Novel compound-peptide nucleic acid-aptamer complexes for targeted protein degradation and their applications

Abstract

It provides a complex for target protein degradation. [Solution] The present invention relates to a novel compound-peptide nucleic acid-aptamer complex for targeted protein degradation and its applications. The complex is manufactured by binding a novel compound to a peptide nucleic acid and introducing an aptamer that can bind complementaryly to the peptide nucleic acid. It has been confirmed to have the effect of targeting and degrading intracellular target proteins such as Tau, nucleolin, and eIF4E, and can be usefully utilized in related industries.

Description

[Technical Field]

[0001] This invention relates to a novel compound-peptide nucleic acid-aptamer complex for targeted protein degradation and its applications. [Background technology]

[0002] Targeted protein degradation (TPD) is attracting attention as a next-generation therapeutic approach, particularly as a promising strategy for targeting proteins that are difficult to treat with conventional drugs. Currently, more than 85% of the proteome lacks the structure of a ligand-binding pocket and has therefore not been developed as a drug, making TPD, which does not limit the range of target proteins, particularly noteworthy.

[0003] Proteolysis-targeting chimera (PROTAC)-based TPD strategies leverage the close-proportioned multifunctionality of E3 ubiquitin ligases and follow proteasome degradation processes. Recently, these strategies have been expanded to include diverse TPD strategies utilizing molecular adhesives and lysosomal degradation, such as lysosomal targeting chimeras (LYTAC), antibody-based PROTACs (AbTAC), covalent nanobody-based PROTACs (GlueTAC), and autophagy-targeting chimeras (AUTAC and AUTOTAC). However, even with these diverse TPD platforms, major obstacles remain in the binding step to target proteins. Current TPD strategies have three main drawbacks: i) they use known small molecule ligands, but no ligand has been reported to be able to handle many proteins; ii) they use antibodies, but antibodies are only applicable to cell surface proteins; and iii) they utilize intrinsic interaction partners based on molecular adhesion structures, but the development of novel substrates is an extremely challenging task.

[0004] On the other hand, aptamers have the unique advantage of allowing for the systematic discovery of selectively target-binding aptamers through SELEX (Systematic Evolution of Ligands by Exponential), and intracellular delivery of oligonucleotides has been established using lipofectamines and liposomes. Nevertheless, aptamers have only been used in a limited way, such as for PROTAC interactions with cancer cells, extracellular or membrane protein targeting of LYTAC, and as functional units of PROTAC through chemical binding to VHL E3 ligases and cereblons. Although conventional TPD technology has demonstrated the potential of aptamers, it is crucial to develop each degradation agent as a novel substance in which the binding of aptamers and E3 ligase-binding ligands is individually achieved.

[0005] Based on this, the inventors have completed the present invention by producing a novel compound, AptaGron, in which an aptamer and a peptide nucleic acid are linked via a complementary base sequence linker, and by confirming its effect of specifically degrading intracellular proteins through fluorescence imaging. [Overview of the Initiative] [Problems that the invention aims to solve]

[0006] The object of the present invention is to provide a compound represented by the following chemical formula 1.

[0007] [ka] (In the above chemical formula 1, R1 is an amino acid-R2, and R2 is a peptide nucleic acid.)

[0008] Another object of the present invention is to provide a protein degradation complex comprising a compound represented by chemical formula 1 and an aptamer capable of binding complementaryly to a peptide nucleic acid bound to the compound.

[0009] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating neurodegenerative diseases, which contains the complex as an active ingredient. **Means for Solving the Problems**

[0010] To achieve the above object, the present invention provides a compound represented by the following Chemical Formula 1.

[0011] **Chemical Formula** (In Chemical Formula 1, R1 is amino acid-R2, and R2 is a peptide nucleic acid.)

[0012] The present invention also provides a complex for proteolysis, which includes the compound represented by Chemical Formula 1 and an aptamer that can bind complementarily to the peptide nucleic acid bound to the compound.

