is the nomenclature commonly used in the art, wherein the N-terminal amino group appears on the left and the C-terminal carboxyl group appears on the right, provided that the mimic peptides disclosed in this invention do not contain a carboxylic acid group or an amide group at the C-terminus.

[0163] The capital letter "D" used with amino acid abbreviations refers to D-type amino acid residues. For example, D-Arg is a commercially available D-amino acid.

[0164] The mimetic peptides described in this invention exist in both solvated and solvated forms, including hydrated forms. For example, a solvated form may exist because it is difficult or impossible to remove all solvents after the synthesis of the mimetic peptide. Generally, the solvated form is equivalent to the non-solvated form and is included within the scope of this application. Some mimetic peptides in this application may exist in polycrystalline or amorphous forms. Some mimetic peptides in this application may exist in tautomer forms. Some mimetic peptides in this application may exist in various salt forms. Generally, all physical forms are equivalent to the intended use of this application and should be within the scope of this application.

[0165] In some embodiments, the mitochondrial-targeting mimic peptides disclosed in this invention, such as ((R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (I), or pharmaceutically acceptable salts thereof (such as tartrate, fumarate, citrate, benzoate, succinate, octanoate, lactate, oxalate, phthalate, methanesulfonate, benzenesulfonate, or maleate (in different cases, monohydrochloride, dihydrochloride, trihydrochloride, etc.), monoacetate, diacetate, triacetate, monotrifluoroacetate, ditrifluoroacetate, trifluoroacetate, monohydrochloride, etc. Compositions of salts, dihydrochlorides, and trihydrochlorides (e.g., (Ia), monotoluenesulfonate, ditoluenesulfonate, or tritoluenesulfonate) may be used to treat or prevent ALS, α-connucleopathies, or TDP-43 proteinopathy in subjects of need. In some embodiments, the mitochondrial-targeting mimic peptide is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (I) or a pharmaceutically acceptable salt thereof (e.g., (Ia)). In some embodiments, the subject is diagnosed with ALS, an α-connucleopathy, or TDP-43 proteinopathy.

[0166] In other embodiments, the mitochondrial-targeting mimic peptides disclosed in this invention, such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (I) or pharmaceutically acceptable salts thereof (such as tartrate, fumarate, citrate, benzoate, succinate, octanoate, lactate, oxalate, phthalate, methanesulfonate, benzenesulfonate, or maleate (in different cases, monohydrochloride, dihydrochloride, trihydrochloride, etc.) Hydrochloride, monoacetate, diacetate, triacetate, monotrifluoroacetate, ditrifluoroacetate, trifluoroacetate, monohydrochloride, diacetate, trihydrochloride (e.g., (Ia), monotoluenesulfonate, ditoluenesulfonate or tritoluenesulfonate) can be used to improve muscle weakness, muscle wasting (atrophy), fasciculations, muscle spasms, bradykinesia, poor balance, incoordination, voice changes, dysarthria, dysphagia, incomplete eyelid closure, drooling, pseudobulbar mood, survival, increased expression levels of brain transporter-18kDa (TSPO) and accumulation of neurofilament light chains (NfL) in plasma in subjects with ALS. In some embodiments, the mitochondrial-targeting mimic peptide is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (I) or a pharmaceutically acceptable salt thereof (e.g., (Ia)). In some embodiments, the subject is diagnosed with ALS.

[0167] In some embodiments of the mitochondrial-targeting mimic peptide of the present invention, the treatment or prevention includes treating or preventing one or more signs or symptoms of ALS, including muscle weakness, muscle wasting (atrophy), fasciculations, muscle spasms, bradykinesia, poor balance, incoordination, voice quality changes, dysarthria, dysphagia, incomplete eyelid closure, drooling, pseudobulbar mood, premature death, elevated expression levels of brain transporter-18kDa (TSPO), and NfL accumulation in plasma. In some embodiments, the treatment or prevention refers to delaying the onset of ALS neurological symptoms (assessed using the neurological function score described in the present invention).

[0168] In some embodiments of the mimic peptides of the present invention, the mitochondrial-targeting mimic peptides are intended or formulated for administration, alone, sequentially, or simultaneously, to the subject of other therapeutic agents or other treatments. In some embodiments, the other therapeutic agents are selected from: riluzole. Idaravon Mecaserine, Baclofen stable Danqulin Nonsteroidal anti-inflammatory drugs (NSAIDs), anticonvulsants (e.g., carbamazepine (Tegretol) or phenytoin) Amitriptyline nortriptyline (Pamelor) TM ) and chlorohydroxynordiazepoxide In some embodiments, the therapeutic agent is elamipretide (also known as SS-31 or bendavia). In some embodiments, the mimic peptide is used when the combination of the mimic peptide and other therapeutic agents or treatments has a synergistic effect in the prevention or treatment of ALS. In some embodiments, the other therapeutic agent is levodopa. In some embodiments, the mimic peptide is used when the combination of the mimic peptide and other therapeutic agents or treatments has a synergistic effect in the prevention or treatment of α-connucleoproteinopathy. In some embodiments, the other therapeutic agent is an antidepressant, such as a selective serotonin reuptake inhibitor (SSRI), including trazodone. In some embodiments, the mimic peptide is used when the combination of the mimic peptide and other therapeutic agents or treatments has a synergistic effect in the prevention or treatment of TDP-43 proteinopathy.

[0169] mitochondrial-targeted mimic peptide synthesis

[0170] The mimic peptide compounds of this invention can be prepared, either wholly or partially, using peptide synthesis methods, such as conventional liquid-phase (also known as soluble-phase) peptide synthesis or solid-phase peptide synthesis, or by synthesizing peptides using an automated peptide synthesizer (Kelley et al., Principles and Methods of Genetic Engineering, Setlow, JK, ed., Plenum Press, New York, (1990), Vol. 12, pp. 1-19; Stewart et al., Solid-Phase Peptide Synthesis (1989) WH; Houghten, Proceedings of the National Academy of Sciences (1985) 82: 5132). The resulting mimic peptides can be collected or purified by conventional methods, such as chromatography, including gel filtration chromatography, ion exchange column chromatography, affinity chromatography, reversed-phase column chromatography and HPLC, ammonium sulfate fractionation, ultrafiltration and immunosorbent assay.

[0171] In solid-phase peptide synthesis, peptides are typically synthesized from the carbonyl side (C-terminus) to the amino side (N-terminus) of an amino acid chain. In some embodiments, the amino-protected amino acid is covalently bound to a solid support material via the carboxyl group of the amino acid, generally through an ester or amide bond and selectively through a linker. The amino group is deprotected using a coupling agent and reacted with the carbonyl group of a second amino-protected amino acid (i.e., "coupling") to produce a dipeptide bound to the solid support. After coupling, a capping agent can be used to treat the resin to cap (inactivate) any unreacted amino groups in subsequent coupling steps. These steps (i.e., deprotection, coupling, and selective capping) can be repeated to form the desired peptide chain. Once the desired peptide chain is formed, the peptide can be isolated from the solid support.

[0172] In some embodiments, the protecting groups used on the amino acid residues (of the peptide and / or peptide mimicry) include 9-fluorenylmethoxycarbonyl (Fmoc) and tert-butyloxycarbonyl (Boc). The Fmoc group is removed from the amino terminus with a base, and the Boc group is removed with an acid. In alternative embodiments, the amino protecting group may be a formic acid group, acryloyl (Acr), benzoyl (Bz), acetyl (Ac), trifluoroacetyl, or a substituted or unsubstituted aryl alkoxycarbonyl group, such as benzyloxycarbonyl (Z), p-chlorobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, p-nitrophenyloxycarbonyl, p-methoxybenzyloxycarbon, diphenylmethyloxycarbonyl, 2(p-biphenyl)isopropyloxycarbonyl, 2-(3,5-dimethoxyphenyl)isopropyloxycarbonyl, p-phenylazobenzyloxycarbonyl, triphenylphosphine ethoxycarbonyl, or a substituted or unsubstituted aryl alkoxycarbonyl group (Fmoc). Groups, such as tert-butoxycarbonyl (Boc), p-pentyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethyloxycarbonyl, allyloxycarbonyl, 2-methylsulfonylethoxycarbonyl or 2,2,2-trichloroethyloxycarbonyl, alkyloxycarbonyl groups, such as tripentyloxycarbonyl, trihexyloxycarbonyl, adamantyloxycarbonyl or isobornyloxycarbonyl, and groups containing heteroatoms, such as benzenesulfonyl, p-toluenesulfonyl, mestrimethylbenzenesulfonyl, methoxytrimethylphenylsulfonyl, 2-nitrobenzenesulfonyl, 2-nitrophenoxythio, 4-nitrobenzenesulfonyl or 4-nitrophenoxythio.

[0173] Many amino acids have reactive functional groups on their side chains. In some embodiments, such functional groups are protected to prevent them from reacting with the incoming amino acid. Protecting groups used with these functional groups must remain stable to the conditions of peptide and / or mimic peptide synthesis, but can be removed before, after, or simultaneously with the cleavage of the peptide from the solid support (if the support is bound), or during final deprotection in the case of solubility-phase synthesis. Further reference may also be made to: Isidro-Llobet, A., Alvarez, M., Albericio, F., “Amino Acid Protecting Groups”; Chemistry Review, 109:2455-2504 (2009) as a review of commonly used protecting groups in peptide synthesis (these protecting groups can be used in mimic peptide synthesis, where the mimic peptide contains functional groups found in the peptide).

[0174] In some embodiments, the solid support material used in the solid-phase peptide synthesis method is a gel-type support, such as polystyrene, polyacrylamide, or polyethylene glycol. Alternatively, materials such as controllable-pore glass, cellulose fibers, or polystyrene can be functionalized on their surfaces to provide a solid support for peptide synthesis.

[0175] The coupling agent used in the solid-phase (or soluble-phase) peptide synthesis described in this invention is generally a carbodiimide reagent. Examples of carbodiimide reagents include, but are not limited to, N,N'-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and its hydrochloride salt (EDC.HCl), N-cyclohexyl-N'-isopropylcarbodiimide (CIC), N,N'-diisopropylcarbodiimide (DIC), N-tert-butyl-N'-methylcarbodiimide (BMC), N-tert-butyl-N'-ethylcarbodiimide (BEC), bis[[4-(2,2-dimethyl-1,3-dioxa)]-methyl]carbodiimide (BDDC), and N,N-dicyclohexylcarbodiimide. DCC is a preferred coupling agent. Other coupling agents include HATU and HBTU, which are typically used in combination with organic bases (such as DIEA) and hindered pyridine bases (such as dimethylpyridine or trimethylpyridine).

[0176] In some embodiments, such as those described by Fuller et al., “Ethyl carbamate-protected α-amino acid N-carboxylic acid anhydride and peptide synthesis,” Biopolymers (Peptide Science), Vol. 40, 183-205 (1996) and WO2018 / 034901, the coupling of amino acids with peptides or peptide mimics can be activated by forming N-carboxylic acid anhydrides.

[0177] In some exemplary embodiments, the compounds used in the treatment methods of the present invention can be synthesized by polymerization according to the solid-phase synthesis shown in Figure 1.

[0178] The following diagrams are for reference only. express in, This indicates a solid support, and optionally a connecting base.

[0179] Diagram 1

[0180]

[0181] For example, the compound shown in the figure below can be synthesized in the manner shown in Figure 2.

[0182]

[0183] Diagram 2

[0184] The following diagrams are for reference only. express in, This indicates a solid support, and optionally a connecting base.

[0185]

[0186] The compounds described in this invention can also be synthesized according to conventional liquid-phase peptide synthesis routes (e.g., according to Figure 3).

[0187] Diagram 3

[0188]

[0189] For example, the compound shown in the figure below can be synthesized in the manner shown in Figure 4.

[0190]

[0191] Diagram 4

[0192]

[0193] Synthesis of (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (D-Arg-DMT-NH((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentan-1-yl), 7a)

[0194] In some embodiments, compound 7a can be synthesized according to the following formula 5 (see also WO2019 / 118878 (which is part of this invention by reference)), wherein compound 12a can be prepared according to the following formula 6.

[0195]

[0196] Compound 7a

[0197] Diagram 5

[0198]

[0199] Step a: Synthesis of benzyl(S)-2-((R)-2-((tert-butoxycarbonyl)amino)-5-guanidinopentanamide)-3-(4-hydroxy-2,6-dimethyl)propionic acid (3a). NMM (32.7 mL, 298 mmol) was added to an ACN (800 mL) suspension of 2,6-Dmt-OBn.HCl (2a, 45.0 g, 134 mmol) at 0 °C. The reaction mixture was stirred until it became clear. Then, Boc-D-Arg-OH.HCl (1a, 46.3 g, 149 mmol) and HOBt.H2O (9.11 g, 59.5 mmol) were added to the reaction mixture, and the mixture was stirred for 15 minutes. Finally, EDC.HCl (38.5 g, 201 mmol) was added, and the mixture was stirred at 0 °C for 4 hours. Then, add EtOAc (450 mL) and a 1N HCl brine (300 mL) solution. Wash the combined organic extract with a 1N HCl brine (7 × 150 mL) solution and NaHCO3 / brine (300 mL, until the pH of the aqueous layer is approximately 6-7), dry with Na2SO4, then filter and concentrate to produce 86.0 g (97%) Boc-D-Arg-DMT-OBn (3a) (no further purification required, ready for use). 1 ¹H-NMR (400MHz, methanol-d⁴) δ 7.33–7.18 (m, 5H), 6.43 (s, 2H), 5.06 (s, 2H), 4.71 (t, J = 7.8 Hz, 1H), 4.07 (t, J = 6.7 Hz, 1H), 3.19–3.09 (m, 3H), 3.03–2.97 (m, 1H), 2.23 (s, 6H), 1.72–1.65 (m, 1H), 1.54–1.43 (m, 3H), 1.45 (s, 9H).

[0200] Step b: Synthesis of (S)-2-((R)-2-((tert-butoxycarbonyl)amino)-5-guanidinopentanamide)-3-(4-hydroxy-2,6-dimethyl)propionic acid (4a). Pd / C (10% w / w, 14.0 g) was added to a solution of Boc-D-Arg-DM-Tyr-OBn (3a, 84.0 g, 142 mmol) in 1000 mL of MeOH. The reaction mixture was purged with hydrogen for 4 hours at room temperature. The reaction mixture was then filtered through filter paper and washed with 150 mL of MeOH. The solvent was removed by evaporation. A white foamy product 4a (74.0 g, 93%) was obtained and used (without further processing). 1 ¹H-NMR (400MHz, methanol-d⁴) δ 6.44 (s, 2H), 4.68 (t, J = 7.2Hz, 1H), 4.04 (t, J = 6.8Hz, 1H), 3.15–3.09 (m, 3H), 3.02–2.94 (m, 1H), 2.29 (s, 6H), 1.74–1.59 (m, 1H), 1.54–1.43 (m, 1H), 1.45 (s, 9H).

