Use of 3-hydroxydecanoic acid in the preparation of antiviral drugs

Abstract

This invention relates to the field of pharmaceutical technology, specifically to the application of 3-hydroxydecanoic acid in the preparation of antiviral drugs. In cell experiments, 3-hydroxydecanoic acid showed significant inhibitory effects on a variety of viruses, including RNA viruses (BEFV and BVDV) and DNA viruses (HSV-1 and BoHV-1), indicating that it has inhibitory effects on multiple viruses, is less likely to induce drug resistance, and has the advantage of broad-spectrum antiviral activity.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to the application of 3-hydroxydecanoic acid in the preparation of antiviral drugs. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] Viral infections have always been a major threat to human health and public health security. From the recurring epidemics of seasonal influenza to the global outbreaks of emerging and re-emerging viral infectious diseases such as SARS-CoV-2, and the long-term problems caused by chronic viral infections such as HIV and herpesviruses, they have brought a serious disease burden and socioeconomic losses to the world.

[0004] Antiviral agent research is based on two design principles: one at the level of viral infection, and the other at the level of host cell defense. Research on antiviral agents at the host cell defense level involves altering or eliminating proteins or molecules necessary for viral replication but not essential for cell growth, thereby influencing the viral life cycle and achieving an antiviral effect. Antiviral agents targeting host cells can achieve truly broad-spectrum antiviral activity and minimize the possibility of drug resistance, thus becoming an important research direction in virology. Summary of the Invention

[0005] To overcome the above problems, the present invention provides the application of 3-hydroxydecanoic acid in the preparation of antiviral drugs.

[0006] To achieve the above technical objectives, the present invention adopts the following technical solution: In a first aspect, the invention provides the use of 3-hydroxydecanoic acid in the preparation of antiviral drugs.

[0007] In one or more embodiments, the application includes: inhibiting viral replication.

[0008] In one or more embodiments, the virus includes a DNA virus or an RNA virus; Preferably, the RNA virus is selected from single-stranded positive-sense RNA virus, single-stranded negative-sense RNA virus, double-stranded RNA virus, or retro-transcribed RNA virus, and the DNA virus is selected from double-stranded DNA virus or single-stranded DNA virus.

[0009] More preferably, the virus includes herpes simplex virus type 1 (HSV-1), bovine viral diarrhea virus (BVDV), bovine herpesvirus type 1 (BoHV-1), and bovine ephemeral fever virus (BEFV).

[0010] In a second aspect, the present invention provides an antiviral drug comprising 3-hydroxydecanoic acid.

[0011] In one or more embodiments, the virus includes a DNA virus or an RNA virus; Preferably, the RNA virus is selected from single-stranded positive-sense RNA virus, single-stranded negative-sense RNA virus, double-stranded RNA virus, or retro-transcribed RNA virus, and the DNA virus is selected from double-stranded DNA virus or single-stranded DNA virus.

[0012] More preferably, the virus includes herpes simplex virus type 1 (HSV-1), bovine viral diarrhea virus (BVDV), bovine herpesvirus type 1 (BoHV-1), and bovine ephemeral fever virus (BEFV).

[0013] In one or more embodiments, the drug further includes pharmaceutically acceptable carriers, excipients, and diluents.

[0014] The non-pharmaceutical active ingredients that may be included, such as carriers, excipients, and diluents, are well known in the art, and those skilled in the art can determine that they meet clinical standards.

[0015] Preferably, the carrier, excipients, and diluents include, but are not limited to, lactose, glucose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylparaben, propylparaben, talc, magnesium stearate, and mineral oil.

[0016] Preferably, the dosage form of the drug is a suspension, emulsion, granules, spray, injection, transdermal absorbent, a dosage form suitable for transfection, tablet, powder, granules or capsule.

[0017] A third aspect of the present invention provides a pharmaceutical composition comprising 3-hydroxydecanoic acid.

[0018] The beneficial effects of this invention are as follows: In cell experiments, 3-hydroxydecanoic acid showed significant inhibitory effects on a variety of viruses, including RNA viruses (BEFV and BVDV) and DNA viruses (HSV-1 and BoHV-1), indicating that it has an inhibitory effect on a variety of viruses, is not prone to drug resistance, and has the advantage of broad-spectrum antiviral activity. Attached Figure Description

[0019] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0020] Figure 1 The results show the effect of 3-hydroxydecanoic acid on cell viability, where A represents A549 cells and B represents MDBK cells; Figure 2 The results show the half-maximal effective concentration (WMC) of 3-hydroxydecanoic acid against the virus, where A represents BEFV, B represents BVDV, C represents BoHV-1, and D represents HSV-1. Figure 3 The results show the inhibition of viral titers by 3-hydroxydecanoic acid, where A is BEFV, B is BVDV, C is BoHV-1, and D is HSV-1; where 3-OH-C10 is 3-hydroxydecanoic acid. Detailed Implementation

[0021] It should be noted that the following detailed descriptions are exemplary and intended to provide further illustration of the invention. Unless otherwise specified, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0022] It should be noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of exemplary embodiments according to the invention. As used herein, the singular form is intended to include the plural form as well, unless the context clearly indicates otherwise. Furthermore, it should be understood that when the terms "comprising" and / or "including" are used in this specification, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof.