[0013] Furthermore, the present invention provides a pharmaceutical composition for preventing or treating neurodegenerative diseases, which contains the complex as an active ingredient. **Advantages of the Invention**

[0014] The novel PROTAC-based complex of the present invention is produced by binding a novel compound and a peptide nucleic acid and introducing an aptamer that can bind complementarily to the peptide nucleic acid. It has been confirmed that it has the effect of degrading intracellular target proteins Tau, nucleolin, and eIF4E, and can be usefully utilized in related industries. **Brief Description of the Drawings**

[0015] [Figure 1] It is a diagram showing the structural formula of the novel complex AptaGron of the present invention. [Figure 2] It is a diagram showing the buffer stability of AptaGron of the present invention. [Figure 3] It is a diagram showing the temporal stability of AptaGron of the present invention. [Figure 4]This figure shows the degree of Tau protein degradation of AptaGron according to the present invention. [Figure 5] This figure shows the Tau-GFP degradation of AptaGron according to the present invention. [Figure 6] This figure shows the Tau protein degradation pattern in a TauBiFC mouse model brain sample of AptaGron according to the present invention. [Figure 7] This figure shows intracellular fluorescence imaging of AptaGron in relation to GC18ntAptaGronTau according to the present invention. [Figure 8] This figure shows the quantitative values ​​of the intracellular fluorescence signal of AptaGron in the present invention in relation to GC18ntAptaGronTau. [Figure 9] This figure shows the Tau-GFP degradation fluorescence signal of AptaGron in the present invention against GC18ntAptaGronTau. [Figure 10] This figure shows the quantitative values ​​of the fluorescence signal in the PAGE image of AptaGron according to the present invention. [Figure 11] This figure shows a Western blot of AptaGron from the present invention against AT18ntAptaGronnuc. [Figure 12] This figure shows the fluorescence imaging of AptaGron in the present invention against AT18ntAptaGronnuc. [Figure 13] This figure shows the quantitative values ​​of the fluorescence signal of AptaGron in the present invention against AT18ntAptaGronnuc. [Figure 14] This figure shows Western blots of eIF4E and Tau with and without co-treatment of AptaGron with the proteasome inhibitor MG132 according to the present invention. [Figure 15] This figure shows the fluorescence imaging of AptaGron of the present invention against GC18ntAptaGroneIF4E. [Figure 16] This figure shows the quantitative values ​​of the fluorescence signal of AptaGron in the present invention against GC18ntAptaGroneIF4E. [Modes for carrying out the invention]

[0016] The present invention will be described in detail below based on embodiments of the present invention with reference to the attached drawings. However, the following examples are presented as examples of the present invention, and if it is determined that a specific description of a technique or configuration well known to those skilled in the art would unnecessarily obscure the gist of the present invention, such detailed description may be omitted, and this shall not limit the scope of the present invention. The present invention can be modified and applied in various ways within the scope of equivalents described in the claims below and interpreted therefrom.

[0017] Furthermore, the terminology used herein is intended to appropriately represent preferred embodiments of the present invention and may vary depending on the intent of the user, operator, or the conventions of the art to which the invention pertains. Therefore, the definitions of these terms should be determined based on the content of this specification as a whole. Wherever a part of this specification is described as "containing" a component, unless otherwise stated, this does not exclude other components, but rather means that other components may be further included.

[0018] The following is a description of the terms used in this invention.

[0019] The present invention provides a compound represented by the following chemical formula 1.

[0020] [ka] (In the above chemical formula 1, R1 is an amino acid-R2, and R2 is a peptide nucleic acid.)

[0021] The compound of chemical formula 1 of the present invention can be synthesized using arginine (R), leucine (L), alanine (A), cysteine ​​(C), or derivatives thereof.

[0022] According to one embodiment of the present invention, the amino acid may be selected from the group consisting of alanine, cysteine, or a combination thereof, and preferably alanine and cysteine ​​are linked in that order.

[0023] According to one embodiment of the present invention, the peptide nucleic acid may be a base sequence represented by the following chemical formula 2.

[0024] [ka] (In the above chemical formula 2, a is adenine, x is thymine (t) or guanine (g), and n is 1 or 2.)

