RU2402563C2 - Agent having antiviral activity - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: agent is an N- and C-substituted peptide selected from n-decyl ether (1-tetradecyl-1,4-diazoniabicyclo[2.2,2.]octan-4-yl)-acetyl-glutamyl-glycyl lysyl-glycine (1), n-decyl ether (1-tetradecyl-1,4-diazoniabicyclo[2.2,2.]octan-4-yl)-acetyl-glutamyl-β-alanyl-arginyl-glycine (2) and n-decyl ether glutamyl-β-alanyl-lysyl-glycine (3).

EFFECT: high antiviral activity of the agent.

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Description

The invention relates to the field of chemistry and medicine, namely to new compounds with antiviral activity.

Viral diseases pose a common threat to public health worldwide. Among viruses, viruses containing the genome in the form of RNA cause a number of serious diseases of animals (domestic and wild) and are among the most dangerous for humans. Highly pathogenic RNA viruses such as avian influenza virus (Avian Influenza Virus), tick-borne encephalitis (Tick-borne enchefalitis), Dengue virus (Denge virus), coronavirus (SARS), etc., are a constant threat to public health. To date, viruses of birds and animals that can infect humans are of particular danger (Lipsitch, M. et al. Science, 2006, 312, 845; Krag, RMScience, 2006, 311, 1562-1563; Chen, H. et al. Nature, 2005, 436, 191-192). For example, for a long time it was believed that the avian influenza virus could not spread to humans, but in recent years a large number of virus transmission from birds to humans has been recorded, causing deaths in infected people (Subbarao, K. et al. Science, 1998, 279, 393-396; Fouchier, RA et al. Proc. Natl. Acad. Sci., USA, 2004, 101, 1356-1361). Outbreaks of the highly pathogenic H5N1 virus in some Asian and European countries have caused serious concern from the international community (Koopmans, M. et al. Lancet, 2004, 363, 587-593; Enserink, M., Science, 2006, 311, 932; Fabain NJEnviron. Health 2006, 68, 46-63).

The danger of epidemics and pandemics caused by RNA viruses makes the development of new antiviral drugs and new tools and methods for their inactivation one of the most urgent tasks of today.

Currently, physical methods are used as means of virus inactivation (irradiation with ultraviolet light, ionizing radiation, heating at elevated pressure) and a number of chemical compounds (formalin, β-propiolactone, ethyleneimine, a number of detergents), which differ in the mechanism of action and, therefore, scope, toxicity, virus inactivation efficacy, and cost (De Benedictis; P. et al. Zoonoses Public Health. 2007, 54 (2), 51-68).

The spectrum of compounds that enable inactivation of the virus, including for the preparation of whole-virion vaccines, is limited to several compounds: formaldehyde, β-propiolactone (Goldstein M. and Tauraso N., Applied Microbiol, 1970, 19, 290-294), ethyleneimine and its derivatives (Budowsky EI, et al, Vaccine, 1991, 9, 473-476; Aarthi d., et al, Biologicals, 2004, 32, 153-156), UV irradiation (Budowsky EI, et al, Arch. Virol ., 1981, 68-239-246) or by UV light in the presence of compounds that increase the photosensitivity of the virus (Kasermann F and Kempf C., Antiviral Res., 1997, 34, 65-70), oxidation by atmospheric oxygen in the light (Kasermann F . and Kempf S., Rev. Med. Virol., 1998, 8, 143-151). It is known that treatment of the virus with such compounds leads to partial destruction of the viral antigenic determinants and thereby to a decrease in the immunogenic properties of vaccines, and selective destruction by the formalin of the antigenic determinants of the surface glycoprotein viruses can induce the development of an unbalanced immune response (Kasermann F., et al., Antiviral Res. , 2001, 52, 33-41).

An ideal target for inactivating the influenza virus is its genomic RNA. After the destruction of genomic RNA, the virus loses its ability to replicate and, therefore, cannot multiply.

Closest to the claimed compounds - prototypes are lysine derivatives of the general formula nLm, which, according to published data, have high ribonuclease activity (Zhdan N.S. et al. Bioorgan, chemistry. 1999, 25, 723-732). Figure 1 shows the general structural formula of nLm compounds, which are non-natural peptides based on lysine, where n is the number of lysine residues, m is the total positive charge of the compound at neutral pH. It was shown that although these compounds exhibit high ribonuclease activity, the efficiency of RNA cleavage by them did not correlate with the total positive charge of the molecule.

