Protective agent for retinal pigment epithelial cells

Abstract

The present invention addresses the problem of providing a protective agent for retinal pigment epithelial cells, which is useful for the prevention or treatment of age-related macular degeneration. A protective agent for retinal pigment epithelial cells according to the present invention, which is a solution for the problem, contains, as an active ingredient, a peptide in which a protein transduction domain is attached to the N-terminus of a peptide having an inhibitory effect on mitochondrial calpains. A specific example of the peptide having an inhibitory effect on mitochondrial calpains is a peptide comprising the amino acid sequence (PDALKSRTJR) represented by SEQ ID NO: 1 (wherein J represents L or I). A specific example of the protein transduction domain is a peptide comprising an amino acid sequence that is at least a part of the amino acid sequence for the transduction domain of HIV-1 Tat.

Description

Protective agent for retinal pigment epithelial cells

[0001] The present invention relates to a protective agent for retinal pigment epithelial cells.

[0002] When we see something, light entering the eye is received by the retina as a light stimulus, and the signal is transmitted to the optic nerve to be sent to the brain. The macula, located at the center of the retina and playing a crucial role in enabling us to see, is damaged with age, resulting in a decline in vision. Age-related macular degeneration (AMD) is one of the most common age-related eye diseases, affecting approximately 170 million people worldwide, with the number of patients predicted to continue to rise. There are two types of AMD: exudative (wet) AMD and atrophic (dry) AMD. While the mechanisms of onset differ between the two, both types of AMD result in a decline in vision due to functional damage to retinal pigment epithelium (RPE) cells located beneath the macula. Currently, treatments for exudative age-related macular degeneration include intravitreal injection of anti-VEGF drugs into the eyeball to inhibit the development of new blood vessels from the choroid, which leads to functional damage to retinal pigment epithelial cells, and photodynamic therapy. However, there are currently no effective methods for treating atrophic age-related macular degeneration. Given this clinical background, methods that protect retinal pigment epithelial cells have attracted attention as a method for preventing or treating age-related macular degeneration. For example, Patent Document 1 reports that (S)-4-fluoro-5-(2-methyl-1,4-diazepan-1-ylsulfonyl)isoquinoline has a protective effect on retinal pigment epithelial cells. However, a method for preventing or treating age-related macular degeneration by protecting retinal pigment epithelial cells has not yet been established, and the search for new components that have a protective effect on retinal pigment epithelial cells remains significant.

[0003] Japanese Patent Application Laid-Open No. 2015-229671

[0004] Therefore, an object of the present invention is to provide a protective agent for retinal pigment epithelial cells that is useful for preventing and treating age-related macular degeneration.

[0005] In light of the above points, the present inventors have conducted extensive research and have found that a peptide having an inhibitory effect on mitochondrial calpain to which a protein transduction domain has been added at the N-terminus, which was reported by the present inventors' research group in Patent No. 6183879 to have a protective effect on retinal photoreceptor cells, has an excellent protective effect on retinal pigment epithelial cells.

[0006] The protective agent for retinal pigment epithelial cells of the present invention, developed based on the above findings, comprises as an active ingredient a peptide having an inhibitory effect on mitochondrial calpain, wherein a protein transduction domain is added to the N-terminus of a peptide having inhibitory effect on mitochondrial calpain, as set forth in claim 1. Furthermore, the protective agent for retinal pigment epithelial cells of claim 2 is the protective agent for retinal pigment epithelial cells of claim 1, wherein the peptide having inhibitory effect on mitochondrial calpain is either: (a) a peptide consisting of the amino acid sequence (PDALKSRTJR) shown in SEQ ID NO: 1 (J is L or I), (b) a peptide consisting of an amino acid sequence in which up to five amino acids have been added to the N-terminus and / or C-terminus of the amino acid sequence shown in SEQ ID NO: 1, and which has inhibitory effect on mitochondrial calpain, or (c) a peptide consisting of an amino acid sequence in which up to two amino acids at the N-terminus and / or C-terminus of the amino acid sequence shown in SEQ ID NO: 1 have been substituted with or deleted from other amino acids, and which has inhibitory effect on mitochondrial calpain. The protective agent for retinal pigment epithelial cells according to claim 3 is the protective agent for retinal pigment epithelial cells according to claim 1, wherein the protein transduction domain is a peptide consisting of at least a part of the amino acid sequence of the HIV-1 Tat transduction site. The preventive and / or therapeutic agent for age-related macular degeneration of the present invention comprises, as an active ingredient, a peptide having an inhibitory effect on mitochondrial calpain and a protein transduction domain added to the N-terminus of the peptide, as described in claim 4.