[0025] According to one embodiment of the present invention, the peptide nucleic acid may be one selected from the base sequences shown in SEQ ID NOs: 1 to 4.

[0026] In the present invention, R1 in the chemical formula 1 may be one selected from the following amino acid-base sequence group. AC-attattatt, AC-attattattattattatt, AC-aggaggagg, AC-aggaggaggaggaggagg. In the aforementioned amino acid-base sequence, A is alanine and C is cysteine.

[0027] Furthermore, the present invention provides a protein degradation complex comprising a compound represented by chemical formula 1 and an aptamer capable of binding complementaryly to a peptide nucleic acid bound to the compound.

[0028] In this invention, a "complex" refers to a complex composed of two or more related polypeptides. It is also called a polyprotein complex. Protein complexes are distinguished from polyenzyme complexes, in which multiple catalytic domains reside on a single polypeptide chain.

[0029] The composite according to the present invention may hereinafter be referred to as "AptaGron".

[0030] The "peptide nucleic acid (PNA)" of the present invention is a synthetic compound having a structure similar to DNA or RNA and capable of recognizing gene sequences. Instead of the typical sugar-phosphate backbone of DNA / RNA, PNA has a backbone composed of amino acids. As a result, PNA has higher stability and durability and a strong binding affinity to specific base sequences.

[0031] In this invention, "complementary" generally refers to a relationship in which two or more elements work together in a complementary or harmonious manner. In the field of biology, this means that in complementary base pairing of DNA, A (adenine) binds with T (thymine), and C (cytosine) binds with G (guanine). This principle plays an important role in DNA replication and transcription.

[0032] The "aptamer" of this invention is a short DNA or RNA molecule that binds to specific molecules, mainly proteins and small molecule compounds. Aptamers are selectively selected by SELEX and possess high specificity and affinity. Aptamers have diverse applications in diagnostic, therapeutic, and research fields, and can play a particularly important role in drug delivery systems and in recognizing and regulating target proteins in cancer treatment.

[0033] According to one embodiment of the present invention, the amino acid may be selected from the group consisting of alanine, cysteine, or a combination thereof.

[0034] According to one embodiment of the present invention, the amino acids may be linked in the order of alanine and cysteine.

[0035] According to one embodiment of the present invention, the base sequence may be the base sequence represented by the chemical formula 2.

[0036] The peptide nucleic acid may be one selected from the base sequences shown in Sequence ID No. 1 to 4.

[0037] According to one embodiment of the present invention, the aptamer may be one selected from the base sequences shown in SEQ ID NOs. 5 to 10.

[0038] According to one embodiment of the present invention, the compound may recruit intracellular proteins.

[0039] In this invention, "protein recruiting" refers to the process by which a specific protein binds to other proteins or molecules within a cell or accumulates at a specific location. This process plays a crucial role in regulating cellular function, signal transduction, and maintaining cellular structure. Protein recruitment is regulated through protein-protein interactions, phosphorylation, or other chemical modifications.

[0040] According to one embodiment of the present invention, the aptamer may specifically target intracellular proteins.

[0041] According to one embodiment of the present invention, the protein may include tau (SEQ ID NO: 11), nucleolin (SEQ ID NO: 12), or eIF4E (eukaryotic initiation factor 4E (SEQ ID NO: 13)).

[0042] The "Tau" protein of this invention is primarily found in nerve cells and plays a role in maintaining microtubule stability. Tau protein plays a crucial role in neurodegenerative diseases such as Alzheimer's disease, and abnormal phosphorylation can lead to the formation of aggregates that interfere with cellular function. Such abnormal aggregates of tau protein are associated with neuronal cell death and cognitive decline.

[0043] The "nucleolin" of this invention is a protein primarily found in the nucleus, playing a crucial role in cell proliferation, division, and survival. This protein is involved in the synthesis and processing of ribosomal RNA and also influences the regulation of gene expression in cells. Nucleolins tend to be overexpressed, particularly in cancer cells, and are attracting attention as a target for anti-cancer therapy. Furthermore, nucleolins are involved in cellular stress responses, cell migration, and the regulation of the cell cycle, thereby playing an important role in various physiological and pathological processes.