[0201] Step c: Synthesis of tert-butyl((6R,9S,12S)-1-amino-12-(3-benzyl-1,2,4-oxadiazol-5-yl)-9-(4-hydroxy-2,6-dimethyl)-1-imino-20,20-dimethyl-7,10,18-trioxo-19-oxo-2,8,11,17-tetraazacoecicosan-6-yl)carbamate (6a). DMF (200 mL) was added to 4a (11.17 g, 24 mmol), and the mixture was stirred at room temperature for 15 minutes. 12a (10.65 g, 20 mmol) was then added to the resulting suspension, and the mixture was stirred at room temperature for 20 minutes. HOBt (612 mg, 4.00 mmol) was added, and the suspension was cooled in an ice bath. Add one part EDC.HCl (5.38 g, 28 mmol), and stir the reaction mixture for 2.5 h while cooling in an ice bath, then stir for another 2.5 h at room temperature. Quench the near-homogeneous reaction mixture with EtOAc (1500 mL) and wash the resulting solution 10 times with a brine / 0.5 M HCl aqueous solution (1:1; 400 mL). A gel forms in the aqueous phase during the 6th and 9th washes. The layers reappear clearly after the addition of iPrOH (40 mL, depending on the condition) and repeated shaking. Subsequently, wash the organic phase 6 times with a brine / saturated NaHCO3 aqueous solution (9:1; 400 mL). A gel forms in the aqueous phase during the 4th wash. The layers separate easily after the addition of iPrOH (40 mL) and repeated shaking. Wash the organic phase with brine (200 mL) and water (100 mL) to remove the solvent under reduced pressure. When washing with water, avoid vigorous shaking to prevent difficulties in phase separation. Therefore, 16.8 g of crude product (6a, purity: 97.0% (by HPLC), white amorphous solid) was obtained. 1 H-NMR (300MHz, methanol-d4)ppm: δ=7.33–7.16(m,5H),6.38(s,2H),5.18-5.07(m,1H),4.64-4.55(m,1H),4.10–3 .92(m,3H),3.18-2.77(m,6H),2.20(s,6H),1.97-1.76(m,2H),1.75-1.14(m,8H),1.43(s,9H),1.41(s,9H).

[0202] Step d: Synthesis of (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-xylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (7a, but also referred to in this invention as (Ia – trihydrochloride of compound I)). 6a (16.8 g) was dissolved in DCM (100 mL) and cooled to 0 °C. TFA (20 mL) was added dropwise, and the solution was stirred for 10 minutes at 0 °C, followed by stirring at room temperature for 3 hours (as confirmed by LC / MS, without starting material). The reaction mixture was then evaporated (at 0–5 °C) and then again from DCM (100 mL, at 0–5 °C). The crude sample (fractionated into 4 fractions) was purified by reversed-phase (column C-18, 120 G) rapid chromatography. Then, all solvent was evaporated under reduced pressure at <40°C. The white foam was dissolved in 100 mL of isopropanol, and 5 mL of a 5-6 M solution of HCl in isopropanol was added at 0°C, followed by evaporation under reduced pressure. This step was repeated three times. Additionally, 100 mL of ACN was added, and the suspension was evaporated again. Thus, a white powder (i.e., trihydrochloride) of 7a was obtained. 1 H-NMR (300Mhz, methanol-d4) δ7.36–7.14(m,5H),6.40(s,2H),5.15(dd,J=8.5,6.3Hz,1H),4.68(dd,J=8.7,7.5Hz,1H),4.07(s,2H),3.97(t,J =6.3Hz,1H),3.18(t,J=6.9Hz,2H),3.11(dd,J=14.2,8.8Hz,1H),2.95–2.84(m,3H),2.22(s,6H),2.02–1.59(m,6H),1.57–1.28(m,4H). MS:EI-MS:m / z 608.4[M+1].

[0203] Synthesis of (S)-1-(3-benzyl-1,2,4-oxadiazol-5-yl)-5-((tert-butoxycarbonyl)amino)pentane-1-amine-4-methylbenzenesulfonate (12a)

[0204] Diagram 6

[0205]

[0206] Step a: NH2OH; Step b: T3P, NaHCO3; Step c: TEA; Step d: PTSA

[0207] Step a: Synthesis of N-hydroxy-2-phenylacetamidine (9a). NH₂OH (50% aqueous solution, 130 g, 2.0 mol) was added to a solution of nitrile 8a (1.0 mol) in EtOH (1.2 L). The solution was heated to allow it to reflux and stirred for 12 hours. After completion, the reaction mixture was concentrated under reduced pressure. The resulting residue was redissolved in EtOH (350 mL) and concentrated again under reduced pressure (this procedure was repeated three times). The resulting solid was pulverized in hexane (350 mL), filtered, washed with hexane (100 mL), and then dried to yield the desired product 9a as a white solid (10.5 kg; KF = 1295), with good results (purity >98.9% as determined by HPLC; content = 22.2 wt%, yield = 91%). 1 H NMR (300MHz, DMSO-d6): δ8.90(s,1H),7.28-7.18(m,5H),5.40(s,2H),3.25(s,2H)ppm. MS:(M+H) + :m / z=151.1.

[0208] Step b: Synthesis of (9H-fluorene-9-yl)methyl tert-butyl (1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentane-1,5-diyl)(S)-dicarbamate (11a). NaHCO3 (3.0 equivalents) was added to a protected optically pure ethyl acetate solution of N2-(((9H-fluorene-9-yl)methoxy)carbonyl)-N6-(tert-butoxycarbonyl)-L-lysine (10a, 4.31 kg, 9.2 mol) and hydroxyacetamidine 9a (1.1 equivalents (“equiv.” or “eq.”)). The mixture was stirred for 20 min at 25 °C. Then, propanephosphonic anhydride (T3P, 50% ethyl acetate solution, 3.0 equivalents) was added, and the reaction mixture was heated to 80 °C and stirred for 4 h (the conversion of compound 10a was approximately 60% according to HPLC). Then, compound 9a (1.1 equivalents) was added, and the reaction mixture was stirred at 80°C for 20 hours (the conversion of the remaining compound 10a was approximately 10%). The reaction mixture was cooled to room temperature, and saturated NaHCO3 aqueous solution (2.0 L) was added. The mixture was then extracted with ethyl acetate (3 × 1.0 L). The combined organic layer was washed with brine (1 L), dried with anhydrous Na2SO4, filtered, and concentrated to produce a crude residue, which was usually purified by silica gel column chromatography (petroleum ether (PE):EtOAc = 5:1) to produce the crude product, (9H-fluorene-9-yl)methyl tert-butyl (1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentane-1,5-diyl)(S)-dicarbamate (11a), and ACN solution (19.7 kg, content determined = 20%, chiral HPLC purity = 99.12A, yield = 73%). 1 H-NMR (300MHz, CDCl3): δ7.78(d,J=7.5Hz,2H),7.61(d,J=6.3Hz,2H),7.42(t,J=7.5Hz,2H),7.35-7.30(m,7H),5.52(br, 1H),5.09-5.05(m,1H),4.56-4.37(m,3H),4.22(t,J=6.6Hz,1H),4.08(s,2H),1.95-1.86(m,2H),1.48-1.42(m,11H)ppm. MS:(M-100+H) + :m / z=483.2.

[0209] Step c: Synthesis of tert-butyl(S)-(5-amino-5-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)-carbamate (5a). TEA (2.5 equivalents) was added to a solution of compound (9H-fluorene-9-yl)methyltert-butyl(1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentane-1,5-diyl)(S)-dicarbamate (11a). The mixture was stirred continuously for 15 hours using a mechanical stirrer at 20–25 °C. The reaction mixture was diluted with tap water and MTBE. The aqueous layer was separated once by MTBE extraction. The two MTBE layers were combined and then washed with NH4Cl. Then, anhydrous Na2SO4 was added, the solution was stirred for at least 2 hours, filtered and washed with MTBE to produce an MTBE solution of tert-butyl(S)-(5-amino-5-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)-carbamate (5a) (32.9 kg, content determination = 6.5%, yield = 88%). 1 H-NMR (300MHz, DMSO-d6): δ7.33-7.25(m,5H),6.78(br,1H),5.09-5.05(m,1H),4.56-4.37(m,3H),4.06(s,2H) ,3.98(t,J=6.6Hz,1H),2.87-2.84(m,2H),2.10(s,2H),1.38-1.34(m,2H),1.24(s,9H),1.20-1.15(m,2H)ppm. MS:(M+H) + :m / z=361.1.

[0210] Step d: Synthesis of (S)-1-(3-benzyl-1,2,4-oxadiazol-5-yl)-5-((tert-butoxycarbonyl)amino)pentane-1-amine 4-methylbenzenesulfonate (12a). p-Toluenesulfonic acid (PTSA) was added to an MTBE solution of crude tert-butyl(S)-(5-amino-5-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)-carbamate (5a) to produce (S)-1-(3-benzyl-1,2,4-oxadiazol-5-yl)-5-((tert-butoxycarbonyl)amino)pentane-1-amine 4-methylbenzenesulfonate (12a) (2.7 kg, yield = 85%, HPLC purity >99%, ee >99%), a white solid. 1H-NMR (400MHz, DMSO-d6): δ8.74(br,3H),7.48(d,J=8.0Hz,2H),7.37-7.26(m,5H),7.11(d,J=8.0Hz,2H),6.77(t,J=5. 2Hz,1H),4.82(t,J=6.8Hz,1H),4,17(s,2H),2.90-2.86(m,2H),2.29(s,3H),1.39-1.36(m,11H),1.35-1.28(m,2H)ppm. MS:(M-172+H) + :m / z=361.1.

[0211] Treatment

[0212] The following discussion is for illustrative purposes only and is not intended to be restrictive.

[0213] One aspect of the present invention includes a method for treating ALS, α-connucleoproteinopathy, or TDP-43 proteinopathy in subjects who are diagnosed with, suspected of having, or likely to have ALS, α-connucleoproteinopathy, or TDP-43 proteinopathy. In therapeutic applications, subjects suspected of having or already having ALS, α-connucleoproteinopathy, or TDP-43 proteinopathy are administered a mitochondrial-targeting mimic peptide (such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (I) or its pharmaceutically acceptable salts (such as tartrate, fumarate, citrate, benzoate, succinate, octanoate, lactate, oxalate, phthalate, methanesulfonate, benzenesulfonate, or maleate (in different cases, monohydrochloride, dihydrochloride, trihydrochloride), monoacetate, diacetate, triacetate, etc.). Compositions or pharmaceuticals of salts, mono- and trifluoroacetic acids, bis- and trifluoroacetic acids, trifluoroacetic acids, monohydrochlorides, bis- and trihydrochlorides (e.g., (Ia), monotoluenesulfonate, bis- and tritoluenesulfonate) are administered in amounts sufficient to cure or at least partially suppress disease symptoms, including their complications and intermediate pathological phenotypes in disease development. In some embodiments of the method described in this invention, the mitochondrial-targeting mimic peptide is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (I) or a pharmaceutically acceptable salt thereof (e.g., (Ia)).

[0214] Other aspects of the present invention include the use of a composition in the preparation of a medicament for the treatment or prevention of ALS, α-connucleopathies, or TDP-43 proteinopathy in subjects in need. Suitable for administration to subjects suspected of having or already having ALS, α-connucleopathies, or TDP-43 proteinopathy is a composition comprising a mitochondrial-targeting mimic peptide (such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (I) or a pharmaceutically acceptable salt thereof (such as tartrate, fumarate, citrate, benzoate, succinate, octanoate, lactate, oxalate, phthalate, methanesulfonate, benzenesulfonate, or maleate (in different cases, monohydrochloride, dihydrochloride, trihydrochloride), monoacetate, diacetate, triacetate, mono ... Compositions or drugs of trifluoroacetate, bis(trifluoroacetate), trifluoroacetate, monohydrochloride, dihydrochloride, trihydrochloride (e.g., (Ia), monotoluenesulfonate, ditoluenesulfonate, or tritoluenesulfonate) are administered in an amount sufficient to alleviate one or more signs or symptoms of ALS, α-connucleoproteinopathy, or TDP-43 proteinopathy in a subject. In some embodiments of the method described in this invention, the mitochondrial-targeting mimic peptide is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (I) or a pharmaceutically acceptable salt thereof (e.g., (Ia)).

[0215] A subject may be diagnosed with ALS, α-connucleoproteinopathy, or TDP-43 proteinopathy by any diagnostic or prognostic test known in the art or a combination thereof.

[0216] In therapeutic applications, subjects are administered a substance comprising a mitochondrial-targeting mimic peptide (such as 2(R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (I) or a pharmaceutically acceptable salt thereof (such as tartrate, fumarate, citrate, benzoate, succinate, octanoate, lactate, etc.). Compositions of amino acids, phthalates, methanesulfonates, benzenesulfonates, or maleates (in different cases, monohydrochlorides, dihydrochlorides, trihydrochlorides, etc.), monoacetates, diacetates, triacetates, monotrifluoroacetates, ditrifluoroacetates, trifluoroacetates, monohydrochlorides, dihydrochlorides, trihydrochlorides (e.g., (Ia), monotoluenesulfonate, ditoluenesulfonate, or tritoluenesulfonate). In some embodiments, the mimetic peptide composition is administered once, twice, three times, four times, or five times daily. In some embodiments, the mimic peptide composition is administered more than five times daily. Additionally, in some embodiments, the mimic peptide composition is administered once daily, every other day, every three days, every four days, every five days, or every six days. In some embodiments, the mimic peptide composition is administered once weekly, every two weeks, every three weeks, or monthly. In some embodiments, the mimic peptide composition is administered for 1, 2, 3, 4, or 5 weeks. In some embodiments, the mimic peptide is administered for 6 weeks or more. In some embodiments, the mimic peptide is administered for 12 weeks or more. In some embodiments, the mimic peptide is administered for no more than one year. In some embodiments, the mimic peptide is administered for more than one year, or until the subject's signs or symptoms of ALS, α-connucleoproteinopathy, or TDP-43 proteinopathy have lessened. In some embodiments, the mimic peptide is administered according to a physician's recommended regimen from the time the subject is diagnosed with, suspected of having, or likely to have ALS, α-connucleoproteinopathy, or TDP-43 proteinopathy until death.

[0217] Subjects treated according to this treatment method can be any mammal, including farm animals (such as sheep, pigs, cattle, and horses); pets (such as dogs and cats); and laboratory animals (such as rats, mice, and rabbits). In some embodiments, the mammal is a human.

