Application of hydroxycamptothecin or stereoisomer, derivative and pharmaceutically acceptable salt thereof in preparation of antiviral drugs

Abstract

The invention discloses application of hydroxycamptothecin or stereoisomers, derivatives and pharmaceutically acceptable salts thereof in preparation of antiviral drugs, and relates to the technical field of antivirus. The invention finds that hydroxycamptothecin screened from 214 traditional Chinese medicine monomer small molecule libraries by screening small molecule compound libraries can significantly inhibit 3-hydroxyl butyrylation modification of IFN signal key protein STAT1. Cell model and mouse model experiments prove that the hydroxycamptothecin can enhance IFN signals to inhibit the replication capacity of viruses in cells. Therefore, the hydroxycamptothecin has a good broad-spectrum antiviral effect, and is expected to have new application clinically. Meanwhile, a new treatment strategy can be provided for virus infection people.

Description

Technical Field

[0001] The present invention relates to the field of antiviral technology, and in particular to the use of hydroxycamptothecin or its stereoisomers, derivatives and pharmaceutically acceptable salts thereof in the preparation of antiviral drugs. Background Art

[0002] At present, interferon (IFN) is a cytokine produced by the body's cells, which has antiviral, antitumor and immunomodulatory effects. Among them, antiviral is one of the most important functions of IFN. Based on the strong and broad-spectrum antiviral activity of IFN, IFN is still a conventional therapy for the clinical treatment of various viral infections (including hepatitis B virus and hepatitis C virus, etc.). Taking the IFN-I signaling pathway as an example, after IFNα / β binds to its receptors (IFNAR1 and IFNAR2), it leads to tyrosine phosphorylation of JAK (JAK1 / TYK2) family kinases. Phosphorylated JAK then induces tyrosine phosphorylation of STAT1 and STAT2. Activated STAT1 and STAT2 recruit IRF9 to form heterotrimers, then enter the nucleus and bind to the upstream sequence of interferon-stimulated genes (ISGs) Interferon-stimulated response elements ISRE (IFN-stimulated response elements), thereby inducing a large amount of transcription and expression of ISGs, and ultimately these ISGs play antiviral and other functions.

[0003] Post-translational modification (PTMs) of proteins plays an important role in protein stability, activity, subcellular localization and various cell signaling pathways. In recent years, Professor Zhao Yingming's research group has reported 10 new acylation modifications on histone lysine in addition to acetylation and methylation, including propionylation, butyrylation, crotonylation, dihydroxyisobutyrylation, 3-hydroxybutyrylation, succinylation, malonylation, glutarylation, benzoylation and lactylation. Among them, 3-hydroxybutyrylation modification is a new type of protein acylation modification mediated by β-hydroxybutyrate that was first reported by Professor Zhao Yingming's team in 2016. 3-Hydroxybutyrylation plays an important role in regulating gene transcription, DNA damage repair and tumorigenesis. However, current basic research has not yet explored its impact on innate immunity, especially IFN-mediated antiviral function.

[0004] Camptothecin is the most abundant cytotoxic alkaloid isolated from Camptotheca acuminata. It has significant biological activity and specifically inhibits topoisomerase I. However, due to its high toxicity, researchers at home and abroad have begun to modify the structure of camptothecin and synthesize a variety of active derivatives, such as hydroxycamptothecin (10-HCPT). Among the alkaloids of the same type, hydroxycamptothecin has the strongest anti-tumor effect and low toxicity, making it a hot spot in anti-tumor research. Therefore, hydroxycamptothecin is widely used in clinical practice due to its reasonable price, safe use, and low toxicity and side effects, such as liver cancer / lung cancer / intestinal cancer. At present, the important function of hydroxycamptothecin in antiviral immunity has not been reported.

[0005] In view of this, the present invention is proposed. Summary of the invention

[0006] The object of the present invention is to provide the use of hydroxycamptothecin or its stereoisomers, derivatives and pharmaceutically acceptable salts thereof in the preparation of antiviral drugs to solve the above technical problems.

[0007] The present invention is achieved in that:

[0008] In a first aspect, the present invention provides a use of hydroxycamptothecin or its stereoisomers, derivatives and pharmaceutically acceptable salts thereof in the preparation of antiviral drugs.

[0009] In a second aspect, the present invention also provides the use of hydroxycamptothecin or its stereoisomers, derivatives and pharmaceutically acceptable salts thereof in the preparation of drugs for preventing, improving or treating viral infection-related diseases, wherein the viral infection-related diseases are hepatitis B, cirrhosis or liver fibrosis.