[0044] The "eIF4E (eukaryotic initiation factor 4E)" of this invention is a protein that plays a crucial role in the early stages of protein translation. This protein binds to the 5' cap structure of mRNA, contributing to the formation of the translation initiation complex, and plays a core role in regulating protein synthesis. eIF4E plays an important role in cell proliferation and survival, and is often overexpressed in cancer cells in particular, potentially contributing to cancer development and progression. Therefore, eIF4E is being studied as a target for anti-cancer therapy, and its suppression is associated with inhibiting cancer cell proliferation. The functional regulation of eIF4E is also closely related to signaling pathways and plays an important role in various physiological and pathological processes.

[0045] According to one embodiment of the present invention, the complex may degrade tau, nucleolin, or eIF4E (eukaryotic initiation factor 4E).

[0046] Furthermore, the present invention provides a pharmaceutical composition for the prevention or treatment of neurodegenerative diseases, comprising the aforementioned complex as an active ingredient.

[0047] As used in this invention, the term "prevention" means all actions that suppress the symptoms or delay the progression of a particular disease by administering the composition of this invention.

[0048] As used in this invention, the term "treatment" means all actions that improve or favorably alter the symptoms of a particular disease by administering the composition of this invention.

[0049] The pharmaceutical composition of the present invention may further contain an adjuvant in addition to the active ingredient. The adjuvant may be any known in the art and is not limited to that which can be used, but the effect can be enhanced by further including, for example, Freund's complete adjuvant or incomplete adjuvant.

[0050] The pharmaceutical compositions according to the present invention can be manufactured in a form in which the active ingredient is mixed with a pharmaceutically acceptable carrier. Here, the pharmaceutically acceptable carrier includes carriers, excipients, and diluents commonly used in the pharmaceutical field. Examples of pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention, but are not limited to these, include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil.

[0051] Each of the pharmaceutical compositions of the present invention can be formulated by conventional methods into oral preparations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, as well as topical preparations, suppositories, or sterile injection solutions.

[0052] When formulation, diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrants, and surfactants are commonly used. Solid formulations for oral administration include tablets, pills, powders, granules, and capsules, and such solid formulations can be prepared by mixing the active ingredient with at least one excipient, such as starch, calcium carbonate, sucrose, lactose, or gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc can also be used. Liquid formulations for oral administration include suspensions, oral solutions, emulsions, and syrups, and in addition to commonly used diluents such as water and liquid paraffin, they can contain various excipients, such as wetting agents, sweeteners, fragrances, and preservatives. Formulations for parenteral administration include sterile aqueous solutions, water-insoluble solvents, suspensions, emulsions, lyophilized formulations, and suppositories. Non-water-soluble solvents and suspending agents that can be used include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases that can be used include witepsol, tween 61, cocoa butter, lauric acid butter, and glycerol gelatin.

[0053] The pharmaceutical composition according to the present invention can be administered to an individual by various routes. All possible methods of administration are conceivable, but for example, it can be administered orally, intravenously, intramuscularly, subcutaneously, or intraperitoneally by injection.

[0054] The dosage of the pharmaceutical composition according to the present invention is selected considering the individual's age, weight, sex, physical condition, etc. It is clear that the concentration of the active ingredient contained in the pharmaceutical composition can be selected in various ways depending on the target, and preferably it is contained in the pharmaceutical composition at a concentration of 0.01 to 5,000 μg / ml. If the concentration is less than 0.01 μg / ml, there is a possibility that no pharmaceutical activity will be observed, and if it exceeds 5,000 μg / ml, it may be toxic to the human body.

[0055] According to one embodiment of the present invention, the neurodegenerative disease may be any one selected from the group consisting of Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jakob disease (CJD), Haller-Vorden-Spatz disease, Huntington's disease, multiple system atrophy, dementia, frontotemporal dementia, amyotrophic lateral sclerosis, spinal muscular atrophy, spinocerebellar degeneration (SCA), meningoencephalitis, bacterial meningoencephalitis, viral meningoencephalitis, CNS autoimmune disease, multiple sclerosis (MS), and acute ischemic injury.