[0218] In some embodiments, treatment of subjects diagnosed with or suspected of having ALS using one or more mitochondrial-targeting mimic peptides can improve or eliminate one or more of the following ALS symptoms: muscle weakness, muscle wasting (atrophy), fasciculations, muscle spasms, bradykinesia, poor balance, incoordination, voice changes, dysarthria, dysphagia, incomplete eyelid closure, drooling, pseudobulbar mood, and premature death. In some embodiments, treatment of subjects diagnosed with or suspected of having ALS using one or more mitochondrial-targeting mimic peptides can improve or eliminate symptoms of elevated brain transporter-18kDa (TSPO) expression levels. In some embodiments, treatment of subjects diagnosed with or suspected of having ALS using one or more mitochondrial-targeting mimic peptides can improve or eliminate NfL accumulation in plasma. In some embodiments, treatment of subjects diagnosed with or suspected of having ALS using one or more mitochondrial-targeting mimic peptides extends the subject's survival / lifespan. In some embodiments, the success of treatment with the mitochondrial-targeting mimic peptide is determined by detecting whether the subject’s symptoms have improved compared to one or more of the following: (1) baseline measurements or symptom levels detected before or during treatment; (2) measurements or symptom levels of a control subject or a group of control subjects, wherein the control subject has one or more ALS symptoms and (i) has not been given the mitochondrial-targeting mimic peptide, or (ii) has been given a control peptide or mimic peptide; or (3) a criterion.

[0219] In some embodiments, treatment of subjects diagnosed with or suspected of having α-connucleoproteinopathy with one or more mitochondrial-targeting mimic peptides can improve or eliminate one or more symptoms of α-connucleoproteinopathy, including but not limited to the loss of dopaminergic neurons in the subjects.

[0220] In some embodiments, treatment of subjects diagnosed with or suspected of having TDP-43 proteinopathy with one or more mitochondrial-targeting mimic peptides may improve or eliminate one or more symptoms of TDP-43 proteinopathy, including but not limited to a reduction in neurite length in the subject.

[0221] Prevention methods

[0222] On the one hand, the present invention provides a method for preventing or delaying the onset of ALS, α-connucleoproteinopathy, or TDP-43 proteinopathy or one or more of their symptoms in subjects who may have ALS, α-connucleoproteinopathy, or TDP-43 proteinopathy. In prophylactic applications, subjects suspected of having or possibly having ALS, α-connucleoproteinopathy, or TDP-43 proteinopathy are administered a mitochondrial-targeting mimic peptide (such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (I) or its pharmaceutically acceptable salts (such as tartrate, fumarate, citrate, benzoate, succinate, octanoate, lactate, oxalate, phthalate, methanesulfonate, benzenesulfonate, or maleate (in different cases, monohydrochloride, dihydrochloride, trihydrochloride), monoacetate, diacetate, triacetate, monotrifluoroacetate, etc.). A pharmaceutical composition or drug of bis(trifluoroacetate), trifluoroacetate, monohydrochloride, dihydrochloride, or trihydrochloride (e.g., (Ia), monotoluenesulfonate, ditoluenesulfonate, or tritoluenesulfonate) is administered in an amount sufficient to eliminate or reduce the risk, or delay the onset of disease, including biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes in disease development. In some embodiments of the method described in this invention, the mitochondrial-targeting mimic peptide is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (I) or a pharmaceutically acceptable salt thereof (e.g., (Ia)).

[0223] Prophylactic mitochondrial-targeting mimic peptides can be administered before the onset of disease- or disorder-specific symptoms, thereby preventing or delaying the progression of the disease or disorder.

[0224] In prophylactic applications, subjects are administered a mitochondrial-targeting mimic peptide (such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (I) or a pharmaceutically acceptable salt thereof (such as tartrate, fumarate, citrate, benzoate, succinate, octanoate, etc.). Compositions of salts, lactates, oxalates, phthalates, methanesulfonates, benzenesulfonates, or maleates (in different cases, monohydrochlorides, dihydrochlorides, trihydrochlorides, etc.), monoacetates, diacetates, triacetates, monotrifluoroacetates, ditrifluoroacetates, trifluoroacetates, monohydrochlorides, dihydrochlorides, trihydrochlorides (e.g., (Ia), monotoluenesulfonate, ditoluenesulfonate, or tritoluenesulfonate). In some embodiments, the mold is applied daily. The peptide-mimicking composition is administered once, twice, three times, four times, or five times. In some embodiments, the peptide-mimicking composition is administered more than five times daily. Additionally, in some embodiments, the peptide-mimicking composition is administered once daily, every other day, every three days, every four days, every five days, or every six days. In some embodiments, the peptide-mimicking composition is administered once weekly, every two weeks, every three weeks, or monthly. In some embodiments, the peptide-mimicking composition is administered for 1 week, 2 weeks, 3 weeks, 4 weeks, or 5 weeks. In some embodiments, the peptide-mimicking composition is administered for 6 weeks or more. In some embodiments, the peptide-mimicking composition is administered for 12 weeks or more. In some embodiments, the peptide-mimicking composition is administered for no more than one year. In some embodiments, the peptide-mimicking composition is administered for more than one year. In some embodiments, the peptide-mimicking composition is administered according to a physician's recommended regimen from the time the subject is diagnosed with, suspected of having, or likely to have ALS, α-connucleoproteinopathy, or TDP-43 proteinopathy until death.

[0225] In some embodiments, treatment with mitochondrial-targeting mimic peptides will prevent or delay the onset of one or more of the following symptoms: muscle weakness, muscle wasting (atrophy), fasciculations, muscle spasms, bradykinesia, poor balance, incoordination, voice quality changes, dysarthria, dysphagia, incomplete eyelid closure, drooling, pseudobulbar mood, and / or premature death. In some embodiments, treatment with mitochondrial-targeting mimic peptides will prevent or delay the onset of elevated brain transporter-18kDa (TSPO) expression levels. In some embodiments, treatment with mitochondrial-targeting mimic peptides will prevent or delay the onset of neurofilament light chain (NfL) accumulation in plasma. In some embodiments, treatment with mitochondrial-targeting mimic peptides will prevent or delay premature death. In some embodiments, treatment refers to delaying the onset of ALS neurological symptoms (assessed using the neurological function score described in this invention).

[0226] In some embodiments, treatment using mitochondrial-targeting mimic peptides can prevent, delay, or reduce the loss of dopaminergic neurons in subjects.

[0227] In some embodiments, treatment with mitochondrial-targeting mimic peptides can prevent or delay symptoms of reduced neurite length in subjects.

[0228] The mammals treated according to this preventive method can be any mammal, including farm animals (such as sheep, pigs, cattle, and horses); pets (such as dogs and cats); and laboratory animals (such as rats, mice, and rabbits). In some embodiments, the mammal is a human.

[0229] Determining the biological effects of mitochondrial-targeting mimic peptide therapeutics

[0230] In each embodiment, appropriate in vitro or in vivo assays are performed to determine the efficacy of a specific mitochondrial-targeting mimic peptide therapeutic agent and its suitability for treatment. In each embodiment, representative animal models may be used for in vitro assays to determine whether a given mitochondrial-targeting mimic peptide therapeutic agent has the intended effect in reducing or eliminating signs and / or symptoms of ALS, α-commonopathies, or TDP-43 proteinopathy.

[0231] animal models

[0232] Before testing in human subjects, the compound used in the treatment may be detected in appropriate animal model systems (including, but not limited to, rats, mice, chickens, cattle, monkeys, rabbits, etc.). Similarly, for in vivo testing, any animal model system known in the art may be used before administration to human subjects. In some embodiments, in vitro or in vivo testing aims to determine (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (I) or a pharmaceutically acceptable salt thereof (such as tartrate, fumarate, citrate, benzoate, succinate, octanoate, lactate, etc.). Biological functions of oxalates, phthalates, methanesulfonates, benzenesulfonates, or maleates (in different cases, monohydrochlorides, dihydrochlorides, and trihydrochlorides), monoacetates, diacetates, triacetates, monotrifluoroacetates, ditrifluoroacetates, trifluoroacetates, monohydrochlorides, dihydrochlorides, and trihydrochlorides (e.g., (Ia), monotoluenesulfonate, ditoluenesulfonate, or tritoluenesulfonate). In some embodiments, the animal model is an SOD1 G93A mouse model of ALS. In some embodiments, the animal model is a Sprague Dawley rat. In some embodiments, the animal model is a mutant α-synuclein transduced mouse. In some embodiments, the animal model is ppr-TDP-43. A315T -UeGFP mouse model (Gautam et al., Acta Neuropathologica Sinica, January 2019; 137(1):47-69).

[0233] Administration method and effective dosage

[0234] The mitochondrial-targeting mimic peptides (such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (I) or pharmaceutically acceptable salts thereof (such as tartrate, fumarate, citrate, benzoate, succinate, octanoate, lactate, oxalate, phthalate, methanesulfonate, benzenesulfonate, or maleate (in different cases, monohydrochloride, dihydrochloride, etc.)) described in this invention can be used to target cells, organs, or tissues. Any method of contacting trihydrochloride, monoacetate, diacetate, triacetate, monotrifluoroacetate, ditrifluoroacetate, trifluoroacetate, monohydrochloride, dihydrochloride, trihydrochloride (e.g., (Ia), monotoluenesulfonate, ditoluenesulfonate, or tritoluenesulfonate)). In some embodiments of the method described in this invention, the mitochondrial-targeting mimic peptide is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (I) or thereof. Medicinal salts (e.g., (Ia)). Suitable methods include in vitro, ex vivo, or in vivo methods. In vivo methods typically involve administration of the mitochondrial-targeting mimic peptide to a mammal (appropriately, a human). When used for treatment in vivo, the subject is given an effective amount (i.e., an amount with the intended therapeutic effect) of the said mitochondrial-targeting mimic peptide (e.g., (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (I) or a pharmaceutically acceptable salt thereof (e.g., tartrate, corydalis). Oxalate, citrate, benzoate, succinate, octanoate, lactate, oxalate, phthalate, methanesulfonate, benzenesulfonate, or maleate (as monohydrochloride, dihydrochloride, or trihydrochloride, respectively), monoacetate, diacetate, triacetate, monotrifluoroacetate, ditrifluoroacetate, trifluoroacetate, monohydrochloride, dihydrochloride, or trihydrochloride (e.g., (Ia), monotoluenesulfonate, ditoluenesulfonate, or tritoluenesulfonate)). Dosage and administration regimen will depend on the subject's disease, disorder, or severity of condition, the characteristics of the specific mitochondrial-targeting mimic peptide used (e.g., its therapeutic index), the subject, and the subject's medical history.

[0235] The effective amount can be determined in preclinical and clinical trials using methods known to physicians and clinicians. The effective amount of the mimic peptide used in the method of administration of any pharmaceutical compound known in the art can be administered to the desired mammal using any method of administration. The mimic peptide can be administered systemically or locally.

[0236] The mimetic peptide formulation may be a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" refers to a salt prepared using a base or acid that is administerable to a patient (e.g., a mammal) (e.g., a salt with acceptable safety in mammals under a given dosing regimen). However, it should be understood that the salt need not be a pharmaceutically acceptable salt, such as a salt of an intermediate compound not intended for patient administration. Pharmaceutically acceptable salts may be derived from pharmaceutically acceptable inorganic or organic bases and pharmaceutically acceptable inorganic or organic acids. Furthermore, when a peptide or mimetic peptide contains a basic group (such as an amine, pyridine, or imidazole) and an acidic group (such as a carboxylic acid or tetraazole), an amphoteric ion may be formed and contained within the term "salt" as used herein. Salts derived from pharmaceutically acceptable inorganic bases include ammonium salts, calcium salts, copper salts, ferric salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganese salts, potassium salts, sodium salts, and zinc salts, etc. Salts derived from medicinal organic bases include salts of primary, secondary, and tertiary amines (including substituted amines, cyclic amines, and natural amines, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-methylmorpholine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hepatoamide, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, trimethylamine (NEt3), trimethylamine, tripropylamine, tromethamine, etc.), said salts including protonated forms of organic bases (e.g., [HNEt3]). +Salts derived from pharmaceutically acceptable inorganic acids include salts of boric acid, carbonic acid, hydrohalic acids (hydrobromic acid, hydrochloric acid, hydrofluoric acid, or hydroiodic acid), nitric acid, phosphoric acid, aminosulfonic acid, and sulfuric acid. Salts derived from pharmaceutically acceptable organic acids include aliphatic hydroxy acids (e.g., citric acid, gluconic acid, glycolic acid, lactic acid, lactobionic acid, malic acid, and tartaric acid), aliphatic monocarboxylic acids (e.g., acetic acid, butyric acid, formic acid, propionic acid, and trifluoroacetic acid), amino acids (e.g., aspartic acid and glutamic acid), aromatic carboxylic acids (e.g., benzoic acid, p-chlorobenzoic acid, diphenylacetic acid, gentianic acid, hippuric acid, and triphenylacetic acid), and aromatic hydroxy acids (e.g., o-hydroxybenzoic acid, p-hydroxybenzoic acid, ...). Salts of 1-hydroxynaphthalene-2-carboxylic acid and 3-hydroxynaphthalene-2-carboxylic acid, ascorbic acid, dicarboxylic acids (e.g., fumaric acid, maleic acid, oxalic acid and succinic acid), glucuronic acid, mandelic acid, mucoic acid, nicotinic acid, orotic acid, pamoic acid, pantothenic acid, sulfonic acids (e.g., benzenesulfonic acid, camphorsulfonic acid, ethanedisulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2,6-disulfonic acid and p-toluenesulfonic acid (PTSA)), sine, etc. In some embodiments, the pharmaceutically acceptable balanced ions are selected from a group comprising: acetates, benzoates, benzenesulfonates, bromides, camphorsulfonates, chlorides, theophylline salts, citrates, ethanedisulfonates, fumarates, glucohepanoates, glucuronates, hippurates, iodides, hydroxyethylsulfonates, lactates, lactobionates, lauryl sulfate, malates, maleates, methanesulfonates, methyl sulfates, naphthates, salicylates, nitrates, octadecanoates, oleates, oxalates, dihydroxynaphthyl salts, phosphates, polygalacturonates, succinates, sulfates, sulfosalicylates, tartrates, toluenesulfonates, and trifluoroacetates. In some embodiments, the salt is tartrate, fumarate, citrate, benzoate, succinate, octanoate, lactate, oxalate, phthalate, methanesulfonate, benzenesulfonate, or maleate (in different cases, monohydrochloride, dihydrochloride, trihydrochloride), monoacetate, diacetate, triacetate, monotrifluoroacetate, ditrifluoroacetate, trifluoroacetate, monohydrochloride, dihydrochloride, trihydrochloride (e.g., (Ia), monotoluenesulfonate, ditoluenesulfonate, or tritoluenesulfonate). In some embodiments, the mimetic peptide formulation may be a monohydrochloride, dihydrochloride, or trihydrochloride (e.g., (Ia)).