[0023] Viral infections have always been a major threat to human health and public health security, for example: Herpes simplex virus type 1 (HSV-1) is a common viral pathogen. Primary infection of HSV-1 is often localized to the oropharynx, with gingivostomatitis being the most common. Clinical manifestations include clusters of herpes on the gums and cheeks, fever, and sore throat, which rupture to form ulcers. In addition, it can also cause encephalitis and herpetic eczema. In adults, it can cause pharyngitis and tonsillitis.

[0024] Bovine viral diarrhea virus (BVDV) is the pathogen of bovine viral diarrhea-mucosal disease. It is an enveloped, single-stranded RNA virus, approximately 12.5 kb in length. Globally, BVDV is a widespread infectious disease affecting most cattle herds. Due to its widespread transmission and lack of effective treatment, it has become a globally prevalent infectious disease and one of the most common and prevalent bovine diseases. This disease can cause significant economic losses, including decreased fertility and milk production, diarrhea, respiratory symptoms, persistent calf infection (PI), and reproductive disorders, including embryo resorption, slow fetal growth, malformations, mummification, and stillbirth. It can also lead to immune dysfunction, secondary infections, and decreased herd performance, resulting in substantial economic losses.

[0025] Bovine herpesvirus type 1 (BoHV-1) infection in cattle can cause upper respiratory tract disorders, conjunctivitis, genital inflammation, and immunosuppression. BoHV-1 causes infectious bovine rhinotracheitis, with symptoms mainly including fever, rhinitis, dyspnea, and upper respiratory tract inflammation, leading to abortion and pneumonia in dairy cows. Co-infection with bacteria can delay the growth and weight gain of finishing cattle, affecting milk production and fertility in adult cattle. If treatment is not timely, it often leads to death; the younger the animal, the more severe the clinical symptoms and pathological damage.

[0026] Bovine ephemeral fever is an acute, febrile infectious disease of cattle caused by bovine ephemeral fever virus (BEFV). The disease is characterized by its rapid onset, rapid spread, and high morbidity, often causing large-scale epidemics within 10 days of the onset of symptoms. Affected dairy cows experience a decrease in milk production and milk quality, breeding bulls suffer impaired semen quality, some pregnant cows experience abortions, and some cows become paralyzed or even die, causing severe economic losses to the cattle industry.

[0027] Antiviral agent research is based on two design principles: one at the level of viral infection, and the other at the level of host cell defense. Research on antiviral agents at the host cell defense level involves altering or eliminating proteins or molecules necessary for viral replication but not essential for cell growth, thereby influencing the viral life cycle and achieving an antiviral effect. Antiviral agents targeting host cells can achieve truly broad-spectrum antiviral activity and minimize the possibility of drug resistance, thus becoming an important research direction in virology.

[0028] 3-Hydroxydecanoic acid (3-HDCA) is a chemically stable saturated fatty acid. Previous studies have confirmed that 3-HDCA regulates seed germination and enhances stress resistance; however, no reports have been found regarding its effects on viral replication. In the cell experiments of this invention, 3-HDCA showed significant inhibitory effects against various viruses, including RNA viruses (BEFV and BVDV) and DNA viruses (HSV-1 and BoHV-1), indicating its broad-spectrum antiviral advantage, low likelihood of inducing drug resistance.

[0029] The structural formula of 3-hydroxydecanoic acid described in this invention is shown below:

[0030] To enable those skilled in the art to better understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments.

[0031] In the following examples, A549 cells and MDBK cells were preserved by the Ruminant Disease Research Center of Shandong Normal University. Herpes simplex virus type 1 (HSV-1), bovine viral diarrhea virus (BVDV), bovine herpesvirus type 1 (BoHV-1), and bovine ephemeral fever virus (BEFV) were all preserved in our laboratory.

[0032] TCID 50 The half-maximal infectious dose (50% tissue culture infectious dose) is expressed as the reciprocal logarithm of the dilution of the virus that produces an infectious response in 50% of the test culture cells. Most viruses, after infecting cultured cells in vitro, often cause morphological changes such as cell clumping, lysis, and cell swelling. These changes are called the cytopathic effect (CPE), which can be observed directly under a microscope or identified and judged through staining. The degree of CPE can indirectly reflect viral virulence; therefore, this characteristic can be used to determine viral virulence.