[0007] According to the present invention, a protective agent for retinal pigment epithelial cells can be provided, which is useful for preventing and treating age-related macular degeneration.

[0008] 1 is a histological photograph of a retinal section showing that the retinal pigment epithelial cell layer is protected by instillation of 20 mM Tat-μCL peptide in an experiment using age-related macular degeneration model mice in Example 1. Also, a graph showing that an increase in the number of deposits derived from the retinal pigment epithelial cell layer is suppressed. Also, a graph showing that thinning of the retinal photoreceptor layer is suppressed. Also, a histological photograph of a retinal section showing that the retinal pigment epithelial cell layer is protected by instillation of 2 mM Tat-μCL peptide in an experiment using age-related macular degeneration model mice in Example 2. Also, a graph showing that an increase in the number of deposits derived from the retinal pigment epithelial cell layer is suppressed. Also, a graph showing that thinning of the retinal photoreceptor layer is suppressed. Also, a histological photograph of a retinal section showing that the retinal pigment epithelial cell layer is protected by instillation of 200 μM Tat-μCL peptide in an experiment using age-related macular degeneration model mice in Example 3. Also, a graph showing that an increase in the number of deposits derived from the retinal pigment epithelial cell layer is suppressed. 10 is a graph showing that thinning of the retinal photoreceptor layer is suppressed.

[0009] The protective agent for retinal pigment epithelial cells of the present invention contains as an active ingredient a peptide having an inhibitory effect on mitochondrial calpain and a protein transduction domain added to the N-terminus thereof. The peptide having an inhibitory effect on mitochondrial calpain and a protein transduction domain added to the N-terminus thereof is a peptide that the present inventors' research group reported in Japanese Patent No. 6183879 to have a protective effect on retinal photoreceptor cells.

[0010] Examples of peptides having inhibitory activity against mitochondrial calpain, which are composed of a protein transduction domain added to the N-terminus of a peptide having inhibitory activity against mitochondrial calpain, include a peptide consisting of the amino acid sequence (PDALKSRTJR) shown in SEQ ID NO: 1 (J is L or I). A peptide consisting of an amino acid sequence in which J is L is contained in the amino acid sequence of domain III of the active subunit of rat μ-calpain (also known as CAPN1 or μCL) identified by accession number NP_062025.1. Domain III of the active subunit of μ-calpain is a functional domain also known as the C2L (C2-like) domain. A peptide consisting of an amino acid sequence in which J is I is contained in the amino acid sequence of domain III of the active subunit of human μ-calpain identified by accession number NP_005177. In a peptide having an inhibitory effect on mitochondrial calpain, the peptide having an inhibitory effect on mitochondrial calpain, which is obtained by adding a protein transduction domain to the N-terminus of the peptide, may be a peptide having an inhibitory effect on mitochondrial calpain, which comprises an amino acid sequence having up to five amino acids added to the N-terminus and / or C-terminus of the amino acid sequence shown in SEQ ID NO: 1. Specific examples thereof include a peptide having an amino acid sequence having up to five amino acids added to the N-terminus of the amino acid sequence shown in SEQ ID NO: 1 (e.g., a peptide consisting of the amino acid sequence shown in SEQ ID NO: 2), a peptide having an amino acid sequence having up to five amino acids added to the C-terminus of the amino acid sequence shown in SEQ ID NO: 1 (e.g., a peptide consisting of the amino acid sequence shown in SEQ ID NO: 3), and a peptide having an amino acid sequence having up to five amino acids added to each of the N-terminus and C-terminus of the amino acid sequence shown in SEQ ID NO: 1 (e.g., a peptide consisting of the amino acid sequence shown in SEQ ID NO: 4).Furthermore, the peptide having inhibitory activity against mitochondrial calpain in a peptide having a protein transduction domain added to the N-terminus of the peptide having inhibitory activity against mitochondrial calpain may be a peptide having an amino acid sequence in which up to two amino acids at the N-terminus and / or C-terminus of the amino acid sequence shown in SEQ ID NO: 1 have been substituted with or deleted from other amino acids, and having inhibitory activity against mitochondrial calpain.