[0237] The mitochondrial-targeting mimic peptides described in this invention (such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (I) or their pharmaceutically acceptable salts (such as tartrate, fumarate, citrate, benzoate, succinate, octanoate, lactate, oxalate, or phthalate) Dicarboxylate, methanesulfonate, benzenesulfonate, or maleate (in different cases, monohydrochloride, dihydrochloride, trihydrochloride, etc.), monoacetate, diacetate, triacetate, monotrifluoroacetate, ditrifluoroacetate, trifluoroacetate, monohydrochloride, dihydrochloride, trihydrochloride (e.g., (Ia), monotoluenesulfonate, ditoluenesulfonate, or tritoluenesulfonate)) are contained in a pharmaceutical composition (which may be administered to a subject alone or in combination to treat or prevent the disease, disorder, or impairment described herein). In the context of the disease, the mimic peptide can be formulated using other compounds (such as therapeutic agents, peptides, another mimic peptide, or mixtures thereof). In some embodiments of the method described in this invention, the mitochondrial-targeting mimic peptide is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (I) or a pharmaceutically acceptable salt thereof (e.g., (Ia)). Such compositions typically contain an active agent and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition can be used as a medicament for administration to subjects with ALS, α-connucleoproteinopathy, or TDP-43 proteinopathy, or in the preparation of such medicaments. Pharmaceutically acceptable carriers include saline, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic absorption delay agents, etc., and are compatible with drug administration. Additional active compounds may also be added to the composition.

[0238] Pharmaceutical compositions are typically formulated in a manner compatible with their intended route of administration. Examples of routes of administration include parenteral (e.g., intravenous, intradermal, intraperitoneal, or subcutaneous), oral, intravitreal, inhalation, transdermal (topical), intraocular, ocular, intrathecal, intraventricular, iontophoresis, and mucosal administration. In some embodiments, the route of administration is oral. In some embodiments, the route of administration is subcutaneous. Solutions or suspensions for parenteral, intradermal, or epidermal application may include the following components: a sterile diluent (such as water for injection, saline solution, fixative oil, polyethylene glycol, glycerol, propylene glycol, or other synthetic solvents); an antibacterial agent (such as benzyl alcohol or methylparaben); an antioxidant (such as ascorbic acid or sodium bisulfite); a chelating agent (such as ethylenediaminetetraacetic acid); a buffer (such as acetate, citrate, or phosphate); and an agent for adjusting tension (such as sodium chloride or glucose). The pH may be adjusted using an acid or base (such as hydrochloric acid or sodium hydroxide). Parenteral preparations may be packaged in ampoules, disposable syringes, or multi-dose vials made of glass or plastic. For ease of use by patients or treating physicians, a course of treatment (e.g., 7 days) may be provided alone or in a kit containing all necessary equipment (e.g., vials, diluent bottles, syringes, and needles).

[0239] Injectable pharmaceutical compositions may include sterile aqueous solutions (with water solubility) or dispersions, as well as sterile powders for the ad hoc preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, antibacterial water, and CREMOPHOR EL. TM (BASF (Parsipani, NJ)) or phosphate-buffered saline (PBS). In all cases, the parenteral composition must be sterile and should be an easily injectable liquid. The composition should be stable under the conditions of manufacture and storage and must be protected against contamination by microorganisms such as bacteria and fungi during storage.

[0240] Compositions containing mitochondrial-targeting mimic peptides may include a carrier, which may be a solvent or dispersion medium comprising water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), and suitable mixtures thereof. Appropriate flowability can be maintained by using coatings such as lecithin, maintaining the desired particle size in the dispersed state, and using surfactants. Microbial activity can be prevented by using various antimicrobial and antifungal agents such as parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal. Glutathione and other antioxidants may be included to prevent oxidation. In many cases, the inclusion of isotonic agents (e.g., sugars, polyols such as mannitol, sorbitol, or sodium chloride) in the composition is advantageous. The addition of absorption-delaying agents (e.g., aluminum monostearate or gelatin) to the composition can prolong the absorption of the injectable composition.

[0241] A sterile injectable solution is prepared by adding the required amount of the active compound and one or more of the aforementioned components or combinations to a suitable reagent, followed by filtration and sterilization as needed. Typically, the active compound is added to a sterile carrier (containing the base dispersion medium and the other required components described above) to prepare a dispersion. For the preparation of sterile powders for sterile injectable solutions, typical preparation methods include vacuum drying and freeze-drying, by which powders containing the active ingredient and any additional desired components can be produced from previously sterile filtered solutions.

[0242] Oral compositions typically contain an inert diluent or an edible carrier. For oral therapeutic administration, the active compound may contain excipients and be used in the form of tablets, lozenges, or capsules (e.g., gelatin capsules). Oral compositions may also be prepared using liquid carriers (as mouthwash). Pharmaceutically compatible binders and / or excipients may be included as part of the composition. Tablets, capsules, pills, lozenges, etc., may contain any of the following components or compounds with similar properties: binders (e.g., microcrystalline cellulose, tragacanth gum, or gelatin); excipients (e.g., starch or lactose); disintegrants (e.g., alginate, Primogel, or corn starch); lubricants (e.g., magnesium stearate or stearate esters); gliding agents (e.g., colloidal silica); sweeteners (e.g., sucrose or saccharin); or flavoring agents (e.g., peppermint, methyl salicylate, or orange flavoring).

[0243] Inert substances can be used to dilute or increase the volume of compounds, therapeutic agents, peptides, peptide analogs, or mixtures thereof. These diluents may include carbohydrates, particularly mannitol, lactose, anhydrous lactose, cellulose, sucrose, modified dextran, and starch. Certain inorganic salts may also be used as fillers, including calcium triphosphate, magnesium carbonate, and sodium chloride. Some commercially available diluents include Fast-Flo, Emdex, STA-Rx 1500, Emcompress, and Avicel.

[0244] Disintegrants and inert substances can be included in the formulation of compounds, therapeutic agents, peptides, peptide mimics, or mixtures thereof to form solid dosage forms. Substances used as disintegrants include, but are not limited to, starch, including the commercially available starch-based disintegrant Explotab. Sodium carboxymethyl starch, Amberlite, sodium carboxymethyl cellulose, hyperbranched starch, sodium alginate, gelatin, orange peel, acidic carboxymethyl cellulose, natural sponges, and bentonite can be used. Another form of disintegrant is an insoluble cation exchange resin. Powdered gums can be used as disintegrants and binders, including powdered gums such as agar, sycamore gum, or tragacanth gum. Alginic acid and its sodium salts can also be used as disintegrants.

[0245] Binders can be used to immobilize compounds, therapeutic agents, peptides, peptide mimics, or mixtures thereof, as well as inert substances, to form hard tablets, and may contain substances composed of natural products such as gum arabic, tragacanth, starch, and gelatin. Other binders include methylcellulose (MC), ethylcellulose (EC), and carboxymethylcellulose (CMC). Polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose (HPMC) may be included in alcoholic solutions to granulate the therapeutic agent.

[0246] Friction reducers may be included in the formulation of compounds, therapeutic agents, peptides, peptide mimics, or mixtures thereof to prevent sticking during formulation. A lubricant may be added between the therapeutic agent and the mold wall, said lubricant including, but not limited to, stearic acid (including its magnesium and calcium salts), polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils, and waxes. Soluble lubricants such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol (of different molecular weights), Carbowax 4000, and 6000 may also be used.

[0247] A flow aid may be added to improve drug flow properties during formulation and promote rearrangement during compression. The flow aid may include starch, talc, fumed silica, pyrolytic silica, and hydrated aluminosilicate.

[0248] To facilitate the dissolution of compounds, therapeutic agents, peptides, peptide mimics, or mixtures thereof into an aqueous environment, surfactants may be added as wetting agents. Surfactants may include anionic detergents such as sodium lauryl sulfate, sodium dioctyl sulfosuccinate, and sodium dioctyl sulfonate. Suitable anionic detergents may include benzalkonium chloride and benzyl chloride. Potential nonionic detergents that may be included as surfactants in formulation include polidocanol 400, polyethylene glycol stearate 40, polyoxyethylene hydrogenated castor oil 10, 50, and 60, glyceryl monostearate, polysorbate 40, 60, 65, and 80, sucrose fatty acid esters, methylcellulose, and carboxymethylcellulose. These surfactants may be present when formulating compounds, therapeutic agents, peptides, peptide mimics, or mixtures thereof described in this technology, or when formulating derivatives alone or in mixtures at different ratios.

[0249] Orally edible pharmaceutical formulations include push-fit capsules made of gelatin and sealed soft capsules made of gelatin and plasticizers (such as glycerin or sorbitol). The push-fit capsules may contain the active ingredient, as well as fillers (such as lactose), binders (such as starch), and / or lubricants (such as talc or magnesium stearate), and stabilizers (optionally). In the soft capsules, the active compound may be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers may be added. Oral microspheres may also be used. Such microspheres are clearly defined in the art. All oral formulations should be administered at a dose appropriate for the route of administration.

[0250] For inhalation administration, compounds, therapeutic agents, peptides, peptide mimics, or mixtures thereof used according to this application may be delivered in the form of an aerosol spray using a pressurized pack or nebulizer, wherein a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas, will be used. In some embodiments, the compound may be delivered in the form of an aerosol spray using a pressurized container, applicator (containing a suitable propellant, such as a gas like carbon dioxide), or nebulizer. Such methods include those described in U.S. Patent No. 6,468,798. When using a pressurized aerosol, a metering valve may be provided to determine the dose unit. Gelatin capsules and cartridges for inhalers or blowpipes may contain a mixture of the compound and a suitable powder matrix (lactose or starch).

[0251] Upon inhalation, compounds, therapeutic agents, peptides, peptide mimics, or mixtures thereof can be delivered to the lungs of mammals and cross the endothelial membrane of the lungs to enter the bloodstream. Other inhaled molecules reported include Adjei et al., *Pharmaceutical Research*, 7:565-569 (1990); Adjei et al., *International Journal of Pharmacy*, 63:135-144 (1990) (leuprolide acetate); Braquet et al., *American Journal of Cardiovascular Pharmacology*, 13(Supplement 5):143-146 (1989) (endothelin-1); Hubbard et al., *Annals of Internal Medicine*, 3:206-212 (1989) (antitrypsin); Smith et al., *Journal of Clinical Research*, 1989. , 84:1145-1146 (α-1-protease); Oswein et al., 1990, “Protein Nebulization,” Proceedings of the Symposium on Respiratory Drug Delivery II, Giston, Colorado, March, (Recombinant Human Growth Hormone); Debs et al., 1988, Journal of Immunology, 140:3482-3488 (Interferon γ and Tumor Necrosis Factor α); and Platz et al., U.S. Patent No. 5,284,656 (Granocyte Colony-Stimulating Factor; which is incorporated herein by reference). U.S. Patent No. 5,451,569 (Wong et al., Issued September 19, 1995; which is incorporated herein by reference) describes methods and compositions for pulmonary drug delivery with systemic effects.

[0252] Consider using various mechanical devices suitable for lung delivery therapeutic products in this technical practice, including but not limited to nebulizers, metered-dose inhalers and dry powder inhalers well known to those skilled in the art.

[0253] Some specific examples of commercially available devices suitable for this technical practice are the Ultravent nebulizer manufactured by Marlinkro Corporation (St. Louis, Missouri); the Acorn II nebulizer manufactured by Marquest Medical Products Corporation (Englewood, Colorado); the Ventolin metered-dose inhaler manufactured by GlaxoSmithKline (Triangle Science Park, North Carolina); and the Spinhaler dry powder inhaler manufactured by Faisons Corporation (Bedford, Massachusetts).

[0254] For ocular or intraocular formulations, any suitable mitochondrial-targeted mimetic peptide delivery modality described in this invention (with or without a therapeutic agent, peptide, or other mimetic peptide, such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (I) or its pharmaceutically acceptable salts (such as tartrate, fumarate, citrate, benzoate, succinate, octanoate, lactate, oxalate, phthalate) can be used on the eye or surrounding area. Dicarboxylate, methanesulfonate, benzenesulfonate, or maleate (in different cases, monohydrochloride, dihydrochloride, trihydrochloride, etc.), monoacetate, diacetate, triacetate, monotrifluoroacetate, ditrifluoroacetate, trifluoroacetate, monohydrochloride, dihydrochloride, trihydrochloride (e.g., (Ia), monotoluenesulfonate, ditoluenesulfonate, or tritoluenesulfonate)). For ophthalmic formulations, see Mitra (ed.), *Ophthalmic Drug Delivery Systems*, Marcel Decker, NY, NY, 1993, and also Havener, WH, *Ophthalmic Pharmacology*, CV Mosby. Co. Publishers (St. Louis), (1983). Non-limiting examples of formulations suitable for intraocular or periocular administration include, but are not limited to, ophthalmic inserts, microtablets, and topical formulations such as eye drops, creams, and in situ gels. In one embodiment, the contact lens is coated with the mitochondrial-targeting mimic peptide of the present invention (such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (I) or a pharmaceutically acceptable salt thereof (such as tartrate, corydalis). Salts, citrates, benzoates, succinates, octanoates, lactates, oxalates, phthalates, methanesulfonates, benzenesulfonates, or maleates (in different cases, monohydrochlorides, dihydrochlorides, trihydrochlorides), monoacetates, diacetates, triacetates, monotrifluoroacetates, ditrifluoroacetates, trifluoroacetates, monohydrochlorides, dihydrochlorides, trihydrochlorides (e.g., (Ia), monotoluenesulfonate, ditoluenesulfonate, or tritoluenesulfonate)). In some embodiments, when administered to the eye, a single dose comprises 0.1 ng–5000 μg, 1 ng–500 μg, or 10 ng–100 μg of mitochondrial-targeting mimic peptide.

[0255] The eye drops comprise a sterile liquid formulation for direct administration to the eye. In some embodiments, they comprise one or more mitochondrial-targeting mimic peptides of the present invention (such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (I) or pharmaceutically acceptable salts thereof (such as tartrate, fumarate, monoacetate, citrate, benzoate, succinate, octanoate, lactate, oxalate). Eye drops containing salts, phthalates, methanesulfonates, benzenesulfonates, or maleates (in different cases, monohydrochlorides, dihydrochlorides, and trihydrochlorides, respectively), monoacetates, diacetates, triacetates, monotrifluoroacetates, ditrifluoroacetates, trifluoroacetates, monohydrochlorides, dihydrochlorides, and trihydrochlorides (e.g., (Ia), monotoluenesulfonate, ditoluenesulfonate, or tritoluenesulfonate)) further contain one or more preservatives. In some embodiments, the optimal pH of the eye drops is equal to the pH of the tear film, approximately 7.4.