[0056] The present invention will be described in more detail below with reference to the following examples. However, these examples are for illustrative purposes only, and the scope of the present invention is not limited by these examples.

[0057] <Example 1> Preparation of a novel complex, Aptagron A novel complex was prepared by combining the compound represented by the following chemical formula 1 with an aptamer.

[0058] [ka] (In the above chemical formula 1, R1 is an amino acid-R2, and R2 is a peptide nucleic acid.)

[0059] Specifically, substituents were introduced at the R1 position of the compound, in which amino acid-peptide nucleic acid (PNA) sequences were sequentially linked. The amino acids were alanine (A) and cysteine ​​(C), and the peptide nucleic acid was linked complementaryly to the 5'-terminus of the aptamer using Sequence IDs 1-4 shown in Table 1 below, forming a single complex linking the aptamer and the compound.

[0060] Table 1 below shows the nucleotide sequences represented by Sequence IDs 1 to 4 of the peptide nucleic acid of the present invention.

[0061] [Table 1]

[0062] Furthermore, the nucleotide sequences of the aptamers of the present invention, as shown in SEQ ID NOs. 5 to 10, are shown in Table 2 below.

[0063] [Table 2] TIFF2026103877000009.tif210169

[0064] Specifically, the amino acid-PNA-bound compound and aptamer were mixed in PBS buffer (pH 7.4) at a concentration of 5 μM, denatured by heating at 95°C for 5 minutes, then cooled to 30°C at a rate of 1.38°C per minute. The mixture was incubated at 30°C for 10 minutes and then maintained at 10°C.

[0065] The structure of the novel complex AptaGron of the present invention is shown in Figure 1.

[0066] <Example 2> Cell stability analysis The HEK293T and MCF7 cells of the present invention were added to Dulbecco's modified Eagle medium (DMEM) containing 10% fetal bovine serum (FBS) and penicillin-streptomycin, and then cultured at 37°C under a 5% CO2 atmosphere.

[0067] Specifically, 4 × 10⁶ MCF7 and HEK293T cells were placed per well in a 96-well plate (Corning). 4Cells were dispensed at a cell density and cultured at 37°C for 24 hours. Afterward, the cells were washed twice with cooled Dulbecco's Phosphate-Buffered Saline (DPBS). On an ice bath, the cells were added to a lysis buffer containing 50 mM Tris-HCl pH 7.4, 150 mM NaCl, 1% Triton X, 1 mM EDTA, 1 mM DTT, and a 1× protease inhibitor cocktail. The cell lysates were centrifuged at 13,000 rpm for 15 minutes at 4°C to collect the protein supernatant. The cell lysates were mixed with 4× SDS load buffer and heated at 95°C for 5 minutes. 20 μL of the heated lysates were loaded onto an SDS-PAGE gel and processed on a PVDF membrane. The membranes were blocked with 3% BSA in TBST (Tris-Buffered Saline containing 0.01% Tween-20), incubated with primary antibody at 4°C for 24 hours, and then treated with fluorescently labeled secondary antibody at room temperature for 1 hour. Visualization was performed using the ChemiDoc MP imaging system.

[0068] To confirm the stability of aptamers in buffer or cell culture, each PNA and aptamer mixture was diluted to a 10 μM concentration in PBS buffer (pH 7.4) and incubated at 37°C for 48 hours. The reaction mixture was analyzed on a 4% agarose gel.

[0069] Furthermore, each PNA and aptamer mixture at a concentration of 10 μM was incubated at 37°C for 1 hour, 2 hours, 4 hours, 6 hours, 10 hours, 20 hours, and 24 hours to obtain samples. The samples were treated with 3'-ACGCTACTAAGTCGAAAG-5' (reverse primer) and 5'-GACTGATTTACGGAAGCT-3' (forward primer). The generated DNA was analyzed on a 4% agarose gel.