[0011] The protein transduction domain (PTD) added to the N-terminus of the peptide having an inhibitory effect on mitochondrial calpain can be a known cell-penetrating peptide that has the ability to pass not only the peptide itself but also other compounds such as oligonucleotides, peptides, proteins, and oligosaccharides bound to it through the bilayer of cell membrane phospholipids. Specific examples thereof include peptides consisting of at least a portion of the amino acid sequence of the HIV-1 Tat transduction site, peptides consisting of 3 to 12 arginines, peptides consisting of 3 to 12 lysines, peptides consisting of 3 to 16 histidines, PEP-1 peptide, ANTP, VP22 protein, etc. (see, if necessary, Morris et al., Nat. Biotechnol., 19:1173-1175, 2001; Schwarze et al., Trends Cell Biol., 10:290-295, 2000; Vives et al., J. Biol. Chem., 272:16010-16017, 1997, etc.). Examples of protein transduction domains that are desirable to add to the N-terminus of peptides that have inhibitory activity against mitochondrial calpain include peptides consisting of the amino acid sequence shown in SEQ ID NO: 5, which corresponds to amino acid positions 49 to 57 of the HIV-1 Tat transduction site; peptides consisting of the amino acid sequence shown in SEQ ID NO: 5 in which one or more amino acids have been substituted, deleted, and / or added (the number of substitutions and deletions is up to 5, and the number of additions is up to 10) and that have the ability to allow not only itself but also other compounds such as oligonucleotides, peptides, proteins, and oligosaccharides that are bound to it to pass through the cell membrane phospholipid bilayer; and peptides consisting of 3 to 16 histidines. A specific example of a peptide that has inhibitory activity against mitochondrial calpain and has a protein transduction domain added to its N-terminus is a peptide consisting of the amino acid sequence shown in SEQ ID NO: 6.

[0012] In addition, a peptide having an inhibitory effect on mitochondrial calpain and a protein transduction domain added to the N-terminus thereof can be prepared by a method known per se, for example, chemical synthesis using a peptide synthesizer, or by genetic engineering techniques.

[0013] A peptide having an inhibitory effect on mitochondrial calpain and a protein transduction domain added to the N-terminus thereof has an excellent protective effect on retinal pigment epithelial cells, and is therefore useful for the prevention and treatment of age-related macular degeneration, in which functional damage to retinal pigment epithelial cells is a cause of visual impairment. When a peptide having an inhibitory effect on mitochondrial calpain and a protein transduction domain added to the N-terminus thereof is administered to a human or non-human animal, the administration method is not particularly limited, and the peptide can be formulated into a form suitable for the administration method by a method known per se, but the formulation is preferably in the form of a non-invasive eye drop.

[0014] The eye drops can be prepared by blending various additives, such as buffers, solubilizers, isotonicity agents, stabilizers, preservatives, thickeners, chelating agents, pH adjusters, and cooling agents, with a solvent, followed by sterile filtration under a sterile environment and filling into a suitable sterilized container. Specific examples of buffers include boric acid and its salts (e.g., borax), citric acid and its salts (e.g., sodium citrate), phosphoric acid and its salts (e.g., sodium monohydrogen phosphate), tartaric acid and its salts (e.g., sodium tartrate), gluconic acid and its salts (e.g., sodium gluconate), acetic acid and its salts (e.g., sodium acetate), various amino acids, and combinations thereof. Specific examples of solubilizing agents include polyoxyethylene hydrogenated castor oil (e.g., polyoxyethylene hydrogenated castor oil 60), polyethylene glycol (e.g., macrogol 4000), polyoxyethylene sorbitan higher fatty acid esters (e.g., polysorbate 80), polyoxyethylene (POE)-polyoxypropylene (POP) block copolymers (e.g., poloxamer 407), and propylene glycol. Specific examples of isotonic agents include inorganic salts (e.g., sodium chloride, potassium chloride, calcium chloride), sugars (e.g., mannitol, glucose), and polyhydric alcohols (e.g., glycerin, propylene glycol). Specific examples of stabilizers include sodium edetate, cyclodextrin, sulfites, citric acid and its salts, and butylhydroxytoluene. Specific examples of preservatives include benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, polyquartenium-1, polyaminopropylbiguanide, alkylaminoethylglycine hydrochloride, cetylpyridinium chloride, and thimerosal.Specific examples of thickening agents include polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, hydroxyethyl cellulose, hydroxypropylmethylcellulose, methylcellulose, sodium chondroitin sulfate, sodium hyaluronate, carboxymethylcellulose, and carboxyvinyl polymer. Specific examples of chelating agents include sodium edetate and sodium citrate. Specific examples of pH adjusters include hydrochloric acid, citric acid and its salts, boric acid and its salts, phosphoric acid and its salts, acetic acid and its salts, tartaric acid and its salts, sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate. Specific examples of freshening agents include menthol, borneol, camphor, geraniol, limonene, eugenol, peppermint oil, eucalyptus oil, fennel oil, and bergamot oil. Specific examples of solvents include sterilized purified water, purified water, and physiological saline. The pH of the eye drops is not particularly limited as long as it is within an ophthalmologically acceptable range, and is typically in the range of pH 4 to 9, preferably 5 to 8.