[0010] The present invention has the following beneficial effects:

[0011] The present invention finds that 3-hydroxybutyrylation modification of STAT1, a key protein in the IFN signaling pathway, can lead to a weakening of the antiviral activity of IFN. By screening a small molecule compound library (Selleck, L2000-Z659310), hydroxycamptothecin was screened from 214 small molecules to significantly inhibit the 3-hydroxybutyrylation modification of STAT1, a key protein in the IFN signal. Through cell model and mouse model experiments, it was confirmed that hydroxycamptothecin can enhance IFN signals (increase the expression of antiviral genes in the body) to inhibit the replication ability of intracellular viruses. Therefore, hydroxycamptothecin has a good anti-broad-spectrum viral effect, which is expected to have new uses in clinical practice. At the same time, it may also provide new treatment strategies for people infected with viruses. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required for use in the embodiments are briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present invention and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other related drawings can be obtained based on these drawings without creative work.

[0013] Figure 1 Screening diagram for small molecule compound library;

[0014] Figure 2 The results of the detection of IFN-induced ISGs in HEK293T and HT1080 cells upregulated by hydroxycamptothecin;

[0015] Figure 3 This is a graph showing the detection results of hydroxycamptothecin promoting IFN signal activation in HEK293T cells and inhibiting viral VSV replication;

[0016] Figure 4 Develop a flow chart for the hydroxycamptothecin antiviral mouse model;

[0017] Figure 5 The figure shows the detection result of hydroxycamptothecin up-regulating the transcription of ISGs in the heart, liver, spleen, lung and kidney of mice;

[0018] Figure 6 This is the result of the test that hydroxycamptothecin inhibits the transcription of VSV virus in the liver, spleen, lung and kidney of mice;

[0019] Figure 7 This is the result of the test on hydroxycamptothecin inhibiting the level of viral VSV in the spleen, lungs and kidneys of mice. DETAILED DESCRIPTION

[0020] References to embodiments of the present invention will now be provided in detail, one or more examples of which are described below. Each example is provided as an explanation rather than a limitation of the present invention. In fact, it will be apparent to those skilled in the art that various modifications and variations may be made to the present invention without departing from the scope or spirit of the present invention. For example, a feature illustrated or described as part of one embodiment may be used in another embodiment to produce a further embodiment.

[0021] The practice of the present invention will employ, unless otherwise indicated, conventional techniques of cell biology, molecular biology (including recombinant techniques), microbiology, biochemistry, and immunology, which are within the capabilities of a skilled artisan. This technique is fully explained in the literature, such as Molecular Cloning: A Laboratory Manual, 2nd Edition (Sambrook et al., 1989); Oligonucleotide Synthesis (MJ Gait, ed., 1984); Animal Cell Culture (RI Freshney, ed., 1987); Methods in Enzymology (Academic Press, Inc.); Handbook of Experimental Immunology (DM Weir and CC Blackwell, eds.); Gene Transfer Vectors for Mammalian Cells (JM Miller and MP Calos, eds., 1987); Current Protocols in Molecular Biology (FM Ausubel et al., eds., 1987); PCR: The Polymerase Chain Reaction (PCR: The Polymerase Chain Reaction) (Academic Press, Inc., 1987). Reaction" (Mullis et al., eds., 1994); and Current Protocols in Immunology (JE Coligan et al., eds., 1991), each of which is expressly incorporated herein by reference.

[0022] In a first aspect, the present invention provides a use of hydroxycamptothecin or its stereoisomers, derivatives and pharmaceutically acceptable salts thereof in the preparation of antiviral drugs.

[0023] The present invention finds that 3-hydroxybutyrylation modification of STAT1, a key protein in the IFN signaling pathway, can lead to a weakening of the antiviral activity of IFN. By screening a small molecule compound library (Selleck, L2000-Z659310), hydroxycamptothecin was screened from 214 small molecules to significantly inhibit the 3-hydroxybutyrylation modification of STAT1, a key protein in the IFN signaling pathway. Through cell model and mouse model experiments, it was confirmed that hydroxycamptothecin can enhance IFN signals (increase the expression of antiviral genes in the body) to inhibit the replication ability of intracellular viruses. Therefore, hydroxycamptothecin has a good antiviral effect and has a good application prospect in the preparation of antiviral drugs. At the same time, it may also provide a new treatment strategy for people infected with viruses.

[0024] Hydroxycamptothecin, CAS No. 19685-09-7, has a molecular structure as shown in Formula I below.