The disadvantages of the known nLm compounds are their low antiviral activity.

An object of the invention is the creation of funds based on synthetic compounds with high antiviral activity.

The stated technical problem is solved by the proposed compounds, which are N- and C-substituted tetrapeptides of the general formula A1D-Glu-AK1-AK2-GlyA2 (compounds 1, 2 and 3), where A1D = 1-tetradecyl-1,4-diazoniabicyclo [2.2 .2] octan-4-yl for 1 and 2 and = H for 3; AK1- = glycine for 1 and β-alanine for 2 and 3; AK2 = lysine for 1 and 3 and arginine for 2; GlyA2 = n-decyl ester of glycine.

Figure 2 presents the General structural formula of the compounds (1), (2) and (3).

The inventive compounds (1) to (3) of the General formula A1D-Glu-AK1-AK2-GlyA2 were obtained according to the General scheme shown in Fig.3. In the synthesis of peptides, activated N-hydroxysuccinimide amino acid esters were used. The introduction of tert-butyloxycarbonyl protection and the synthesis of activated esters was carried out according to standard methods [A.A. Gershkovich, V.K. Kibirev. The synthesis of peptides. Reagents and methods. // Kiev. Naukova Dumka. 1987]. Figure 3 used the following abbreviations: β-Ala - β - alanine, Gly - glycine, Arg - arginine, Glu - glutamic acid, Lys - lysine, Boc - tert-butyloxycarbonyl protective group, Z (2Cl) - 2-chlorobenzyloxycarbonyl protective group, Bzl - benzyl protecting group, TFA - trifluoroacetic acid, DMF - dimethylformamide, Et ₃ N - triethylamine, DABCO - 1,4-diazabicyclo [2.2.2] octane.

NMR spectra were recorded on Bruker AM-400 and Bruker AV-300 (Germany) spectrometers in CD ₃ OD, (СО ₃ ) ₂ СО (Aldrich, USA). For ¹ H NMR spectra, tetramethylsilane or residual proton signals of solvents were used as internal standard. Chemical shifts are given in the scale δ, ppm

High resolution mass spectra were obtained using a MALDI time-of-flight mass spectrometer Bruker reflex III MALDI TOP (Bruker Analytical Systems, Inc., Germany), Agilent 1100 series LC / MSD (Agilent, Germany) by electrospray.

Kieselgel 60 silica gel (63-100 μm, Merck, Germany) was used for column chromatography.

To increase the antiviral activity of the claimed compounds, the hydrophobicity of the compounds was increased by attaching tetradecyl-1,4-diazoniabicyclo- [2.2.2] octane to the amino group of the N-terminal glutamine, and the carboxyl group of the C-terminal glycine residue was esterified with n-decyl alcohol. In order to optimize the geometry of the molecule and the relative positions of the functional groups of the side radicals of amino acids, residues of lysine (1 and 3) or arginine (2) were placed in the center of the molecule.

The antiviral activity of these compounds was investigated in experiments on the inactivation of RNA-containing viruses (influenza virus and tick-borne encephalitis virus) and in experiments to suppress the reproduction of these viruses in an in vitro culture of eukaryotic cells.

A comparative analysis of the claimed compounds with known and widely used compounds for virus inactivation of viruses, such as formalin, UV light or monomeric or binary ethyleneimine (Budowsky. EI, et al., Vac. Res., 1996, 5, 29-39), showed that the proposed compounds have the following advantages.

1) The inventive compounds have antiviral activity, which allows us to consider them as promising drug agents.

2) The claimed compounds are low toxic to humans and do not require special precautions (gas mask, gloves, work under the hood) when working with them. In addition, these compounds are storage stable in the form of concentrated aqueous solutions or solutions in aprotic solvents such as dimethyl sulfoxide.

3) The inventive compounds do not have side effects on the protein components of virions, which does not reduce the immunogenic properties of inactivated viruses and improves the properties of vaccines derived from them.

A search by sources of scientific, technical and patent literature showed that N- and C-substituted tetrapeptides with antiviral activity were not described in known sources.

The invention is illustrated by the following examples.