[0015] The active ingredient is a peptide having an inhibitory effect on mitochondrial calpain, with a protein transduction domain added to the N-terminus of the peptide. The amount of the peptide is 0.00001 to 100 mg per mL of the eye drops. By instilling one to several drops at a time, one to several times per day, the eye drops protect retinal pigment epithelial cells, thereby exerting preventive and therapeutic effects against age-related macular degeneration.

[0016] The present invention will be described in detail below with reference to examples, but the present invention should not be construed as being limited to the following description.

[0017] Example 1: Protective effect on retinal pigment epithelial cells of a peptide having an inhibitory effect against mitochondrial calpain, with a protein transduction domain added to the N-terminus (effect of eye instillation into a mouse model of age-related macular degeneration) Part 1 (Experimental method) The eye instillation effect of a peptide having an inhibitory effect against mitochondrial calpain, with a protein transduction domain added to the N-terminus, was evaluated using sodium iodate (SI)-administered mice (Investigative Ophthalmology & Visual Science, 58, 2239-2249, 2017), which are widely used as an experimental model of atrophic age-related macular degeneration. Specifically, a peptide consisting of the amino acid sequence shown in SEQ ID NO: 6 (GRKKRRQRRRPPQPDALKSRTLR) (hereinafter abbreviated as "Tat-μCL peptide"; identical to the μ-N2-10-2 (HIV-Nμ) peptide described in Japanese Patent No. 6183879) was used as a peptide with inhibitory activity against mitochondrial calpain, with a protein transduction domain added to the N-terminus. This peptide was dissolved in physiological saline to a concentration of 20 mM and sterilized by filtration. This solution was then instilled into both eyes of 8-week-old C57BL / 6J mice (three times daily for seven days). Following this, SI was administered at 12.5 mg / kg by intraperitoneal administration of a solution prepared by dissolving SI in physiological saline and sterilizing it with a filter. Furthermore, Tat-μCL peptide was dissolved in physiological saline to a concentration of 20 mM and sterilized by filtration. This solution was then instilled into both eyes three times daily for seven days. After 7 days, mice were euthanized, and both eyes were enucleated and fixed in 4% paraformaldehyde. The anterior segment and lens were removed. Frozen section slides of the tissue were then prepared, stained with hematoxylin and eosin, and observed under a phase-contrast microscope to count the number of retinal pigment epithelial (RPE)-derived deposits (pigmented deposits formed by the accumulation of degenerated RPE cells). Furthermore, images were taken at approximately 300, 600, 900, 1200, and 1500 μm nasally and temporally from the center of the optic disc, respectively, to measure the thickness of the retinal photoreceptor layer (OS+IS).

[0018] (Experimental Results) Figure 1 shows a histological photograph of a retinal section, Figure 2 shows the results of measuring the number of deposits derived from the retinal pigment epithelium cell layer, and Figure 3 shows the results of measuring the thickness of the retinal photoreceptor cell layer at positions approximately 300, 600, 900, 1200, and 1500 μm nasally and temporally from the center of the optic disc (20 mM Tat-μCL; the results in Figure 2 and Figure 3 are the average values ​​of specimens (n=6) from both eyes of three mice). 1 to 3 show the results of a similar experiment using a solution prepared by dissolving Tat-μCL peptide in physiological saline to 20 mM and sterilizing it by filtration, but instead using a peptide consisting of the amino acid sequence shown in SEQ ID NO: 7 (GRKKRRQRRRPPQASLRLDRPTK), in which the amino acid sequence of the μCL portion of Tat-μCL peptide was randomly rearranged, dissolved in physiological saline to 20 mM and sterilized by filtration (hereinafter referred to as "Tat-μCL scrambled peptide"). These results are also shown for healthy mice that had not received any administration into the eyeball (none). As is clear from FIGS. 1 and 2, Tat-μCL peptide effectively protected the retinal pigment epithelial cell layer when administered at a concentration of 20 mM. The inhibition of thinning of the retinal photoreceptor layer by administration of Tat-μCL peptide, which is evident from FIG. 3, was considered to be a secondary effect of the Tat-μCL peptide protecting the retinal pigment epithelial cell layer.