[0070] As a result, as shown in Figures 2 and 3, wt aptaGron Tau , GC18nt aptaGron Tau and hybridized GC18ntAptaGron Tau None of them were degraded during the 48-hour incubation period, and it was confirmed that AptaGron or the aptamer band could be detected in HEK293T cells for up to 6 hours.

[0071] <Example 3> Proteolysis inhibition To monitor the degradation of the target protein, GFP-fused Tau (Tau-GFP) that can be overexpressed in HEK293T cells was used.

[0072] Specifically, after transducing the Tau-GFP expression construct into cultured HEK293T cells, they were grown in Dulbecco's Modified Eagle Medium (DMEM) until they reached a density of 70-80%. The cells were harvested and centrifuged at 14,000 rpm for 20 minutes to obtain a supernatant containing the overexpressed Tau protein. Then, 100 μM GC18nt AptaGron Tau or 10 μM of the proteolysis inhibitor MG132 (Sigma, M7449) was added, and the mixture was incubated at 37 °C for 16 hours to obtain a soluble protein lysate. After incubation, the lysate samples were subjected to SDS-PAGE and Western blot analysis. The degradation mediated by AptaGron was monitored through the GFP signal in the fluorescent PAGE image.

[0073] As a result, as shown in Figures 4 and 5, in the aptamer with an 18-nt linker compared to the 9-nt linker, Tau-GFP decreased due to proteolysis. AT9nt AptaGron Tau In the case of, it was confirmed that little Tau proteolysis occurred due to its short length and low affinity due to fewer hydrogen bond pairs.

[0074] <Example 4> Targeting neurodegenerative disease-related proteins 4-1. Tau Proteolysis Three TauP301L-BiFC transduced 12-month-old mouse models free of the pathogen were reared at 12-hour intervals day and night, perfused with 0.9% physiological saline, and then their brains were extracted. After weighing the brains, they were suspended in RIPA lysis buffer containing a mixture of protease and phosphate hydrolase inhibitors. The brain tissue was disrupted using a 2 mL glass Downs homogenizer and incubated at 4°C for 2 hours. The homogenized mixture was centrifuged at 20,000 g for 20 minutes at 4°C, and the supernatant was collected and stored at -80°C. For immunoblot analysis, 25 μg and 100 μM of each lysis solution were used. GC18nt AptaGron Tau The mixture was incubated at 37°C for 24 hours to obtain a brain protein lysate. All experiments were repeated three times, and the data were analyzed using Student's t-test. A p-value of less than 0.05 was considered statistically significant.

[0075] As a result, as shown in Figures 6 to 10, GC18nt AptaGron Tau In cells treated with the drug, Tau protein was degraded after 24 hours, and both in vivo cell fluorescence imaging and PAGE analysis confirmed lower fluorescence intensity of the Tau-GFP protein compared to the control group.

[0076] 4-2. Nucleoline Decomposition As a target protein for binding to aptamers, Tau( wt aptamer Tau :57-nt), Nucleoline ( wt aptamer nuc :26-nt), and eIF4E( wt aptamer elF A 10 μM aptamer was prepared by conjugating an 18-nt linker to :53-nt. Information on the target protein in this invention is shown in Table 3 below.

[0077] [Table 3]

[0078] Specifically, PNA and AT18nt aptamer nuc After mixing, thermal annealing is performed to obtain a 10 μM solution. AT18nt AptaGron nuc The obtained solution was mixed with a whole cell lysate of MCF7 breast cancer cells and incubated. The degradation pattern of nucleolins was monitored by Western blot analysis.

[0079] As a result, as shown in Figures 11 to 13, nucleolins were detected in the intracellular nucleus, and it was confirmed that nucleolin expression decreased and fluorescence decreased with increasing incubation time.

[0080] 4-3. eIF4E Decomposition Using the same protocol as in Table 3, the AptaGron eIF4E decomposition pattern for eIF4E configured with an 18-nt linker was monitored.