Example 1. Obtaining n-decyl ester of glutamyl-β-alanyl-lysyl-glycine (3)

N ^α- Boc-glycine (16) (28 mmol, 5 g) was dissolved in 15 ml of ethyl acetate, N-ethyldiisopropylamine (34 mmol, 5.8 ml) and 1-bromodecane (4) (28 mmol, 5.9 ml) were added. The reaction mixture was refluxed for 24 hours. The precipitated N-ethyldiisopropylamine bromide was filtered off. The resulting solution was washed successively with 2% citric acid solution (20 ml), water (20 ml), saturated NaHCO ₃ solution (20 ml) and water (20 ml). The organic layer was dried with anhydrous Na ₂ SO ₄ . The solvent was removed in vacuo. The resulting N ^α -Boc-Gly-OC ₁₀ H _{21 was} dissolved in a mixture of TFA: CH ₂ Cl ₂ = 1: 1 (5 ml) and the reaction mixture was kept for 1.5 h at room temperature. The solvent and excess TFA were removed in vacuo, the residue was evaporated with ethanol (3 × 10 ml). The resulting oil was triturated with diethyl ether. The resulting white precipitate was filtered off, dried in vacuo. The output of glycine decyl ester trifluoroacetate 4.41 g, 47%.

To a solution of glycine decyl ester trifluoroacetate (3 mmol, 1 g) and N-ethyldiisopropylamine (7.6 mmol, 1.3 ml) in 10 ml of ethyl acetate was added with stirring a solution of N-hydroxysuccinimide ester N ^α -Boc-Lys (Z (2Cl)) (3.6 mmol, 1.9 g) in 5 ml of ethyl acetate. After 2 hours, N, N-dimethylethylenediamine (1 mmol, 110 μl) was added to the reaction mixture and stirred for 30 minutes. The reaction mixture was washed sequentially with 2% citric acid solution (20 ml), water (20 ml), saturated NaHCO ₃ solution (20 ml) and water (20 ml). The organic layer was dried with anhydrous Na ₂ SO ₄ . The solvent was removed in vacuo. The resulting oil was dissolved in a mixture of TFA: CH ₂ Cl ₂ = 1: 1 (5 ml) and the reaction mixture was kept for 1 h at room temperature. The solvent and TFA were removed in vacuo, the residue was evaporated with ethanol (3 × 10 ml), dissolved in ethyl acetate (15 ml) and washed with saturated NaHCO ₃ solution (10 ml) and water (10 ml), dried over anhydrous Na ₂ SO ₄ . The solvent was removed in vacuo. The resulting foam was dried in vacuo. The yield of Z (2Cl) -lysyl-glycine decyl ester 1.47 g, 95.0%.

Next, the condensation procedure was repeated. The reaction of Z (2Cl) -lyl-glycine decyl ester (0.78 mmol, 400 mg) with Boc-β-alanine N-hydroxysuccinimide ester (20) (0.86 mmol, 246 mg) was subsequently carried out, followed by N ^α - Boc-Glu (Bzl) (21) (0.82 mmol, 356 mg). A solution of protected tetrapeptide (12) in ethyl acetate (15 ml) after removal of Boc-protection was washed with saturated NaHCO ₃ solution (10 ml) and water (10 ml), dried with anhydrous Na ₂ SO ₄ . The solvent was removed in vacuo. The resulting foam was dried in vacuo. Yield of Glu (Bzl) -β-Ala-Lys (Z (2Cl)) - Gly-OC ₁₀ H ₂₁ calculated as N ^ε -Z (2Cl) -lyl-glycine decyl ether 463 mg, 74%.

Glu (Bzl) -β-Ala-Lys (Z (2Cl)) - Gly-OC ₁₀ H ₂₁ (0.29 mmol, 230 mg) after removal of the Boc-protection was dissolved in 10 ml of methanol and subjected to hydrogenolysis in the presence of 80 mg 5% - Pd / C. At the end of the reaction, the catalyst was filtered off, and the solvent was evaporated in vacuo. The yield of glutamyl-β-alanyl-lysyl-glycine n-decyl ester after hydrogenation is 133 mg, 85.2%.