[0019] Example 2: Protective Effect of a Peptide Comprising a Mitochondrial Calpain Inhibitory Peptide Added to the N-Terminus of a Protein Transduction Domain on Retinal Pigment Epithelial Cells (Effect of Instillation into Age-Related Macular Degeneration Model Mice) Part 2. A similar experiment to that in Example 1 was performed using a solution of Tat-μCL peptide dissolved in physiological saline to a concentration of 2 mM and sterilized by filtration, and a solution of Tat-μCL scrambled peptide dissolved in physiological saline to a concentration of 2 mM and sterilized by filtration. Figure 4 shows histological photographs of retinal sections, Figure 5 shows the results of counting the number of deposits derived from the retinal pigment epithelial cell layer, and Figure 6 shows the results of measuring the thickness of the retinal photoreceptor layer at positions approximately 300, 600, 900, 1200, and 1500 μm nasally and temporally from the center of the optic disc (none indicates the results for healthy mice that had not received any administration to the eyeball). As is clear from FIGS. 4 to 6, the Tat-μCL peptide effectively protected the retinal pigment epithelial cell layer and inhibited thinning of the retinal photoreceptor cell layer even when instilled at a concentration of 2 mM.

[0020] Example 3: Protective effect on retinal pigment epithelial cells of a peptide comprising a protein transduction domain added to the N-terminus of a peptide that inhibits mitochondrial calpain (effect of instillation into age-related macular degeneration model mice), Part 3. A similar experiment to that in Example 1 was performed using a solution of Tat-μCL peptide dissolved in physiological saline to a concentration of 200 μM and sterilized by filtration, and a solution of Tat-μCL scrambled peptide dissolved in physiological saline to a concentration of 200 μM and sterilized by filtration. Figure 7 shows histological photographs of retinal sections, Figure 8 shows the results of counting the number of deposits derived from the retinal pigment epithelial cell layer, and Figure 9 shows the results of measuring the thickness of the retinal photoreceptor layer at positions approximately 300, 600, 900, 1200, and 1500 μm nasally and temporally from the center of the optic disc (none indicates the results for healthy mice that had not received any administration to the eyeball). As is clear from FIGS. 7 to 9, the Tat-μCL peptide effectively protected the retinal pigment epithelial cell layer and inhibited thinning of the retinal photoreceptor cell layer even when instilled at a concentration of 200 μM.

[0021] Summary of Experimental Results of Examples 1 to 3 In Japanese Patent No. 6183879, the research group of the present inventors reported that Tat-μCL peptide has a protective effect on retinal photoreceptor cells, but the concentration at which this effect could be confirmed by instillation was 40 mM. In light of this, the fact that the protective effect of Tat-μCL peptide on retinal pigment epithelial cells could be confirmed by instillation at a concentration less than 1 / 100 of the concentration at which the protective effect on retinal photoreceptor cells could be confirmed by instillation was a surprising and unexpected result for the present inventors, and demonstrated that peptides comprising a protein transduction domain added to the N-terminus of a peptide having an inhibitory effect on mitochondrial calpain, such as Tat-μCL peptide, are useful for the non-invasive prevention and treatment of age-related macular degeneration.