[0081] As a result, as shown in Figures 14 to 16, GC18nt AptaGron eIF4E It was confirmed that the enzyme degrades eIF4E within cells, leading to a decrease in fluorescence, and that the degradation of eIF4E is suppressed when the MG132 proteolytic inhibitor is added.

[0082] Therefore, the novel complex of the PROTAC base of the present invention was prepared by binding a novel compound to a peptide nucleic acid and introducing an aptamer that can bind complementaryly to the peptide nucleic acid, and it was confirmed that it has the effect of targeting and degrading intracellular target proteins Tau, nucleolin, and eIF4E.

[0083] As described above, specific embodiments of the present invention have been explained in detail. However, those skilled in the art who understand the spirit of the present invention can easily propose other modified inventions and other embodiments that fall within the scope of the present invention by adding, changing, or deleting other components within the same spirit. Therefore, the embodiments described above should be understood to be illustrative and not limiting. The scope of the present invention is indicated not by the detailed description above, but by the claims described below, and all changes or variations derived from the meaning and scope of the claims, and the concept of equivalents thereunder, should be interpreted as being within the scope of the present invention.

Claims

1. The compound represented by the following chemical formula 1. 【Chemistry 1】 (In the above chemical formula 1, R 1 is amino acid-R 2 And the R 2 (It is a peptide nucleic acid.)

2. The compound according to claim 1, wherein the amino acid is selected from the group consisting of alanine, cysteine, or a combination thereof.

3. The compound according to claim 2, wherein the amino acids are linked in the order of alanine and cysteine.

4. The compound according to claim 1, wherein the peptide nucleic acid is a base sequence represented by the following chemical formula 2. 【Chemistry 2】 (In the above chemical formula 2, a is adenine, x is thymine (t) or guanine (g), and n is 1 or 2.)

5. The compound according to claim 4, wherein the peptide nucleic acid is one selected from the base sequences shown in SEQ ID NOs: 1 to 4.

6. The compound represented by the chemical formula 1, A protein degradation complex comprising an aptamer capable of binding complementaryly to a peptide nucleic acid bound to the aforementioned compound. 【Chemistry 1】 (In the above chemical formula 1, R 1 is amino acid-R 2 And the R 2 (It is a peptide nucleic acid.)

7. The complex according to claim 6, wherein the amino acid is selected from the group consisting of alanine, cysteine, or a combination thereof.

8. The complex according to claim 7, wherein the amino acids are linked in the order of alanine and cysteine.

9. The complex according to claim 6, wherein the peptide nucleic acid is a base sequence represented by the following chemical formula 2. 【Chemistry 2】 (In the above chemical formula 2, a is adenine, x is thymine (t) or guanine (g), and n is 1 or 2.)

10. The complex according to claim 9, wherein the peptide nucleic acid is one selected from the base sequences shown in SEQ ID NOs: 1 to 4.

11. The complex according to claim 6, wherein the aptamer is one selected from the base sequences shown in SEQ ID NOs. 5 to 10.

12. The complex according to claim 6, wherein the compound recruits intracellular proteins.

13. The complex according to claim 6, wherein the aptamer specifically targets intracellular proteins.

14. The complex according to claim 13, wherein the protein comprises tau, nucleolin, or eIF4E (eukaryotic induction factor 4E).

15. The complex according to claim 6, wherein the complex degrades tau, nucleolin, or eIF4E (eukaryotic induction factor 4E).

16. A pharmaceutical composition for the prevention or treatment of neurodegenerative diseases, comprising the complex described in claim 6 as an active ingredient.

17. The composition according to claim 16, wherein the neurodegenerative disease is one selected from the group consisting of Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jakob disease (CJD), Haller-Vorden-Spatz disease, Huntington's disease, multiple system atrophy, dementia, frontotemporal dementia, amyotrophic lateral sclerosis, spinal muscular atrophy, spinocerebellar degeneration (SCA), meningoencephalitis, bacterial meningoencephalitis, viral meningoencephalitis, CNS autoimmune disease, multiple sclerosis (MS), and acute ischemic injury.

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