The total yield of glutamyl-β-alanyl-lysyl-glycine n-decyl ester (3) based on glycine decyl ester trifluoroacetate is 61.5%. ¹ H NMR data for n-decyl ester of glutamyl-β-alanyl-lysyl-glycine (1) (CD ₃ OD) δ, ppm (J / Hz): 0.89 (t, 3H, CH ₃ , J = 6.5); 1.32 (m, 16H, CH ₂ (CH ₂ ) ₈ CH ₃ ); 1.71 (m, 8H, [CHCH ₂ CH ₂ ] ^Glu , [CH (CH ₂ ) ₃ CH ₂ ) ^Lys ); 2.52 (m, 4H, [CH ₂ CH ₂ ] ^βAla ); 3.00 (t, 2H, [CHCH ₂ CH ₂ ] ^Glu , J = 7.5); 3.56 (t, 2H, [CH (CH ₂ ) ₃ CH ₂ ] ^Ly s, J = 6.0); 4.01 (m, 3H, [CHCH ₂ CH ₂ ] ^Glu , [CH ₂ ] Gly); 4.15 (t, 2H, OCH ₂ (CH ₂ ) ₈ CH ₃ , J = 6.5); 4.40 (t, 1H, [CH (CH ₂ ) ₄ ] ^Lys , J = 7.0). MALDI-MS, m / z found 544.12 [M + H] ⁺ , calculated 543.36.

Example 2. Obtaining n-decyl ether (1-tetradecyl-1,4-diazoniabicyclo [2.2.2] octan-4-yl) -acetyl-glutamyl-glycyl-lysyl-glycine (1)

The synthesis of glutamyl-glycyl-lysyl-glycine n-decyl ester was carried out analogously to the procedure described in Example 1, using Boc-glycine instead of Boc-β-alanine. Yield of Glu (Bzl) -Gly-Lys (Z (2Cl)) - Gly-OC ₁₀ H ₂₁ calculated as N ^ε -Z (2Cl) -lysyl-glycine decyl ether 370 mg, 55.8%.

Glu (Bzl) -Gly-Lys (Z (2Cl)) - Gly tetrapeptide n-decyl ester - Gly (0.1 mmol, 80.0 mg) was dissolved in 1 ml of dry DMF, triethylamine (0.1 mmol, 14.2 μl) was added. A suspension of 1-tetradecyl-4- (4-nitrophenoxycarbonyl) methyl-1,4-diazoniabicyclo [2.2.2] octane (22) octane (0.1 mmol, 66.0 mg) in 1 ml of DMF was added to the reaction mixture. The reaction mixture was stirred at room temperature for 48 hours. Homogenization of the reaction mixture was observed. The product was precipitated from the reaction mixture with a 10-fold excess of diethyl ether. The precipitated white flocculent precipitate was separated by centrifugation, washed with ether and dried in vacuum. The yield of the protected conjugate (15) in the condensation reaction is 47 mg, 35.8%.

The protected conjugate (15) (0.036 mmol, 47 mg) was dissolved in 10 ml of methanol and subjected to hydrogenolysis in the presence of 40 mg of 5% Pd / C. At the end of the reaction, the catalyst was filtered off, and the solvent was evaporated in vacuo. The yield in the hydrogenation reaction was 29.5 mg, 78.4%.

Total yield of n-decyl ester (1-tetradecyl-1,4-diazoniabicyclo [2.2.2] octan-4-yl) -acetyl-glutamyl-glycyl-lysyl-glycine (2) based on tetrapeptide (with protected functional groups without Vos-protection) 28.1%. ¹ H NMR data for n-decyl ether (1-tetradecyl-1,4-diazoniabicyclo [2.2.2] octan-4-yl) -acetyl-glutamyl-glycyl-lysyl-glycine (2) (CD ₃ OD) δ, ppm (J / Hz): 0.92 (t, 6H, 2 CH ₃ , J = 6.5); 1.33 (m, 40H, CH ₂ (CH ₂ ) ₈ CH ₃ , CH ₂ (CH ₂ ) ₁₂ CH ₃ ); 1.70 (m, 4H, [CHCH ₂ CH ₂ ] ^Glu , [CHCH ₂ CH ₂ CH ₂ CH ₂ ] ^Lys ); 1.88 (m, 4H, [CHCH ₂ CH ₂ CH ₂ CH ₂ ] ^Lys ); 2.52 (t, 2H, [CHCH ₂ CH ₂ ] ^Glu , J = 7.5); 3.00 (m, 2H, [CH (CH ₂ ) ₃ CH ₂ ] ^Lys ); 3.64 (m, 2H, [CH ₂ ] ^Glu ); 3.98 (m, 3H, Glu-CHCH ₂ CH ₂ , -CH ₂ C (O) -OAlk); 4.08-4.50 (m, 16H, DABCO (12H), OCH ₂ (CH ₂ ) ₈ CH ₃ , NCH ₂ (CH ₂ ) ₁₂ CH ₃ ); 4.78 (m, 1H, [CH (CH ₂ ) ₄ ] ^Lys ); 4.90 (m, 2H, N-CH ₂ -C (O) - Glu). ESI-MS, m / z found, 531.75 [M + Na] ²⁺ , calculated 1037.51.