[0022] Example 4: Protective effect on retinal pigment epithelial cells of peptides comprising a protein transduction domain added to the N-terminus of various peptides that inhibit mitochondrial calpains (effect of instillation into age-related macular degeneration model mice) The following nine peptides were prepared by chemical synthesis using a peptide synthesizer, and each was dissolved in physiological saline to a concentration of 200 μM, followed by filtration sterilization, and then an experiment similar to that in Example 1 was performed using these solutions. As a result, it was confirmed that all of the peptides, like the Tat-μCL peptide, had a protective effect on retinal pigment epithelial cells when instilled at 200 μM. a peptide consisting of the amino acid sequence shown in SEQ ID NO: 8 (GRKKRRQRRRPPQICNLTPDALKSRTLR), in which the amino acid sequence of the μCL portion of the Tat-μCL peptide has been altered to an amino acid sequence in which five amino acids have been added to the N-terminus of the amino acid sequence (amino acid sequence shown in SEQ ID NO: 2); a peptide consisting of the amino acid sequence shown in SEQ ID NO: 9 (GRKKRRQRRRPPQPDALKSRTLRRNWNTT), in which the amino acid sequence of the μCL portion of the Tat-μCL peptide has been altered to an amino acid sequence in which five amino acids have been added to the C-terminus of the amino acid sequence (amino acid sequence shown in SEQ ID NO: 3); and a peptide consisting of the amino acid sequence shown in SEQ ID NO: 10 (GRKKRRQRRRPPQICNLTPDALKSRTLRRNWNTT), in which the amino acid sequence of the μCL portion of the Tat-μCL peptide has been altered to an amino acid sequence in which five amino acids have been added to each of the N-terminus and C-terminus of the amino acid sequence (amino acid sequence shown in SEQ ID NO: 4). - A peptide consisting of the amino acid sequence shown in SEQ ID NO: 11 (GRKKRRQRRRPPQALKSRTLR), in which the amino acid sequence of the μCL portion of the Tat-μCL peptide has been changed to an amino acid sequence in which two amino acids at the N-terminus of the amino acid sequence have been deleted. - A peptide consisting of the amino acid sequence shown in SEQ ID NO: 12 (GRKKRRQRRRPPQPDALKSRT), in which the amino acid sequence of the μCL portion of the Tat-μCL peptide has been changed to an amino acid sequence in which two amino acids at the C-terminus of the amino acid sequence have been deleted.a peptide consisting of the amino acid sequence (GRKKRRQRRRPPQALKSRT) shown in SEQ ID NO: 13, in which the amino acid sequence of the μCL portion of the Tat-μCL peptide has been altered to an amino acid sequence in which two amino acids have been deleted from each of the N-terminus and C-terminus of the amino acid sequence; a peptide consisting of the amino acid sequence (GRKKRRQRRRPPQPDALKSRTA) shown in SEQ ID NO: 14, in which an alanine has been added to the C-terminus of the amino acid sequence shown in SEQ ID NO: 12; a peptide consisting of the amino acid sequence (GRKKRRQRRRPPQPDALKSRTIR) shown in SEQ ID NO: 15, in which the second leucine from the C-terminus of the amino acid sequence shown in SEQ ID NO: 1 has been replaced with isoleucine; and a peptide consisting of the amino acid sequence (HHHHHHPDALKSRTLR) shown in SEQ ID NO: 16, in which the amino acid sequence of the Tat portion of the Tat-μCL peptide has been altered to an amino acid sequence consisting of six histidines.

[0023] INDUSTRIAL APPLICABILITY The present invention has industrial applicability in that it can provide a protective agent for retinal pigment epithelial cells that is useful for the prevention and treatment of age-related macular degeneration.

Claims

1. A protective agent for retinal pigment epithelial cells, which comprises as an active ingredient a peptide having an inhibitory effect on mitochondrial calpain and a protein transduction domain added to the N-terminus of the peptide.

2. A protective agent for retinal pigment epithelial cells as described in claim 1, wherein the peptide having an inhibitory effect on mitochondrial calpain is any one of the following: (a) a peptide consisting of the amino acid sequence (PDALKSRTJR) shown in SEQ ID NO: 1 (J is L or I); (b) a peptide consisting of an amino acid sequence in which up to five amino acids have been added to the N-terminus and / or C-terminus of the amino acid sequence shown in SEQ ID NO: 1, and which has an inhibitory effect on mitochondrial calpain; or (c) a peptide consisting of an amino acid sequence in which up to two amino acids at the N-terminus and / or C-terminus of the amino acid sequence shown in SEQ ID NO: 1 have been replaced with or deleted from other amino acids, and which has an inhibitory effect on mitochondrial calpain.

3. The agent for protecting retinal pigment epithelial cells according to claim 1, wherein the protein transduction domain is a peptide consisting of at least a part of the amino acid sequence of the transduction site of HIV-1 Tat.

4. A preventive and / or therapeutic agent for age-related macular degeneration, which comprises as an active ingredient a peptide having an inhibitory effect on mitochondrial calpain and a protein transduction domain added to the N-terminus of the peptide.

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