[0256] In-situ gels are viscous liquids that can undergo a sol-gel transition when influenced by external factors such as appropriate pH, temperature, and the presence of electrolytes. Due to this property, drug drainage across the ocular surface is slow, and the bioavailability of the active ingredient is enhanced. Polymers commonly used in in-situ gel formulations include, but are not limited to, gellan gum, porrosham, and cellulose acetate phthalate.

[0257] For local administration, compounds, therapeutic agents, peptides, peptide mimics, or mixtures thereof can be formulated as solutions, gels, ointments, creams, suspensions, etc., as is well known in the art. Creams are semi-solid dosage forms for topical application, such as to the eyes or skin. In some embodiments, creams comprise a solid or semi-solid hydrocarbon matrix with a melting or softening point close to core body temperature. In some embodiments, creams applied to the eyes decompose into droplets that remain on the conjunctival sac for a longer period, thus improving bioavailability.

[0258] Ophthalmic inlays are solid or semi-solid dosage forms, avoiding the drawbacks of traditional ophthalmic drug formulations. These formulations are less susceptible to defense mechanisms (such as drainage through the nasolacrimal duct), can remain on the conjunctival sac for a longer period, and are more stable than traditional formulations. Furthermore, these formulations offer the following advantages: precise delivery of one or more mitochondrial-targeting mimic peptides; slow, constant-rate release of one or more mitochondrial-targeting mimic peptides; and limitation of systemic absorption of one or more mitochondrial-targeting mimic peptides. In some embodiments, the ophthalmic embedding agent comprises one or more mitochondrial-targeting mimic peptides of the present invention (such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (I) or pharmaceutically acceptable salts thereof (such as tartrate, fumarate, citrate, benzoate, succinate, octanoate, lactate, oxalate, phthalate, methanesulfonic acid). Salts, benzenesulfonates, or maleates (in different cases, monohydrochlorides, dihydrochlorides, and trihydrochlorides, respectively), monoacetates, diacetates, triacetates, monotrifluoroacetates, ditrifluoroacetates, trifluoroacetates, monohydrochlorides, dihydrochlorides, trihydrochlorides (e.g., (Ia), monotoluenesulfonate, ditoluenesulfonate, or tritoluenesulfonate)), and one or more polymeric materials. The polymeric materials include, but are not limited to, methylcellulose and its derivatives (e.g., hydroxypropyl methylcellulose (HPMC)), ethylcellulose, polyvinylpyrrolidone (PVP K-90), polyvinyl alcohol, chitosan, carboxymethyl chitosan, gelatin, and various mixtures of the above polymers.

[0259] Microtablets are biodegradable solid drug formulations that transform into a gel upon application to the conjunctival sac, thereby prolonging the contact time between the active ingredient and the ocular surface and improving its bioavailability. Advantages of microtablets include: ease of application to the conjunctival sac; resistance to defense mechanisms (such as tearing or drainage through the nasolacrimal duct); prolonged contact time with the cornea due to the presence of mucosal adhesive polymers; and gradual release of the active ingredient from the formulation at the application site due to swelling of the outer carrier layer. The microtablets comprise one or more mitochondrial-targeting mimic peptides as described in this invention (such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (I) or pharmaceutically acceptable salts thereof (such as tartrate, fumarate, citrate, benzoate, succinate, octanoate, lactate, oxalate, phthalate, methanesulfonate, benzenesulfonate, or maleate (in different cases, monohydrochloride, dihydrochloride, trihydrochloride, etc.), monoacetate, diacetate, triacetate, or monotrifluoroacetate). The microtablets contain bis(trifluoroacetate), trifluoroacetate, monohydrochloride, dihydrochloride, trihydrochloride (e.g., (Ia), monotoluenesulfonate, ditoluenesulfonate, or tritoluenesulfonate), and one or more polymers. Non-limiting examples of polymers suitable for microtablets include cellulose derivatives (such as hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), sodium carboxymethyl cellulose, ethyl cellulose), acrylates (e.g., polyacrylic acid and its crosslinked forms), carbopol or carbomer, chitosan, and starch (e.g., drum-dried waxy corn starch). In some embodiments, the microtablets further comprise one or more excipients. Non-limiting examples of excipients include mannitol and magnesium stearate.

[0260] Ocular or intraocular preparations may contain non-toxic excipients, such as antimicrobial components that are harmless during use, for example, thimerosal, benzalkonium chloride, methylparaben and propylparaben, benzyl dodecanoate bromide, benzyl alcohol or phenylethanol; buffering components, such as sodium chloride, sodium borate, sodium acetate, sodium citrate or gluconate buffer; and other conventional components, such as sorbitol monolaurate, triethanolamine, polyoxyethylene sorbitol monopalmitate, ethylenediaminetetraacetic acid, etc.

[0261] In some embodiments, an addition is made of one or more mitochondrial-targeting mimic peptides described in this invention (such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (I) or a pharmaceutically acceptable salt thereof (such as tartrate, fumarate, citrate, benzoate, succinate, octanoate, lactate, oxalate, phthalate, methanesulfonate, benzenesulfonate, or maleate (in different cases, monohydrochloride, dihydrochloride, etc.) Viscosity of ophthalmic formulations containing salts, trihydrochlorides, monoacetates, diacetates, triacetates, monotrifluoroacetates, ditrifluoroacetates, trifluoroacetates, monohydrochlorides, dihydrochlorides, and trihydrochlorides (e.g., (Ia), monotoluenesulfonate, ditoluenesulfonate, or tritoluenesulfonate) can be improved to enhance contact with the cornea and increase intraocular bioavailability. To increase viscosity, high molecular weight hydrophilic polymers that do not diffuse through biological membranes and can form a three-dimensional network in water can be added. Non-limiting examples of such polymers include polyvinyl alcohol, poloxamer, hyaluronic acid, carbomer and polysaccharides, cellulose derivatives, gellan gum, and xanthan gum.

[0262] Systemic administration of the compounds, therapeutic agents, peptides, peptide mimics, or mixtures thereof described in this invention can also be achieved via mucosal or transdermal routes. To achieve mucosal or transdermal administration, a penetrant suitable for the target permeability barrier can be used in the formulation. Such penetrants are well known in the art and include detergents, bile salts, and fusidic acid derivatives (for mucosal administration). Mucosal administration can be achieved using nasal sprays. For transdermal administration, the active compound is formulated as a cream, ointment, gel, or ointment well known in the art. In one embodiment, transdermal administration can be achieved via iontophoresis.

[0263] Compounds, therapeutic agents, peptides, peptide mimics, or mixtures thereof can be formulated in a carrier system. The carrier can be a colloidal system. The colloidal system can be a liposome, a phospholipid bilayer carrier. In one embodiment, the compound, therapeutic agent, peptide, peptide mimic, or mixture thereof is encapsulated in a liposome while maintaining its integrity. Those skilled in the art will understand that various methods exist for preparing liposomes. (See Lichtenberg et al., Biochemical Analysis Methods, 33:337-462 (1988); Anselem et al., Liposome Technology, CRC Press (1993)). Liposome formulations can delay clearance and increase cellular uptake (see Reddy, Annals of Pharmacotherapy, 34(7-8):915-923 (2000)). An active agent (including, but not limited to, soluble, insoluble, permeable, impermeable, biodegradable, or gastric-retention polymers or liposomes) can also be encapsulated in particles prepared using pharmaceutically acceptable ingredients. Such particles include, but are not limited to, nanoparticles, biodegradable nanoparticles, microparticles, biodegradable microparticles, nanospheres, biodegradable nanospheres, microspheres, biodegradable microspheres, capsules, emulsions, liposomes, micelles, and viral vector systems.

[0264] The carrier may also be a polymer, such as a biodegradable, biocompatible polymer matrix. In one embodiment, the compound, therapeutic agent, peptide, peptide mimic, or mixture thereof may be embedded in a polymer matrix while maintaining the integrity of the composition. The polymer may be a natural polymer (such as a polypeptide, protein, or polysaccharide) or a synthetic polymer (such as polyalphahydroxy acid). Examples include carriers made from collagen, fibronectin, elastin, cellulose acetate, cellulose nitrate, polysaccharides, fibroin, gelatin, and combinations thereof. In one embodiment, the polymer is polylactic acid (PLA) or lactoglycolic acid copolymer (PLGA). Polymer matrices can be prepared and isolated in various forms and sizes, including microspheres and nanospheres. Polymer formulations can prolong the duration of therapeutic effect. (See Reddy, Annals of Pharmacotherapy, 34(7-8):915-923(2000)). Polymer formulations of human growth hormone (hGH) have been used in clinical trials. (See Kozarich and Rich, Chemical Biology, 2:548-552(1998)).

[0265] Examples of sustained-release formulations of polymeric microspheres can be found in PCT Publication WO 99 / 15154 (Tracy et al.), U.S. Patents Nos. 5,674,534 and 5,716,644 (Zale et al.), PCT Publication WO 96 / 40073 (Zale et al.), and PCT Publication WO 00 / 38651 (Shah et al.). U.S. Patents Nos. 5,674,534 and 5,716,644 and PCT Publication WO 96 / 40073 describe a polymer matrix comprising erythropoietin particles (with salt aggregation stability).

[0266] In some embodiments, the therapeutic compound is prepared using a carrier that prevents the compound from being rapidly expelled from the body, such as a controlled-release formulation, including implants and microcapsule delivery systems. Biodegradable, biocompatible polymers such as ethylene-vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Such formulations can be prepared using known techniques. These materials are also commercially available from Alza and Nova Pharmaceuticals. Liposome suspensions (liposomes containing cells-specific targets (monoclonal antibodies containing cell-specific antigens)) can also be used as pharmaceutically acceptable carriers. These materials can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.

[0267] The therapeutic compounds can also be used to enhance intracellular delivery. For example, liposome delivery systems are well known in the art; see Chonn and Cullis, “Advances in research on liposome drug delivery systems,” *Recent Biotechnology Review*, 6:698-708 (1995); Weiner, “Liposomes for protein delivery: Selective manufacturing and fabrication processes,” *Immunomethods*, 4(3):201-9 (1994); and Gregoriadis, “Engineering liposomes for drug delivery: Advances and problems,” *Trends in Biotechnology*, 13(12):527-37 (1995). The use of membrane-fused liposomes to deliver proteins to cells in vivo and in vitro is described in *Oncology Communications*, Mizguchi et al., 100:63-69 (1996).

[0268] In addition to the formulations described above, compounds, therapeutic agents, peptides, peptide mimics, or mixtures thereof may also be formulated as reservoir-type formulations. Such long-acting formulations may be formulated using suitable polymers or hydrophobic materials (e.g., emulsions in usable oils) or ion exchange resins, or formulated as slightly soluble derivatives (e.g., slightly soluble salts).

[0269] Compounds, therapeutic agents, peptides, peptide mimics, or mixtures thereof can be provided in particles or polymer microspheres. Examples of sustained-release formulations of polymer microspheres are found in PCT Publication WO 99 / 15154 (Tracy et al.), U.S. Patents Nos. 5,674,534 and 5,716,644 (Zale et al.), PCT Publication WO 96 / 40073 (Zale et al.), and PCT Publication WO 00 / 38651 (Shah et al.). U.S. Patents Nos. 5,674,534 and 5,716,644 and PCT Publication WO 96 / 40073 describe a polymer matrix comprising erythropoietin particles (with salt aggregation stability). The core of the particle contains a therapeutic agent and is surrounded by a coating (including, but not limited to, enteric coating). The compound, therapeutic agent, peptide, peptide mimic, or mixture thereof may also be dispersed throughout the particle. The compound, therapeutic agent, peptide, peptide mimic, or mixture thereof may also be adsorbed into the particle. The particles may possess any level of release kinetics, including zero-order release, first-order release, second-order release, delayed release, sustained release, immediate release, and any combination thereof. In addition to the compounds, therapeutic agents, peptides, peptide mimics, or mixtures thereof, the particles may also comprise any materials commonly used in the pharmaceutical and medical fields, including but not limited to soluble, non-soluble, biodegradable, or non-biodegradable materials, or combinations thereof. The particles may be microcapsules containing the compounds described herein, in a solution or semi-solid state. The particles may have various shapes.

[0270] Particles for delivering said compounds, therapeutic agents, peptides, peptide mimics, or mixtures thereof can be produced using both non-biodegradable and biodegradable polymer materials. Such polymers can be natural or synthetic polymers. The polymers can be natural polymers (such as peptides, proteins, or polysaccharides) or synthetic polymers (such as polyalphahydroxy acids). Examples include carriers made from collagen, fibronectin, elastin, cellulose acetate, cellulose nitrate, polysaccharides, fibroin, gelatin, and combinations thereof. Particularly relevant bioadhesive polymers include biocorrosive hydrogels (such as those described in Sawhney HS et al., 1993, Macromolecules, 26:581-7, the guidance of which is incorporated herein by reference). These include polyhyaluronic acid, casein, gelatin, gelatin protein, polyanhydride, polyacrylic acid, alginate, chitosan, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(laurate methacrylate), poly(phenyl methacrylate), poly(methyl methacrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), and polycaprolactone.

[0271] The controlled-release system may contain the compound, therapeutic agent, peptide, peptide mimicry, or mixture thereof. The term "controlled release" refers to any drug-containing formulation that releases the drug from the formulation in a controlled-release manner. This includes both immediate-release and non-immediate-release formulations, with non-immediate-release formulations including, but not limited to, sustained-release and delayed-release formulations. The term "sustained-release" (also known as "delayed-release") conventionally refers to a drug formulation that releases the drug gradually over a longer period of time, preferably but not necessarily resulting in a substantially constant plasma concentration over that period. The term "delayed-release" conventionally refers to a drug formulation in which there is a time delay between administration and drug release. "Delayed-release" may or may not involve the gradual release of the drug over a longer period of time, and therefore may or may not be "sustained-release."

[0272] Long-acting, sustained-release implants are particularly suitable for treating chronic diseases. In this invention, "long-acting" release means that the implant (reservoir) can deliver therapeutic levels of the active ingredient (i.e., a compound, therapeutic agent, peptide, peptide mimicry, or mixture thereof) for at least 7 days (preferably 30-60 days). Long-acting, sustained-release implants are well known to those skilled in the art, including some of the drug delivery systems described above.