Example 3. Obtaining n-decyl ether of (1-tetradecyl-1,4-diazoniabicyclo [2.2.2] octan-4-yl) -acetyl-glutamyl-β-alanyl-arginyl-glycine (2)

The synthesis of n-decyl ester of glutamyl-β-alanyl-arginyl-glycine was carried out analogously to the procedure described in example 1. Yield of Glu (Bzl) -β-Ala-Arg (NO ₂ ) -Gly-OC ₁₀ H ₂₁ calculated on decyl ether N ^ω -NO ₂ -arginyl-glycine 148 mg, 43.7%.

The synthesis of n-decyl ether (1-tetradecyl-1,4-diazoniabicyclo [2.2.2] octan-4-yl) -acetyl-glutamyl-β-alanyl-arginyl-glycine was carried out analogously to the procedure described in example 2. Yield of the protected conjugate (14) in the condensation reaction 45 mg, 61.6%. The product yield in the hydrogenation reaction was 17.9 mg, 44.9%.

Total yield of n-decyl ether (1-tetradecyl-1,4-diazoniabicyclo [2.2.2] octan-4-yl) -acetyl-glutamyl-β-alanyl-arginyl-glycine (3) calculated on the tetrapeptide (with protected functional groups without Boc protection) 27.6%. ¹ H NMR data for n-decyl ether (1-tetradecyl-1,4-diazoniabicyclo [2.2.2] octan-4-yl) -acetyl-glutamyl-β-alanyl-arginyl-glycine (3) (CD ₃ OD) δ, ppm (J / Hz): 0.92 (t, 6H, 2 CH ₃ , J = 6.5); 1.35 (m, 40H, CH ₂ (CH ₂ ) ₈ CH ₃ , CH ₂ (CH ₂ ) ₁₂ CH ₃ ); 1.70 (m, 2H, [CHCH ₂ CH ₂ ] ^Glu ); 1.88 (m, 4H,); 2.54 (m, 4H, [CHCH ₂ CH ₂ ] ^Glu , [CH (CH ₂ ) ₂ CH ₂ ] ^Arg ); 3.60 (m, 2H, [CH ₂ CH ₂ ] ^βAla ); 3.99 (m, 3H, Glu-CHCH ₂ CH ₂ , [CH ₂ ] ^Gly ); 4.03-4.50 (m, 16H, DABCO (12H), OCH ₂ (CH ₂ ) ₈ CH ₃ , NCH ₂ (CH ₂ ) ₁₂ CH ₃ ); 4.60 (m, 1H, [CH (CH ₂ ) ₃ ] ^Arg ); 4.90 (m, 2H, N-CH ₂ -C (O) -Glu). ESI-MS, m / z found, 552.37 [M + Na] ²⁺ , calculated 1079.54.

Example 4. The effect of compounds (1) to (3) on the viability of MDCK cells

MDCK cells (dog kidney cells) were cultured in IMDM medium containing 10% fetal calf serum, antibiotics (100 units / ml penicillin and 0.1 mg / ml streptomycin) and antimycotic amphotericin (0.25 μg / ml) in atmosphere 5 % CO ₂ at 37 ° C.

Cell viability after incubation with compounds (1), (2) or (3) was determined using the MTT test, which is based on the ability of living cells to convert tetrazole (MTT) -based compounds into brightly colored formazan crystals, which allows spectrophotometric estimation of the number of living cells in the drug. For this, cells were plated in 96-well plates (10 cells per well). After 24 hours, the medium was changed in the wells and an aqueous solution of compound (1), (2) or (3) in water was added to the cells to a final concentration in the medium from 10 ^-8 to 10 ^-3 M. Cells were incubated in the presence of compounds for another days under the same conditions. At the end of incubation without changing the medium, MTT solution (5 mg / ml) in phosphate-buffered saline was added to the cells to a concentration of 0.5 mg / ml and incubated for 3 h under the same conditions. The medium was removed, 100 μl of dimethyl sulfoxide, in which the formazan crystals formed in the cells were dissolved, were added to the cells, and the optical density was measured on a multichannel spectrophotometer at wavelengths of 570 and 630 nm, where A ₅₇₀ is the absorption of formazan and A ₆₃₀ is the background of the cells.