[0025]

[0026] In a preferred embodiment of the present invention, the above-mentioned virus is selected from viruses that can infect humans.

[0027] In a preferred embodiment of the present invention, the virus is selected from at least one of a DNA virus, a segmented RNA virus and a non-segmented RNA virus.

[0028] In a preferred embodiment of the present invention, the virus is selected from at least one virus of oncolytic virus, Bunyavirales and Orthomyxoviridae.

[0029] In a preferred embodiment of the present invention, the oncolytic virus is selected from at least one of: rhabdovirus, vaccinia virus, herpes virus, measles virus, Newcastle disease virus, adenovirus, alphavirus, parvovirus and enterovirus.

[0030] In a preferred embodiment of the present invention, the rhabdovirus is selected from vesicular stomatitis virus or Maraba virus.

[0031] In a preferred embodiment of the present invention, the segmented RNA virus is selected from at least one virus of the families Phenuiviridae, Nairoviridae and Arenaviridae under the order Bunyavirales;

[0032] In a preferred embodiment of the present invention, the segmented RNA virus is selected from at least one virus of Severe fever with thrombocytopenia syndrome virus (SFTSV), Heartland virus (HRTV) and Guertu virus (GTV) under the Leucoviridae family; viruses of the Leucoviridae family include but are not limited to the genus Geckovirus, the genus Parseevirus, the genus Termitovirus and the genus Tenuivirus.

[0033] In a preferred embodiment of the present invention, the segmented RNA virus is selected from at least one virus selected from Songling virus (SGLV) and Crimean Congo hemorrhagic fever virus (CCHFV) under the Nairoviridae family;

[0034] In a preferred embodiment of the present invention, the segmented RNA virus is selected from at least one of the lymphocytic choriomeningitis virus LCMV, Machupo virus (MACV) and Lassa virus under the Arenaviridae family;

[0035] In a preferred embodiment of the present invention, the segmented RNA virus is selected from at least one virus of the genus Influenza A virus, genus Influenza B virus, genus Influenza C virus and genus Togotovirus under the family Orthomyxoviridae.

[0036] In a preferred embodiment of the present invention, the non-segmented RNA virus is selected from hepatitis A virus, hepatitis C virus, measles virus, Newcastle disease virus, Coxsackie virus, etc.

[0037] In a preferred embodiment of the present invention, the DNA virus is selected from hepatitis B virus, adenovirus, herpes simplex virus, vaccine virus, etc.

[0038] In a preferred embodiment of the present invention, the above-mentioned drug is antiviral in the following manner:

[0039] (1) Inhibit 3-hydroxybutyrylation modification of STAT1 protein in the IFN-I signaling pathway;

[0040] (2) enhance the interaction between STAT1 and IFNAR2 and promote STAT1 Y701 tyrosine phosphorylation;

[0041] (3) Promote the activation of IFN-I signaling;

[0042] (4) increase the levels of interferon-stimulated genes (ISGs);

[0043] (5) Inhibit viral activity;

[0044] (6) Inhibit the levels of viral capsid protein, envelope protein, surface protein (SU) and transmembrane protein.

[0045] Interferon-stimulated genes (ISGs), as genes induced by interferons (IFNs), play a vital role in the host's resistance to viral infection. More and more studies have shown that ISGs can target different stages of viral replication and thus resist viral infection. Therefore, drugs can increase the level of interferon-stimulated genes, proving that they have a good anti-viral effect.

[0046] Interferon stimulated genes are selected from Ifit1, Viperin and Isg15.

[0047] Antiviral activity includes, but is not limited to, inhibiting viral replication.

[0048] In a preferred embodiment of the present invention, the above-mentioned medicine further comprises a pharmaceutically acceptable carrier.

[0049] Other pharmaceutically acceptable carriers are selected from one or more of starch, pregelatinized starch, microcrystalline cellulose, lactose, lactose starch complex, lactose cellulose complex, mannitol, mannitol starch complex, sorbitol, povidone, copovidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, cross-linked polyvidone, magnesium stearate, sodium stearyl fumarate, talc, and stearic acid.

[0050] In an optional embodiment, the above-mentioned medicine is a liquid pharmaceutical preparation (such as a kind of injection), such as solution, suspension and gel usually contain liquid carrier, such as water and / or pharmaceutically acceptable organic solvent. In addition, such liquid preparations may also include pH adjusting agents, emulsifiers or dispersants, buffers, preservatives, wetting agents, gelling agents (such as methylcellulose), such as defined above. The medicine may be isotonic, that is, they may have the same osmotic pressure as blood. The isotonicity of the medicine may be regulated by using sodium chloride and other pharmaceutically acceptable agents, such as glucose, maltose, boric acid, sodium tartrate, propylene glycol and other inorganic or organic soluble substances. The viscosity of the liquid composition may be regulated by pharmaceutically acceptable thickeners such as methylcellulose. Other suitable thickeners include, for example, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, carbomer, etc. The preferred concentration of the thickener depends on the selected agent.