[0273] The dosage, toxicity, and efficacy of any compound, therapeutic agent, peptide, peptide mimicry, or mixture thereof can be determined using standard pharmaceutical procedures in cell culture or laboratory animals, for example, to determine the LD50 (50% lethal dose) and ED50 (50% therapeutically effective dose). The dose ratio between toxic and therapeutic effects is the therapeutic index, expressed as the LD50 / ED50 ratio. Compounds with higher therapeutic indices are advantageous. Although compounds with toxic side effects can be used, delivery systems should be carefully designed to target such compounds to affected tissue sites to minimize potential damage to uninfected cells, thereby reducing side effects.

[0274] When establishing dosage ranges for human use, data obtained from cell culture assays and animal studies can be used. Doses of such compounds can be found in a range of circulating concentrations including the ED50 (meaning minimal or no toxicity). This dosage may vary within this range depending on the dosage used and the route of administration. For any compound used in the methods described, an initial estimate of the therapeutically effective dose can be made from cell culture assays. Doses can be established in animal models to achieve a range of circulating blood concentrations, including the IC50 (determined in cell culture), i.e., the concentration of the test compound at which half-maximal inhibition of symptoms is achieved. This information can be used to accurately determine the useful dose for human use. Blood concentrations can be measured by high-performance liquid chromatography (HPLC).

[0275] Generally, an effective amount of mitochondrial-targeting mimic peptide is approximately 0.000001 mg / kg body weight to approximately 10,000 mg / kg body weight per day, sufficient to achieve a therapeutic or preventative effect. Suitablely, the dosage range is approximately 0.0001 mg / kg body weight to approximately 100 mg / kg body weight per day. For example, the dosage may be 1 mg / kg body weight or 10 mg / kg body weight per day, every two or three days, or in the range of 1-10 mg / kg per week, every two or three weeks. In one embodiment, a single dose of the peptide or mimic peptide ranges from 0.001 to 10,000 mg / kg body weight. In one embodiment, the concentration of the mitochondrial-targeting mimic peptide in the carrier is 0.2-2000 mg per 1 ml delivered. An exemplary treatment regimen is once daily or weekly administration. In therapeutic applications, it is sometimes necessary to use relatively high doses over relatively short time intervals until disease progression slows or ceases, or until the subject's disease symptoms are partially or completely improved. Thereafter, the patient may be administered the medication as a preventative measure.

[0276] In some embodiments, a therapeutically effective amount of the mitochondrial-targeting mimic peptide can be defined as 10 at the target tissue. -12 -10 -6 Moore (e.g., about 10) -7 The simulated peptide concentration is (in moles). This concentration can be delivered via a systemic dose of 0.001–100 mg / kg or an equivalent dose calculated based on body surface area. Dosing regimens will be optimized to maintain therapeutic concentrations at the target tissue, such as by daily or weekly administration, but also include continuous administration (e.g., parenteral infusion or transdermal administration).

[0277] Those skilled in the art will understand that certain factors may affect the dosage and duration required for effective treatment of a subject, including but not limited to the severity of the subject's disease or disorder, prior treatment, overall health status and / or age, and other existing conditions. Furthermore, treatment of a subject with a therapeutically effective amount of the compound, therapeutic agent, peptide, peptide mimicry, or mixture thereof described in this invention may comprise a single treatment or a series of treatments.

[0278] combination therapy

[0279] In some embodiments, the mitochondrial-targeting mimic peptide (such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-xylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (I) or its pharmaceutically acceptable salts (such as tartrate, fumarate, citrate, benzoate, succinate, octanoate, lactate, oxalate, phthalate, methanesulfonate, benzenesulfonate, or maleate (in different cases, monohydrochloride, dihydrochloride, trihydrochloride, etc.), monoacetate, diacetate, triacetate, monotrifluoroacetate, ditrifluoroacetate, etc.) Trifluoroacetate, monohydrochloride, dihydrochloride, and trihydrochloride (e.g., (Ia), monotoluenesulfonate, ditoluenesulfonate, or tritoluenesulfonate) can be administered in combination with one or more other therapies for the prevention or treatment of ALS. In some embodiments of the method described in this invention, the mitochondrial-targeting mimic peptide is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (I) or a pharmaceutically acceptable salt thereof (e.g., (Ia)). In some embodiments, other therapies include, but are not limited to, administration of riluzole. Idaravon Mecaserine, Baclofen stable Danqulin Nonsteroidal anti-inflammatory drugs (NSAIDs) and anticonvulsants (e.g., carbamazepine) or phenytoin Amitriptyline nortriptyline (Pamelor) TM ) and chlorohydroxynordiazepoxide In some embodiments, the other therapies include combination administration of elamipretide (i.e., SS-31 or bendavia).

[0280] In some embodiments, the mitochondrial-targeting mimic peptide and riluzole are administered alone, simultaneously, or sequentially. In some embodiments, the dose of riluzole is about 0.5 mg / kg to about 2 mg / kg, about 1 mg / kg to about 2 mg / kg, about 0.5 mg / kg to about 5 mg / kg, about 5 mg / kg to about 100 mg / kg, about 10 mg / kg to about 75 mg / kg, or about 25 mg / kg to about 50 mg / kg. In some embodiments, the resveratrol dosage is 0.8 mg / kg, about 5 mg / kg, about 10 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 40 mg / kg, about 50 mg / kg, about 60 mg / kg, about 75 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 110 mg / kg, about 120 mg / kg, about 125 mg / kg, about 130 mg / kg, about 140 mg / kg, about 150 mg / kg, about 160 mg / kg, about 175 mg / kg, about 180 mg / kg, about 190 mg / kg, about 200 mg / kg or more. In some embodiments, riluzole is administered in the following schedules: twice daily, once daily, every 48 hours, every 72 hours, twice weekly, once weekly, every two weeks, once monthly, once every two months, once every three months, or once every six months. In some embodiments, the dosage of riluzole depends on the subject's weight and / or age.

[0281] In some embodiments, the mitochondrial-targeting mimic peptide and mecaseemine are administered alone, simultaneously, or sequentially. In some embodiments, the dosage of mecaseemine is about 0.5 mg / kg to about 2 mg / kg, about 1 mg / kg to about 2 mg / kg, about 0.5 mg / kg to about 5 mg / kg, about 5 mg / kg to about 100 mg / kg, about 10 mg / kg to about 75 mg / kg, or about 25 mg / kg to about 50 mg / kg. In some embodiments, the resveratrol dosage is 0.8 mg / kg, about 5 mg / kg, about 10 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 40 mg / kg, about 50 mg / kg, about 60 mg / kg, about 75 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 110 mg / kg, about 120 mg / kg, about 125 mg / kg, about 130 mg / kg, about 140 mg / kg, about 150 mg / kg, about 160 mg / kg, about 175 mg / kg, about 180 mg / kg, about 190 mg / kg, about 200 mg / kg or more. In some embodiments, mecaserine is administered according to the following schedule: twice daily, once daily, every 48 hours, every 72 hours, twice weekly, once weekly, every two weeks, once monthly, once every two months, once every three months, or once every six months. In some embodiments, the dosage of mecaserine is determined based on the subject's weight and / or age.

[0282] In one embodiment, at least one mitochondrial-targeting mimic peptide is administered to a subject in combination with other therapeutic agents to produce a synergistic therapeutic effect. For example, administration of at least one mitochondrial-targeting mimic peptide along with one or more other therapeutic agents for the prevention or treatment of ALS will have a greater effect in preventing or treating the disease than an additive effect. Therefore, in treating or preventing ALS, lower doses of one or more of any single therapeutic agents can be used to increase efficacy and reduce side effects. In some embodiments, at least one mitochondrial-targeting mimic peptide is administered in combination with one or more of the following: riluzole. Idaravon Mecaserine, Baclofen stable Danqulin Nonsteroidal anti-inflammatory drugs (NSAIDs) and anticonvulsants (e.g., carbamazepine) or phenytoin Amitriptyline nortriptyline (Pamelor) TM ) and chlorohydroxynordiazepoxide This is to produce a synergistic effect in the prevention or treatment of ALS. In some embodiments, the other therapeutic agent is elamipretide (also known as SS-31 or bendavia).

[0283] In some embodiments, the mitochondrial-targeting mimic peptide (such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-xylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (I) or its pharmaceutically acceptable salts (such as tartrate, fumarate, citrate, benzoate, succinate, octanoate, lactate, oxalate) Salts, phthalates, methanesulfonates, benzenesulfonates, or maleates (in different cases, monohydrochlorides, dihydrochlorides, trihydrochlorides, etc.), monoacetates, diacetates, triacetates, monotrifluoroacetates, ditrifluoroacetates, trifluoroacetates, monohydrochlorides, dihydrochlorides, trihydrochlorides (e.g., (Ia), monotoluenesulfonate, ditoluenesulfonate, or tritoluenesulfonate)) may be administered in combination with one or more other therapies for the prevention or treatment of α-connucleoprotein diseases. In the present invention… In some embodiments of the method described herein, the mitochondrial-targeting mimic peptide is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (I) or a pharmaceutically acceptable salt thereof (e.g., (Ia)). In some embodiments, the other therapies include, but are not limited to, levodopa administration. In one embodiment, at least one mitochondrial-targeting mimic peptide is administered to the subject in combination with other therapeutic agents to produce a synergistic therapeutic effect. For example, administration of at least one mitochondrial-targeting mimic peptide and one or more other therapeutic agents for the prevention or treatment of α-connucleoproteinopathy will have a greater effect in preventing or treating the disease than an additive effect. Therefore, in the treatment or prevention of α-connucleoproteinopathy, lower doses of one or more of any single therapeutic agents may be used to increase efficacy and reduce side effects.

[0284] In some embodiments, the mitochondrial-targeting mimic peptide (such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-xylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (I) or its pharmaceutically acceptable salts (such as tartrate, fumarate, citrate, benzoate, succinate, octanoate, lactate, oxalate, phthalate) Formate, methanesulfonate, benzenesulfonate, or maleate (in different cases, monohydrochloride, dihydrochloride, trihydrochloride, etc.), monoacetate, diacetate, triacetate, monotrifluoroacetate, ditrifluoroacetate, trifluoroacetate, monohydrochloride, dihydrochloride, trihydrochloride (e.g., (Ia), monotoluenesulfonate, ditoluenesulfonate, or tritoluenesulfonate)) may be administered in combination with one or more other therapies for the prevention or treatment of TDP-43 proteinopathy. In certain aspects of the methods described in this invention... In the embodiments, the mitochondrial-targeting mimic peptide is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (I) or a pharmaceutically acceptable salt thereof (e.g., (Ia)). In some embodiments, other therapies include, but are not limited to, administration of antidepressants (such as SSRI antidepressants, including trazodone). In one embodiment, at least one mitochondrial-targeting mimic peptide is administered to the subject in combination with other therapeutic agents to produce a synergistic therapeutic effect. For example, administration of at least one mitochondrial-targeting mimic peptide and one or more other therapeutic agents for the prevention or treatment of TDP-43 proteinopathy will have a greater effect in preventing or treating the disease than an additive effect. Therefore, in the treatment or prevention of TDP-43 proteinopathy, lower doses of one or more of any single therapeutic agents may be used to increase efficacy and reduce side effects.

[0285] In some embodiments, multiple therapeutic agents may be administered in any order or even simultaneously. If administered simultaneously, the multiple therapeutic agents may be provided as a single, uniform, or multiple dosage forms (e.g., as a single tablet or two tablets separately). A single therapeutic agent may be administered multiple times, or two therapeutic agents may be administered multiple times. If not administered simultaneously, the intervals between multiple administrations may vary (from more than 0 weeks to at least 4 weeks). Furthermore, the combined methods, compositions, and formulations are not limited to using only two agents.

[0286] Example

[0287] The present invention is further illustrated by the following examples, but these examples should not be construed as limiting in any way.

[0288] Example 1 – Treatment of ALS using mitochondrial-targeting mimic peptide compounds in animal models

[0289] This example demonstrates the use of mitochondrial-targeting mimic peptide compounds (such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (I) or pharmaceutically acceptable salts thereof (such as tartrate, fumarate, citrate, benzoate, succinate, octanediate, etc.) in animal models of disease. Treatment of ALS with lactate, oxalate, phthalate, methanesulfonate, benzenesulfonate or maleate (in different cases, monohydrochloride, dihydrochloride, trihydrochloride, etc.), monoacetate, diacetate, triacetate, monotrifluoroacetate, ditrifluoroacetate, trifluoroacetate, monohydrochloride, dihydrochloride, trihydrochloride (i.e. (Ia), monotoluenesulfonate, ditoluenesulfonate or tritoluenesulfonate), their stereoisomers, tautomers, hydrates and / or solvates.

[0290] method

[0291] Study design. Daily administration via carrier control; (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (in its trihydrochloride-(Ia) form) (0.5 mg / kg); or (R)-2-amino-N- ((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (in its trihydrochloride-(Ia) form) (5.0 mg / kg) was administered intraperitoneally to 20 SOD1 G93A high-replication transgenic mice in three experimental groups (10 males and 10 females). Animals were administered the drug starting at 8 weeks of age and continued administration until humane termination of life (defined as the animal's inability to return to a stable position from lateral to lateral within 30 seconds when lying on its side). The experimental endpoints and intermediate collections and observations are as follows:

[0292] 1. Weight measurement. Record your weight daily.

[0293] 2. Neurological function score. Weekly NeuroScore, a five-point scale for qualitative assessment of neurological disease progression. The score is defined as follows:

[0294] 0 points: When the mouse is suspended by its tail, its hind legs are fully extended outward from the midline of its side. After three consecutive suspensions, the mouse can maintain this extended posture for 2 seconds.

[0295] 1 point: When the tail is hanging, the legs collapse or partially collapse, extending towards the side midline, or the hind legs tremble.

[0296] 2 points: Walk 12 inches, with toes flexing at least twice, or drag your feet along any part of the cage bottom or table.

[0297] 3 points: stiffness or numbness, or minimal joint mobility, with no forward movement of the foot.

[0298] 4 points: The mouse could not recover from bilateral stagnation within 30 seconds.

[0299] 3. Grip strength test. Forelimb grip strength is measured weekly, as follows:

[0300] a. Weigh the subjects and allow them to acclimatize to the laboratory for at least 60 minutes.

[0301] b. Equipment: Bioseb grip dynamometer, equipped with a grid suitable for mouse gripping.

[0302] c. Hold the mouse by its tail and lower it down to the grid. Visually locate the mouse and let it grasp the grid with its front paws.

[0303] d. Pull the subject away from the grid in a horizontal direction (parallel to the workbench), repeat the test three times, and rest briefly between the two tests (about 30 seconds).