From the experimental data, the IC ₅₀ value was calculated — the concentration of compounds at which 50% cell death was observed. IC ₅₀ values are shown in table 1.

Table 1 IC ₅₀ Values of Compounds (1) (2) (3) for MDCK Cells Compound IC ₅₀ mm (one) 0.1 ± 0.035 (2) 10.1 ± 0.038 (3) 2.5 ± 0.5

From the above data it is seen that treatment of cells with compounds (1) - (3) causes their effective death only at concentrations of compounds higher than 130 μM, which indicates a low toxicity of the compounds. In this case, the compound (3) is the least toxic to cells (IC ₅₀ = 2.5 mm)

Example 5. Inactivation of influenza virus compounds (1) to (3)

The virucidal activity of compounds (1) - (3) was studied on the model of influenza virus A / WSN / 33, (H1N1). In these experiments, the influenza virus A / WSN / 33, (H1N1) with an infectious titer of 10 ⁶ focus-forming units (PFU) of the virus-containing material was used. Infectious activity of the virus was determined by FOE on MDCK cells. The method is based on a modified enzyme-linked immunosorbent reaction: viral proteins expressed in virus-infected cells specifically bind to monoclonal antibodies labeled with the enzyme. Further, the enzyme interacts with the substrate, which leads to staining of the infected cell. Inactivation of influenza virus by compounds (1) - (3) was carried out at 37 ° C in 50 mM Tris-HCl buffer, pH 7.0, containing 0.2 M KCl and 2 mM EDTA, for 18 h at 37 ° C at concentrations of compounds (1) - (3) from 1 μM to 1 mm.

Compounds (1) to (3) effectively inactivate the influenza virus, and the degree of inactivation of the virus increases with increasing concentration of the compounds at which the inactivation of the virus is carried out. Thus, incubation of the virus for 18 h at 37 ° C with compounds (1), (2) at a concentration of 20 μM reduces the titer of the virus by 1.1 lg compared to the control. With an increase in the concentration of compounds (1), (2) to 100 μM, complete inactivation of the influenza virus is observed (table 2). In the case of compound (3), complete inactivation of the virus is observed when the concentration of the compound is 0.2 mm. It should be noted that the concentration of compounds (1) - (3), at which complete inactivation of the influenza virus is observed, is lower than the IC ₅₀ value for these compounds.

Example 6. Inactivation of tick-borne encephalitis virus (TBE) compounds (1) to (3)

The virucidal activity of compounds (1) - (3) was studied using the TBE virus model (Sofjin strain) with an infectious titer of 10 ⁶ plaque-forming units (PFU). Infectious activity of TBE virus was determined on SPEV cells. CE virus inactivation by compounds (1) - (3) was carried out at concentrations of compounds from 3 μM to 1 mM in 50 mM Tris-HCl buffer, pH 7.0, containing 0.2 M KCl and 2 mM EDTA, for 18 h at 37 ° С.

Compounds (1), (2) under these conditions even at a concentration of 6 μM (18 h, 37 ° C) completely inactivate the TBE virus. For compound (3), complete inactivation of the virus is observed at a concentration of 1 mM (table 2).

Incubation of cells infected with TBE virus with compound (1) at a concentration of 6 and 20 μM, led to a decrease in virus reproduction by almost 100 times in comparison with the control.

The results obtained clearly indicate a high antiviral activity of compounds (1) - (3).

Thus, the above examples clearly indicate a high antiviral activity of the compounds, which allows them to be used as an active component for the development of dosage forms of drugs intended for the treatment of viral diseases.

Claims (1)

An antiviral agent that is an N- and C-substituted peptide selected from n-decyl ether (1-tetradecyl-1,4-diazoniabicyclo [2.2.2.] Octan-4-yl) -acetyl-glutamyl- glycyl-lysyl-glycine (1), n-decyl ether (1-tetradecyl-1,4-diazoniabicyclo [2.2.2.] octan-4-yl) -acetyl-glutamyl-β-alanyl-arginyl-glycine (2) and n-decyl ester of glutamyl-β-alanyl-lysyl-glycine (3).

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