A pharmaceutical composition for the prevention or treatment of coronavirus infection containing a cell-penetrating peptide-nucleic acid oligomer as an active ingredient.

Abstract

This invention provides PNA oligomers containing modified PNA for the prevention or treatment of coronavirus infections. The PNA oligomers of this invention can be delivered into virus-infected cells without the use of a delivery carrier and can suppress viral replication. Therefore, they do not have the side effects of delivery carriers used to increase cell permeability in conventional drugs, and because they have high binding affinity to the target, they can bind to the target and suppress viral replication even in the event of mismatch. Accordingly, they are expected to be used as effective coronavirus treatments that can cope with rapidly mutating viral infections.

Claims

[Claim 1] A pharmaceutical composition for the prevention or treatment of coronavirus infection, comprising a peptide nucleic acid (PNA) oligomer represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient, The PNA oligomer can complementarily bind to a portion of the coronavirus genomic (+) RNA or genomic (-) RNA in the pharmaceutical composition: [Chemical formula 1] 【Chemistry 1】 In the above formula, n is an integer between 10 and 30; X is one selected from the group consisting of hydrogen [H], formyl [H-C(=O)-], aminocarbonyl [NH2-C(=O)-], substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylacyl, substituted or unsubstituted arylacyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted alkylaminocarbonyl, substituted or unsubstituted arylaminocarbonyl, substituted or unsubstituted alkylsulfonyl, and substituted or unsubstituted arylsulfonyl; Z is one selected from the group consisting of hydroxy[-OH], substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, amino[-NH2], substituted or unsubstituted alkylamino, substituted or unsubstituted arylamino, substituted or unsubstituted alkyl, and substituted or unsubstituted aryl; B １ , B ２ , ..., B ｎ－１ and B ｎ Each of these is independently selected from the native and non-native nucleic acid bases of adenine (A), guanine (G), thymine (T), or cytosine (C); B １ ~B ｎ One or more of these are independently selected from the group consisting of modified non-natural nucleic acid bases of chemical formulas 2 to 4 below; [Chemical formula 2] 【Chemistry 2】 [Chemical formula 3] 【Transformation 3】 [Chemical formula 4] 【Chemistry 4】 In the aforementioned chemical formulas 2 to 4, j, k, l, and m are each independent integers between 1 and 16. [Claim 2] The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition does not contain a delivery carrier for intracellular transport of the PNA oligomer. [Claim 3] The pharmaceutical composition according to claim 1, wherein X is Fmoc[(9-fluorenyl)methyloxy]carbonyl], Fethoc[2-(9-fluorenyl)ethyl-1-oxy]carbonyl], acetyl (Ac), benzoyl (Benzyl), or hydrogen. [Claim 4] The aforementioned X is Fethoc[2-(9-fluorenyl)ethyl-1-oxy]carbonyl], The aforementioned Z is NH2, The aforementioned j is 2, The aforementioned k is 1, The aforementioned l is 5, The pharmaceutical composition according to claim 1, wherein m is 6. [Claim 5] The pharmaceutical composition according to claim 1, wherein the coronavirus is one or more selected from the group consisting of human coronavirus 229E (HCoV-229E), human coronavirus OC43 (HCoV-OC43), severe acute respiratory syndrome coronavirus (SARS-CoV), human coronavirus NL63 (HCoV-NL63), human coronavirus HKU1 (HCoV-HKU1), Middle East respiratory syndrome coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). [Claim 6] The aforementioned coronavirus is human coronavirus OC43 (HCoV-OC43), The pharmaceutical composition according to claim 1, wherein the PNA oligomer is one or more selected from the group consisting of PNA oligomers in Table 1. [Claim 7] The aforementioned coronavirus is Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), The pharmaceutical composition according to claim 1, wherein the PNA oligomer is one or more selected from the group consisting of PNA oligomers in Table 2. [Claim 8] The pharmaceutical composition according to claim 7, wherein the pharmaceutical composition contains PNA123 [Fethoc-A(5)GC-C(1O2)CT-G(6)TA-TA(5)C-GA(5)C-ATC(1O2)-AG-NH2] as shown in Table 2. [Claim 9] The aforementioned coronavirus is one or more selected from the group consisting of human coronavirus OC43 (HCoV-OC43) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The pharmaceutical composition according to claim 1, wherein the PNA oligomer is one or more selected from the group consisting of PNA oligomers in Table 3. [Claim 10] The pharmaceutical composition according to claim 1, wherein the PNA oligomer is 80% or more complementary to a portion of the coronavirus genomic (+) RNA or genomic (-) RNA. [Claim 11] The pharmaceutical composition according to claim 1, wherein the PNA oligomer is 90% complementary to a portion of the coronavirus genomic (+) RNA or genomic (-) RNA. [Claim 12] A method for preventing or treating coronavirus infection, comprising the step of administering a peptide nucleic acid (PNA) oligomer represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof to an individual, The PNA oligomer can complementarily bind to a portion of the coronavirus's genomic (+) RNA or genomic (-) RNA, in a method of prevention or treatment: [Chemical formula 1] 【Transformation 5】 In the above formula, n is an integer between 10 and 30; X is one selected from the group consisting of hydrogen [H], formyl [H-C(=O)-], aminocarbonyl [NH2-C(=O)-], substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylacyl, substituted or unsubstituted arylacyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted alkylaminocarbonyl, substituted or unsubstituted arylaminocarbonyl, substituted or unsubstituted alkylsulfonyl, and substituted or unsubstituted arylsulfonyl; Z is one selected from the group consisting of hydroxy[-OH], substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, amino[-NH2], substituted or unsubstituted alkylamino, substituted or unsubstituted arylamino, substituted or unsubstituted alkyl, and substituted or unsubstituted aryl; B １ 、B ２ 、……、B ｎ－１ 以及B ｎ are each independently selected from natural nucleobases and unnatural nucleobases of adenine (Adenine, A), guanine (Guanine, G), thymine (Thymine, T), or cytosine (Cytosine, C); B １ ~B ｎ One or more of these are independently selected from the group consisting of modified non-natural nucleic acid bases of chemical formulas 2 to 4 below; [Chemical formula 2] 【Transformation 6】 [Chemical formula 3] 【Transformation 7】 [Chemical formula 4] 【Transformation 8】 In the aforementioned chemical formulas 2 to 4, j, k, l, and m are each independent integers between 1 and 16. [Claim 13] A method for inhibiting the proliferation of coronavirus (coronavirus), comprising the step of administering a peptide nucleic acid (PNA) oligomer represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof to an individual, The PNA oligomer can complementarily bind to a portion of the coronavirus's genomic (+) RNA or genomic (-) RNA, a method for inhibiting coronavirus replication: [Chemical formula 1] 【Chemistry 9】 In the above formula, n is an integer between 10 and 30; X is one selected from the group consisting of hydrogen [H], formyl [H-C(=O)-], aminocarbonyl [NH2-C(=O)-], substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylacyl, substituted or unsubstituted arylacyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted alkylaminocarbonyl, substituted or unsubstituted arylaminocarbonyl, substituted or unsubstituted alkylsulfonyl, and substituted or unsubstituted arylsulfonyl; Z is one selected from the group consisting of hydroxy[-OH], substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, amino[-NH2], substituted or unsubstituted alkylamino, substituted or unsubstituted arylamino, substituted or unsubstituted alkyl, and substituted or unsubstituted aryl; B １ , B ２ , ..., B ｎ－１ and B ｎ Each of these is independently selected from the native and non-native nucleic acid bases of adenine (A), guanine (G), thymine (T), or cytosine (C); B １ ~B ｎ One or more of these are independently selected from the group consisting of modified non-natural nucleic acid bases of chemical formulas 2 to 4 below; [Chemical formula 2] 【Chemistry 10】 [Chemical formula 3] 【Chemistry 11】 [Chemical formula 4] 【Chemistry 12】 In the aforementioned chemical formulas 2 to 4, j, k, l, and m are each independent integers between 1 and 16. [Claim 14] For the manufacture of drugs for the prevention or treatment of coronavirus infection, the peptide nucleic acid (PNA) oligomer represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof, The PNA oligomer can complementarily bind to a portion of the coronavirus genomic (+) RNA or genomic (-) RNA. Applications: [Chemical formula 1] 【Chemistry 13】 In the above formula, n is an integer between 10 and 30; X is one selected from the group consisting of hydrogen [H], formyl [H-C(=O)-], aminocarbonyl [NH2-C(=O)-], substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylacyl, substituted or unsubstituted arylacyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted alkylaminocarbonyl, substituted or unsubstituted arylaminocarbonyl, substituted or unsubstituted alkylsulfonyl, and substituted or unsubstituted arylsulfonyl; Z is one selected from the group consisting of hydroxy[-OH], substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, amino[-NH2], substituted or unsubstituted alkylamino, substituted or unsubstituted arylamino, substituted or unsubstituted alkyl, and substituted or unsubstituted aryl; B １ , B ２ , ..., B ｎ－１ and B ｎ Each of these is independently selected from the native and non-native nucleic acid bases of adenine (A), guanine (G), thymine (T), or cytosine (C); B １ ~B ｎ One or more of these are independently selected from the group consisting of modified non-natural nucleic acid bases of chemical formulas 2 to 4 below; [Chemical formula 2] 【Chemistry 14】 [Chemical formula 3] 【Chemistry 15】 [Chemical formula 4] 【Chemistry 16】 In the aforementioned chemical formulas 2 to 4, j, k, l, and m are each independent integers between 1 and 16.

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