[0304] e. Analyze the mean force (in grams) of the three forepaw and three full-claw tests under normalized and unnormalized weight conditions.

[0305] 4. Retroorbital Blood Collection. Retroorbital hemorrhage was performed every two weeks to determine drug exposure levels and neurofilament light chain (a biomarker of axonal injury) levels, which were associated with ALS progression in human patients. Briefly, mice were sedated using O2 gas with isoflurane (5% induction, 2% maintenance). Isoflurane administration was discontinued when the anesthesia level was reached, and blood was collected from the retroorbital sinus using 25 μL glass capillaries, alternating between bilateral hemorrhages. 200 μL of whole blood was collected into a BD K2EDTA microtainer containing 3.5 μL of a 25X HALT protease inhibitor mixture and stored on ice for later processing. Mice were returned to their living cages after recovery from anesthesia.

[0306] result

[0307] Systemic administration of (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentamide delayed the progression of neurological symptoms in ALS. As described above, mice were administered (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentamide (Ia) or a carrier control via intraperitoneal injection daily, starting at 8 weeks of age, until humane termination of life. Neurological disease progression was assessed weekly using a five-point neurological function rating scale (see study design for the rating scale above). Compared to animals treated with a carrier, administration of 5.0 mg / kg of (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (in its trihydrochloride (Ia) form) delayed the onset of neurological symptoms in male animals (determined by two-way ANOVA). Figure 1A It had no effect in female mice, and the phenotype was milder in this transgenic model. Figure 1B ).

[0308] Systemic administration of (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentamide prolonged the lifespan of an ALS mouse model. Compared with the vector control, male mice administered 5.0 mg / kg of (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentamide experienced a significantly prolonged lifespan. Figure 1C It had no effect in female mice, and the disease phenotype was milder in this transgenic model. Figure 1D ).

[0309] Systemic administration of (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide can alleviate muscle weakness in an ALS mouse model. Figure 2AAs shown in Table 1A, systemic administration of (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (in the form of its trihydrochloride (Ia)) attenuated grip strength loss in male SOD1 G93A transgenic mice. Grip strength values ​​were determined from baseline (8 weeks) to the end of life for each animal. The mean decrease in individual animals was plotted 10 weeks after administration. In male animals treated with a high dose (5.0 mg / kg) of (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (in the form of its trihydrochloride (Ia)), there was a tendency to prevent grip loss, but the extent of the effect was not statistically significant (p = 0.08).

[0310]

[0311]

[0312] Systemic administration of (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentamide reduced the accumulation of neurofilament light chains (NfL) in plasma in an ALS mouse model. Systemic administration of (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentamide reduced the accumulation of neurofilament light chains (NfL) in the plasma of male SOD1 G93A transgenic mice. Figures 3A-3B(and Tables 2A-2B) show the plasma levels of NfL (a marker of axonal injury) 10 weeks after administration of (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentamide or the carrier control. 5.0 mg / kg of (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (in its trihydrochloride (Ia) form) had a statistically significant effect on NfL accumulation in male transgenic mice, thus preventing axonal damage in the CNS. Figure 3A Note that the overall NfL level was lower in female mice, which is consistent with the milder disease phenotype in female mice in this model. Figure 3B ).

[0313]

[0314]

[0315] like Figure 4 As shown in (and Table 3), there was a significant correlation between plasma neurofilament levels and animal survival in male SOD1 G93A transgenic mice. The figure depicts the plasma NfL level of each male mouse in this study as a function of their age at the time of humane termination of life. The accumulation of axonal injury biomarkers was highly significantly correlated with animal lifespan, suggesting that (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (Ia) can prolong the lifespan of male SOD1 G93A mice, at least by preventing axonal loss or damage in the CNS.

[0316]

[0317] These results indicate that mitochondrial-targeting mimic peptide compounds (such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-xylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (I) or their pharmaceutically acceptable salts (such as tartrate, fumarate, citrate, benzoate, succinate, octanoate, lactate, oxalate, phthalate, methanesulfonate, benzenesulfonate, or maleate (in different cases, monohydrochloride, dihydrochloride, trihydrochloride), monoacetate, diacetate, triacetate, monotrifluoroacetate, ditrifluoroacetate, trifluoroacetate, monohydrochloride, dihydrochloride, dihydrochloride) or monohydrochloride, dihydrochloride, monotrifluoroacetate, dihydrochloride, monohydrochloride, dihydrochloride, monohydrochloride, dihydrochloride) are effective targets for mitochondrial-targeting mimic peptide compounds (such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-xylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (I) or their pharmaceutically acceptable salts (such as tartrate, fumarate, citrate, benzoate, succinate, octanoate, octanoate, octanoate, octanoate, monotrifluoroacetate, ditrifluoroacetate, monohydrochloride, dihydrochloride), are effective targets for mitochondrial-targeting mimic peptide compounds (such as (R Trihydrochlorides (i.e., (Ia), monotoluenesulfonate, ditoluenesulfonate, or tritoluenesulfonate), their stereoisomers, tautomers, hydrates, and / or solvates can be used to treat ALS because they help improve one or more of the following symptoms: delaying the onset of ALS neurological symptoms, prolonging survival, alleviating muscle weakness, and / or reducing plasma neurofilament light chain (NfL) levels. Therefore, (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentamide can be used in treatment of patients requiring ALS therapy.

[0318] Example 2 – Treatment of ALS with Mitochondrial-Targeted Mimic Peptide Compounds

[0319] This example predictively demonstrates the use of mitochondrial-targeted mimetic peptide compounds (such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (I) or its pharmaceutically acceptable salts (such as tartrate, fumarate, citrate, benzoate, succinate, octanediic acid) in subjects in need. Treatment of ALS with salts, lactates, oxalates, phthalates, methanesulfonates, benzenesulfonates or maleates (in different cases, monohydrochloride, dihydrochloride, trihydrochloride, etc.), monoacetates, diacetates, triacetates, monotrifluoroacetates, ditrifluoroacetates, trifluoroacetates, monohydrochloride, dihydrochloride, trihydrochloride (i.e. (Ia), monotoluenesulfonate, ditoluenesulfonate or tritoluenesulfonate), their stereoisomers, tautomers, hydrates and / or solvates.

[0320] method

[0321] (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (I) or its pharmaceutically acceptable salts (such as tartrate, fumarate, citrate, benzoate, succinate, caprylate, lactate, oxalate, phthalate, methanesulfonate, benzenesulfonate, or maleate (in different cases, monohydrochloride, dihydrochloride, trihydrochloride), monoacetate, diacetate, triacetate, monotrifluoroacetate, ditrifluoroacetate, trifluoroacetate, monohydrochloride, dihydrochloride, trihydrochloride (i.e., (Ia), monotoluenesulfonate, ditoluenesulfonate, or tritoluenesulfonate)) at a dose of 1 mg / kg body weight daily in subjects suspected of having or diagnosed with ALS. The mimic peptide and / or other therapeutic agents may be administered, either as their stereoisomers, tautomers, hydrates, and / or solvates, or in combination with one or more other therapeutic agents for the treatment or prevention of ALS. The mimic peptide and / or other therapeutic agents may be administered via oral, local, systemic, intravenous, subcutaneous, intravitreal, intraperitoneal, or intramuscular routes of administration, according to methods known in the art. Subjects shall be assessed weekly to determine the presence and / or severity of ALS-related signs or symptoms, including but not limited to muscle weakness, muscle wasting (atrophy), fasciculations, muscle spasms, bradykinesia, poor balance, incoordination, voice changes, dysarthria, dysphagia, incomplete eyelid closure, drooling, pseudobulbar mood, premature death, elevated expression levels of brain transporter-18kDa (TSPO), and accumulation of neurofilament light chains (NfL) in plasma. Treatment shall continue until one or more ALS signs or symptoms improve or disappear.

[0322] result

[0323] In patients suspected of or diagnosed with ALS and treated with a therapeutically effective dose of (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-xylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (I) or its pharmaceutically acceptable salts (such as tartrate, fumarate, citrate, benzoate, succinate, octanoate, lactate, oxalate, phthalate, methanesulfonate, benzenesulfonate, or maleate (in different cases, monohydrochloride, dihydrochloride, trihydrochloride), monoacetate, diacetate, triacetate, monotrifluoroacetate, ditrifluoroacetate, trifluoroacetate, monohydrochloride, dihydrochloride, dihydrochloride, dihydrochloride) In subjects receiving trihydrochloride salts (i.e., (Ia), monotoluenesulfonate, ditoluenesulfonate, or tritoluenesulfonate), their stereoisomers, tautomers, hydrates, and / or solvates, a reduction or elimination of the severity of one or more ALS-related symptoms is expected. In this regard, further synergistic effects are anticipated with the combined administration of (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethyl)-1-oxopropyl-2-yl)-5-guanidinopentamide and one or more other therapeutic agents, compared to results observed in subjects treated alone with mitochondrial-targeted mimic peptide compounds or other therapeutic agents.

[0324] These results indicate that (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (I) or its pharmaceutically acceptable salts (such as tartrate, fumarate, citrate, benzoate, succinate, octanoate, lactate, oxalate, phthalate, methanesulfonate, benzenesulfonate, or maleate (in different cases, monohydrochloride, dihydrochloride, trihydrochloride, etc.) Hydrochloride, monoacetate, diacetate, triacetate, monotrifluoroacetate, ditrifluoroacetate, trifluoroacetate, monohydrochloride, dihydrochloride, trihydrochloride (i.e., (Ia), monotoluenesulfonate, ditoluenesulfonate, or tritoluenesulfonate), their stereoisomers, tautomers, hydrates, and / or solvates may be used to treat ALS. These results indicate that (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-di ...dioxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dioxadiazol-5-dioxadiazol-5- Tolyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (I) or its pharmaceutically acceptable salts (such as tartrate, fumarate, citrate, benzoate, succinate, octanoate, lactate, oxalate, phthalate, methanesulfonate, benzenesulfonate or maleate (in different cases monohydrochloride, dihydrochloride, trihydrochloride), monoacetate, diacetate, triacetate, monotrifluoroacetate, ditrifluoroacetate, trifluoroacetate, monohydrochloride, dihydrochloride, trihydrochloride (i.e. (Ia), monotoluenesulfonate, ditoluenesulfonate or trimethylbenzenesulfonate) Sulfonates, their stereoisomers, tautomers, hydrates, and / or solvates, can be used to improve one or more of the following symptoms: muscle weakness, muscle wasting (atrophy), fasciculations, muscle spasms, bradykinesia, poor balance, incoordination, voice changes, dysarthria, dysphagia, incomplete eyelid closure, drooling, pseudobulbar mood, premature death, increased expression levels of brain transporter-18kDa (TSPO) and accumulation of neurofilament light chains (NfL) in plasma. Therefore, the mimic peptides described herein can be used in methods to treat patients requiring ALS treatment.

[0325] Example 3 – Brain contact of the mitochondrial-targeting mimic peptide compound described in this invention, compared to Elamipretide. It has a high content and a protective effect on mitochondria.

[0326] This example compares the brain uptake of (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (Ia) and elamipretide in a rat model, as well as the pharmacological effects of compound Ia on reducing mitochondrial reactive oxygen species (ROS) and preventing the maintenance of ATP production under oxidative stress.

[0327] method

[0328] Sprague Dawley rats were subcutaneously injected with 5 mg / kg of compound Ia or elamipretide (n=4 at each time point). Animals were sacrificed at designated time points and subjected to percutaneous perfusion. Drug levels in whole brain homogenates were determined by LC-MS / MS. Results are shown below. Figure 5A .

[0329] Ischemic stroke was induced in Sprague Dawley rats by occlusion of the middle cerebral artery using the angiotensin-constricting peptide endothelin-1 (ET-1; 240 pmol per injection). Compound Ia was administered subcutaneously to each rat at 24 hours and 4 hours prior to ischemic onset by injection of 5 mg / kg. Mitochondrial respiration was measured in brain homogenates excised from the infarcted area using a high-resolution OxyGraph O2K assay 24 hours after ischemic onset. Respiratory control rate was calculated by dividing complex I-supported oxidative phosphorylation by complex I-related leakage respiration. Results are shown in […]. Figure 5B **p<0.01, one-way ANOVA.

[0330] result

[0331] The brain exposure of compound Ia is higher than that of elamipretide. Figure 5A Compound Ia can restore brain mitochondrial respiration under oxidative stress conditions. Figure 5B These findings suggest that compound Ia is suitable for treating neurodegenerative diseases in which mitochondrial damage to the central nervous system contributes to the pathological mechanisms.

[0332] Example 4 – Mitochondrial-targeting mimic peptide compounds alleviate substantia nigra excess in mutant α-synuclein transduced mice Loss of dopaminergic neurons.

[0333] This example demonstrates a way to use (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (Ia) in a mouse model of dopaminergic neuron loss induced by mutant α-synuclein.

[0334] method

[0335] In wild-type C57BL / 6 mice, loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) was induced by AAV9-mediated viral delivery of human α-synuclein (with a pathogenic A53T mutation). Four x 10⁴ cells were injected bilaterally into each SNc cell using stereotactic techniques. 10 One virus particle. Animals were nine weeks old at the time of virus transduction. Animals were treated daily via (Ia) intraperitoneal administration for 5 weeks, starting 24 hours before virus transduction. The experimental groups are as follows:

[0336] Group A - Injection of AAV A53T, carrier therapy (n=7)

[0337] 2. Group B1 - Treatment with injection of AAV A53T, 0.5 mg / kg (Ia) (n=8)

[0338] 3. Group B2 - Treatment with injection of AAV A53T, 5.0 mg / kg (Ia) (n=8)

[0339] 4. Group C1 - Treatment with injection of Sham AAV9, 0.5 mg / kg (Ia) (n=6)

[0340] 5. Group C2 - Treatment with injection of Sham AAV9, 5.0 mg / kg (Ia) (n=7)

[0341] Five weeks after viral transduction, animals were euthanized, and their brains were removed and processed for immunohistochemical analysis and cell counting in the substantia nigra pars compacta (i.e., the number of TH-positive neurons) using an automated stereochemical method. Serial sections were excised and stained with tyrosine hydroxylase (TH) to count the number of dopaminergic neurons. Results are as follows: Figure 6A and Figure 6B As shown; **p<0.01 with each group; ***p<0.001 with group A; OO p<0.001 compared to groups C1 and C2.

[0342] The level of plasma neurofilament light chains in blood collected at the time of sacrifice was determined using SIMOA assay, and the results were as follows: Figure 6CAs shown. One-way ANOVA confirmed that there was no statistically significant difference between groups.