[0033] Example 1 1.1 Cell viability assay (CC) 50 (Measurement) A549 and MDBK cells in the logarithmic growth phase were digested, and 10 cells were extracted. 5Cells were seeded at 100 cells / mL into 96-well cell culture plates and incubated at 37°C with 5% CO2 for 18 h. The supernatant was discarded, and 100 μL of MEM medium containing 1, 5, 10, 20, 40, 60, 80, and 100 μM 3-hydroxydecanoic acid was added. Dimethyl sulfoxide (DMSO) was used as a solvent control and a blank control. Cells were cultured in the cell culture incubator for another 24 h, and 10 μL of CCK-8 solution was added. Cells were then cultured in the cell culture incubator for another 4 h. The absorbance at 450 nm was measured using a microplate reader, and cell viability was calculated using formula (1) to obtain the effect of 3-hydroxydecanoic acid on cell viability. The results are as follows: Figure 1 As shown, from Figure 1 The results show that the concentration of 3-hydroxydecanoic acid that had no effect on A549 cell viability was 20 μM, and the concentration that had no effect on MDBK cell viability was 10 μM. 50 >100 μM.

[0034] Formula (1); Where A (drug addition) is the absorbance of the pore containing cells, CCK-8 solution and small molecule compound 3-hydroxydecanoic acid solution; A (blank) represents the absorbance of the pores containing culture medium and CCK-8 solution but without cells; A(DMSO) is the absorbance of a pore containing cells, CCK-8 solution, and solvent DMSO.

[0035] 1.2 Determination of the median effective concentration (EC50) of the drug 50 ) To measure the half-maximal effective concentration (WMC) of 3-hydroxydecanoic acid (3-HDC) as an antiviral drug for various viruses, MDBK and A549 cells were seeded in 96-well plates at 80% confluency. Viruses were then inoculated: BVDV, BEFV, or BoHV-1 in MDBK cells, and HSV-1 in A549 cells. Two hours later, DMSO and different concentrations of 3-HDC were added, and the WMC of 3-HDC in various viruses was determined.

[0036] The results are as follows Figure 2 As shown in Table 1, from Figure 2 As can be seen, 3-hydroxydecanoic acid exhibited antiviral activity in both MDBK and A549 cells, and this activity was concentration-dependent.

[0037] Table 1. Median effective concentration (LD50) of 3-hydroxydecanoic acid as an antiviral drug against various viruses.

[0038] 1,3-Hydroxydecanoic acid inhibits viral replication. MDBK cells were inoculated with BVDV, BEFV, or BoHV-1, and A549 cells were inoculated with HSV-1. Two hours later, negative control DMSO and 3-hydroxydecanoic acid were added. After 12 hours, the cells were subjected to a freeze-thaw cycle, and the viral titer of 3-hydroxydecanoic acid in the cells (TCID) was measured. 50 The results showed that the small molecule compound 3-hydroxydecanoic acid could reduce the viral titers of BVDV, BEFV, BoHV-1, and HSV-1 in cells in vitro, as shown in the following results. Figure 3 As shown.

[0039] The results above show that 3-hydroxydecanoic acid has a significant inhibitory effect on RNA viruses (BEFV and BVDV) and DNA viruses (HSV-1 and BoHV-1) in cell experiments, indicating that it has an inhibitory effect on a variety of viruses, is not prone to drug resistance, and has the advantage of broad-spectrum antiviral activity.

[0040] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

Application of 1,3-hydroxydecanoic acid in the preparation of antiviral drugs.

2. Use according to claim 1, wherein The applications include: inhibiting viral replication.

3. The use according to claim 1, wherein The viruses include DNA viruses or RNA viruses; Preferably, the RNA virus is selected from single-stranded positive-sense RNA virus, single-stranded negative-sense RNA virus, double-stranded RNA virus, or retro-transcribed RNA virus, and the DNA virus is selected from double-stranded DNA virus or single-stranded DNA virus.

4. The use according to claim 3, wherein the compound is ###0002### The viruses include herpes simplex virus type 1 (HSV-1), bovine viral diarrhea virus (BVDV), bovine herpesvirus type 1 (BoHV-1), and bovine ephemeral fever virus (BEFV).

5. An antiviral medicament, characterized by comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof. Including 3-hydroxydecanoic acid.

6. The medicament according to claim 5, wherein The viruses include DNA viruses or RNA viruses; Preferably, the RNA virus is selected from single-stranded positive-sense RNA virus, single-stranded negative-sense RNA virus, double-stranded RNA virus, or retro-transcribed RNA virus, and the DNA virus is selected from double-stranded DNA virus or single-stranded DNA virus.

7. The medicament according to claim 6, wherein The viruses include herpes simplex virus type 1 (HSV-1), bovine viral diarrhea virus (BVDV), bovine herpesvirus type 1 (BoHV-1), and bovine ephemeral fever virus (BEFV).

8. The medicament according to claim 5, wherein The drug also includes pharmaceutically acceptable carriers, excipients, and diluents.

9. The medicament according to claim 6, wherein The carrier, excipients, and diluents include, but are not limited to, lactose, glucose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylparaben, propylparaben, talc, magnesium stearate, and mineral oil. Alternatively, the dosage form of the drug may be a suspension, emulsion, granules, spray, injection, transdermal absorbent, a dosage form suitable for transfection, tablet, powder, granules, or capsule.

10. A pharmaceutical composition, characterized by, Including 3-hydroxydecanoic acid.

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