[0343] result

[0344] Compound Ia significantly reduced the loss of dopaminergic neurons induced by mutant α-synuclein in the substantia nigra. Figure 6A and Figure 6B In this induction protocol, neurofilament levels do not increase. Figure 6C Therefore, treatment with compound Ia can prevent the loss of dopaminergic neurons in the substantia nigra following mutant α-synuclein toxicity. These data suggest that compound Ia may be used in the treatment and prevention of neurodegenerative diseases caused by α-synuclein disorders such as Parkinson's disease (PD), PD with dementia, Lewy body dementia, or multiple system atrophy.

[0345] Example 5 – Mitochondrial-targeting mimic peptide compounds exhibit neurogenic activity against the primary mutant TDP43 expressing upmotor neurons. Protective effect

[0346] This example studies (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide (Ia) derived from ppr-TDP-43 A315T Neuroprotective effects in primary cells of the -UeGFP mouse model.

[0347] method

[0348] Originating from PRP-TDP-43 A315T The study was conducted in primary cells of the -UeGFP mouse model (Gautam et al., Acta Neuropathologica Sinica, January 2019; 137(1):47-69). In short, these mice expressed a pathogenic human TDP43 transgene, resulting in severe structural changes in mitochondria, nucleus, and endoplasmic reticulum in the context of eGFP reporter mice. The transgene (prp) and reporter gene (UCHL1) were driven by tissue-specific promoter elements, leading to the production of fluorescent green cortical-spinal motor neurons carrying the TDP43 mutation. Cortical-spinal motor neurons could be directly observed in situ using the endogenous fluorescence of the eGFP reporter gene. The hybrid cortical culture was derived from ppr-TDP-43. A315T-UeGFP mouse brain cells underwent three cell divisions in serum-free minimum control medium. Medium was removed and replenished daily with and without the drug. Compound Ia was used at doses of 10 nM, 100 nM, and 1000 nM. The drug was prepared in a DMSO vector, with DMSO used as a vector control (<1% v / v). Cells were imaged using standard fluorescence microscopy. Neuron length was calculated on GFP-expressing cells using automated imaging software (NIH Image J). Three independent biological replications were performed, with at least 10 motor neurons imaged per replication. The mean neuron length per cell is shown in [Figure number missing]. Figure 7 Dunnet's multiple comparison test was used, and statistical analysis was performed using one-way ANOVA. ***p<0.001 for the carrier; ****p<0.0001 for the carrier.

[0349] result

[0350] Treatment with compound Ia at all doses (evaluated in primary upper motor neuron cultures derived from A315T mutant TDP43 transgenic mice) increased neurite length. Therefore, these data suggest that compound Ia may be effective in treating or preventing TDP-43 protein disorders, including ALS and frontotemporal degeneration (FTLD).

[0351] Equivalent

[0352] The present invention is not limited to the specific embodiments described in this application, but is used as a single illustration of various aspects of the invention. It will be apparent to those skilled in the art that numerous modifications and variations can be made to the invention without departing from its spirit and scope. In addition to the items listed herein, those skilled in the art will clearly understand from the foregoing description functionally equivalent methods and apparatus within the scope of the present invention. Such modifications and variations are within the scope of the appended claims. The present invention is limited only by the terminology of the appended claims and the full scope of such claim equivalents. It should be understood that the present invention is not limited to various specific methods, reagents, compound compositions, or biological systems. It should also be understood that the terminology used in this invention is for illustrative purposes only and is not intended to be limiting.

[0353] Furthermore, when the features or aspects of the invention are described in accordance with the Markush group, those skilled in the art will recognize that the invention may also be described in accordance with any individual element or subgroup of the Markush group elements.

[0354] Those skilled in the art will understand that, for any and all purposes, particularly in providing a written description, all scopes disclosed in this invention also include any and all possible subscopes and combinations thereof. Any listed scope can be readily regarded as sufficient to describe and divide the same scope into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each scope discussed in this invention can easily be divided into a lower third, a middle third, and an upper third, etc. Those skilled in the art will also understand that all terms such as “up to,” “at least,” “greater than,” “less than,” etc., include the listed numbers and refer to a scope that can subsequently be divided into the aforementioned subscopes. Finally, those skilled in the art will understand that a scope includes each individual member. Thus, for example, a group comprising 1-3 cells means a group comprising 1, 2, or 3 cells. Similarly, a group comprising 1-5 cells means a group comprising 1, 2, 3, 4, or 5 cells.

[0355] All patents, patent applications, provisional applications and publications referenced in this invention are incorporated herein by reference in their entirety, including all drawings and tables, and are not, to some extent, contradictory to the explicit guidance of this specification.

[0356] Other embodiments are listed in the claims.

Claims

1. Use of the mimetic peptide (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt thereof, its hydrate and / or its solvates, in the preparation of a medicament for the treatment of amyotrophic lateral sclerosis in subjects of need.

2. Use according to claim 1, wherein, The subject was diagnosed with amyotrophic lateral sclerosis (ALS).

3. Use according to any one of claims 1-2, wherein, The amyotrophic lateral sclerosis mentioned is familial amyotrophic lateral sclerosis.

4. Use according to claim 3, wherein, The familial amyotrophic lateral sclerosis is caused by mutations in the superoxide dismutase 1 gene or the TARDBP gene.

5. The use according to claim 1, wherein, The mimic peptide is administered daily for 2 weeks or more.

6. The use according to claim 1, wherein, The mimic peptide is administered daily for 12 weeks or more.

7. The use according to claim 1, wherein, The treatment includes treating one or more signs or symptoms of amyotrophic lateral sclerosis (ALS), including muscle weakness, muscle wasting, fasciculations, muscle spasms, bradykinesia, poor balance, incoordination, voice changes, dysarthria, dysphagia, incomplete eyelid closure, drooling, pseudobulbar mood, premature death, and increased expression of brain transporter protein-18 kDa.

8. The use according to claim 1, wherein, The treatment includes treating plasma accumulation in the neurofilament light chains.

9. The use of claim 1, wherein, The subjects were mammals.

10. Use according to claim 9, wherein, The mammalian subjects were humans.

11. The use according to claim 1, wherein, The mimic peptide is administered orally or subcutaneously.

12. The use according to claim 1, wherein, The mimic peptide is administered intranasally, intravenously, intraperitoneally, intradermally, ocularly, intrathecally, intraventricularly, or intramuscularly.

13. The use according to claim 1, wherein, The mimic peptide can be administered locally or systemically.

14. The use according to claim 1, wherein, The mimic peptide is administered intraocularly or via iontophoresis.

15. The use according to claim 1, wherein, The mimic peptide is administered via mucosal or intravitreal delivery.

16. The use according to claim 1, wherein the treatment further comprises administering other treatments to the subject alone, sequentially, or simultaneously.

17. The use according to claim 16, wherein, The other treatments include the administration of therapeutic agents.

18. The use according to claim 17, wherein, The therapeutic agents are selected from the group consisting of: riluzole, edaravone, mecaserine, baclofen, diazepam, dantrolene, nonsteroidal anti-inflammatory drugs, anticonvulsants, amitriptyline, nortriptyline, and chlorhexidine.

19. The use according to claim 18, wherein, The anticonvulsant was selected from the group consisting of carbamazepine and phenytoin.

20. The use according to claim 1, wherein, The pharmaceutically acceptable salts include tartrates, fumarates, monoacetates, diacetates, triacetates, monotrifluoroacetates, ditrifluoroacetates, trifluoroacetates, monohydrochlorides, dihydrochlorides, trihydrochlorides, monotoluenesulfonates, ditoluenesulfonates, or tritoluenesulfonates.

21. The use according to claim 1, wherein, The mimic peptide is formulated as a trihydrochloride, dihydrochloride, or monohydrochloride.

22. Use of the composition in the preparation of a medicament for treating amyotrophic lateral sclerosis (ALS) in a subject of need, wherein, The composition comprises a therapeutically effective amount of a mimetic peptide (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt thereof, its hydrate, and / or its solvates.

23. The use according to claim 22, wherein, The subject was diagnosed with amyotrophic lateral sclerosis (ALS).

24. The use according to claim 22 or 23, wherein, The amyotrophic lateral sclerosis mentioned is familial amyotrophic lateral sclerosis.

25. The use according to claim 24, wherein, The familial amyotrophic lateral sclerosis is caused by mutations in the superoxide dismutase 1 gene or the TARDBP gene.

26. The use according to claim 22, wherein, The mimic peptide is intended for daily administration for two weeks or more.

27. The use according to claim 22, wherein, The mimic peptide is designed for daily administration for 12 weeks or more.

28. The use according to claim 22, wherein, The treatment includes treating one or more signs or symptoms of amyotrophic lateral sclerosis (ALS), including muscle weakness, muscle wasting, fasciculations, muscle spasms, bradykinesia, poor balance, incoordination, voice changes, dysarthria, dysphagia, incomplete eyelid closure, drooling, pseudobulbar mood, premature death, and increased expression of brain transporter protein-18 kDa.

29. The use according to claim 22, wherein, The treatment includes treating plasma accumulation in the neurofilament light chains.

30. The use according to claim 22, wherein, The subjects were mammals.

31. The use according to claim 30, wherein, The mammalian subjects were humans.

32. The use according to claim 22, wherein, The mimic peptide is formulated for oral or subcutaneous administration.

33. The use according to claim 22, wherein, The mimic peptide is formulated for administration via intranasal, intravenous, intraperitoneal, intradermal, ocular, intrathecal, intraventricular, or intramuscular routes.

34. The use according to claim 22, wherein, The simulated peptides are formulated for local or systemic administration.

35. The use according to claim 22, wherein, The simulated peptide is formulated for intraocular or iontophoresis administration.

36. The use according to claim 22, wherein, The mimic peptide is formulated for administration via mucosa or vitreous cavity.

37. The use according to claim 22, wherein, The mimic peptides are intended to be used alone, sequentially, or simultaneously with other treatments.

38. The use according to claim 37, wherein, The other treatments include the use of therapeutic agents.

39. The use according to claim 38, wherein, The therapeutic agents are selected from the group consisting of: riluzole, edaravone, mecaserine, baclofen, diazepam, dantrolene, nonsteroidal anti-inflammatory drugs, anticonvulsants, amitriptyline, nortriptyline, and chlorhexidine.

40. The use according to claim 39, wherein, The anticonvulsant was selected from the group consisting of carbamazepine and phenytoin.

41. The use according to claim 22, wherein, The pharmaceutically acceptable salts include tartrates, fumarates, monoacetates, diacetates, triacetates, monotrifluoroacetates, ditrifluoroacetates, trifluoroacetates, monohydrochlorides, dihydrochlorides, trihydrochlorides, monotoluenesulfonates, ditoluenesulfonates, or tritoluenesulfonates.

42. The use according to claim 22, wherein, The mimic peptide is formulated as a trihydrochloride, dihydrochloride, or monohydrochloride.

43. Use of the mimetic peptide (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt thereof, its hydrate and / or its solvates, in the preparation of a medicament for the treatment of Parkinson's disease in a subject in need.

44. The use according to claim 43, wherein, The mimic peptide is administered daily for 2 weeks or more.

45. The use according to any one of claims 43-44, wherein, The mimic peptide is administered daily for 12 weeks or more.

46. ​​The use according to claim 43, wherein, Treatment for Parkinson's disease involves reducing the loss of dopaminergic neurons in subjects compared to untreated controls.

47. The use according to claim 43, wherein, The subjects were mammals.

48. The use according to claim 47, wherein, The mammalian subjects were humans.

49. The use according to claim 43, wherein, The mimic peptide is administered orally or subcutaneously.

50. The use according to claim 43, wherein, The mimic peptide is administered intranasally, intravenously, intraperitoneally, intradermally, ocularly, intrathecally, intraventricularly, or intramuscularly.

51. The use according to claim 43, wherein, The mimic peptide can be administered locally or systemically.

52. The use according to claim 43, wherein, The mimic peptide is administered intraocularly or via iontophoresis.

53. The use according to claim 43, wherein, The mimic peptide is administered via mucosal or intravitreal delivery.

54. The use according to claim 43, wherein the treatment further comprises administering other treatments to the subject alone, sequentially, or simultaneously.

55. The use according to claim 54, wherein, The other treatments include the administration of therapeutic agents.

56. The use according to claim 55, wherein, The therapeutic agent includes levodopa.

57. The use according to claim 43, wherein, The pharmaceutically acceptable salts include tartrates, fumarates, monoacetates, diacetates, triacetates, monotrifluoroacetates, ditrifluoroacetates, trifluoroacetates, monohydrochlorides, dihydrochlorides, trihydrochlorides, monotoluenesulfonates, ditoluenesulfonates, or tritoluenesulfonates.

58. The use according to claim 43, wherein, The mimic peptide is formulated as a trihydrochloride, dihydrochloride, or monohydrochloride.

59. Use of the composition in the preparation of a medicament for treating Parkinson's disease in a subject in need, wherein, The composition comprises a therapeutically effective amount of a mimetic peptide (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethyl)-1-oxopropyl-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt thereof, its hydrate, and / or its solvates.

60. The use according to claim 59, wherein, The composition is intended for daily administration for 2 weeks or more.

61. The use according to any one of claims 59-60, wherein, The composition is intended for daily administration for 12 weeks or more.

62. The use according to claim 59, wherein, Treatment for Parkinson's disease involves reducing the loss of dopaminergic neurons in subjects compared to untreated controls.

63. The use according to claim 59, wherein, The subjects were mammals.

64. The use according to claim 63, wherein, The mammalian subjects were humans.

65. The use according to claim 59, wherein, The composition is formulated for oral or subcutaneous administration.

66. The use according to claim 59, wherein, The composition is formulated for intranasal, intravenous, intraperitoneal, intradermal, ocular, intrathecal, intraventricular, or intramuscular administration.

67. The use according to claim 59, wherein, The composition is formulated for local or systemic administration.

68. The use according to claim 59, wherein, The composition is formulated for intraocular or iontophoresis administration.

69. The use according to claim 59, wherein, The composition is formulated for administration via mucosa or intravitreal cavity.

70. The use according to claim 59, wherein the treatment further comprises administering other treatments to the subject alone, sequentially, or simultaneously.

71. The use according to claim 70, wherein, The other treatments include the administration of therapeutic agents.

72. The use according to claim 71, wherein, The therapeutic agent includes levodopa.

73. The use according to claim 59, wherein, The pharmaceutically acceptable salts include tartrates, fumarates, monoacetates, diacetates, triacetates, monotrifluoroacetates, ditrifluoroacetates, trifluoroacetates, monohydrochlorides, dihydrochlorides, trihydrochlorides, monotoluenesulfonates, ditoluenesulfonates, or tritoluenesulfonates.

74. The use according to claim 59, wherein, The mimic peptide is formulated as a trihydrochloride, dihydrochloride, or monohydrochloride.

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