[0051] In a preferred embodiment of the present invention, the dosage form of the drug is selected from any one of tablets, pills, powders, suspensions, gels, emulsions, granules, capsules, injections and sprays.

[0052] In a preferred embodiment of the present invention, the drug is administered orally or by injection.

[0053] In a second aspect, the present invention also provides the use of hydroxycamptothecin or its stereoisomers, derivatives and pharmaceutically acceptable salts thereof in the preparation of drugs for preventing, improving or treating viral infection-related diseases, wherein the viral infection-related diseases are hepatitis B, hepatitis C, hepatitis A, cirrhosis or liver fibrosis.

[0054] The terms "disease" or "disorder" refer to disorders and / or abnormalities that are generally regarded as pathological conditions or functions and that may manifest themselves in the form of specific signs, symptoms, and / or malfunctions.

[0055] The term "treating" a disease or condition means eliminating, inhibiting, alleviating or relieving the disease or condition, and the term "preventing" means avoiding and preventing the disease or condition or causing the disease or condition not to occur or appear.

[0056] In order to make the purpose, technical scheme and advantages of the embodiments of the present invention clearer, the technical scheme in the embodiments of the present invention will be described clearly and completely below. If the specific conditions are not specified in the embodiments, they are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.

[0057] The features and performance of the present invention are further described in detail below in conjunction with the embodiments.

[0058] Example 1

[0059] This example provides a specific method for screening a small molecule compound library:

[0060] The study found that 3-hydroxybutyrylation of STAT1, a key protein in IFN signaling, can lead to a weakening of IFN antiviral activity. By screening a small molecule compound library (Selleck, L2000-Z659310), hydroxycamptothecin was screened from 214 small molecules to significantly inhibit 3-hydroxybutyrylation of STAT1, a key protein in IFN signaling. Figure 1 ).

[0061] The specific screening methods are as follows:

[0062] HEK293T cells were plated at 1 × 10 6The number of cells was inoculated in a 6-well plate. The next day, after the cells adhered to the wall, the cells were treated with a small molecule at a concentration of 10 μM for 24 hours, and then RIPA lysis buffer was added to collect the cells. The cells were lysed on ice for 30 minutes, and the protein supernatant was taken and the protein was quantified by the BCA method. The endogenous STAT1 protein was immunoprecipitated using STAT1 antibody (Cell Signaling Technology, 9172S), incubated overnight at 4°C, and Protein G beads were added the next day for IP for 4 hours. The effect of small molecules on 3-hydroxybutyrylation modification of STAT1 protein was detected by Western Blot (WB) technology. The specific experiment is as follows:

[0063] First, the immunoprecipitated proteins were denatured (96°C, 10 min), and then the denatured samples were run on gel (protein immunoblotting, 80 V, 100 min). After the samples were run on gel, they were transferred to a PVDF membrane (360 mA, 1.5 h). After the transfer, the PVDF membrane was blocked (5% milk powder, 30 min). After the blocking, the PVDF membrane was incubated with primary antibody (3-hydroxybutyrylated antibody, Jingjie Bio, PTM-1201RM) at 4°C overnight. The next day, the membrane was washed with PBST 3 times for 10 min each time. After the washing, the membrane was incubated with secondary antibody (Bioworld, BS13278). After the secondary antibody incubation, the membrane was washed with PBST 3 times for 10 min each time, and finally developed (ECL: New Cyme, P10300; exposure 1 min).

[0064] Figure 1 The vertical axis is the relative expression of 3-hydroxybutyrylation modification of STAT1 protein in HEK293T cells after treatment with 214 small molecules (the 3-hydroxybutyrylation modification level of STAT1 protein in the control group is 1), and the horizontal axis is 214 small molecules. The results showed that hydroxycamptothecin can significantly inhibit the 3-hydroxybutyrylation modification of STAT1, a key protein of IFN signaling.

[0065] Example 2

[0066] Construction and functional testing of hydroxycamptothecin antiviral cell model.

[0067] HEK293T and HT1080 cells were plated at 5 × 10 5The number of cells was inoculated in a 12-well plate. The next day, after the cells adhered to the wall, the cells were pretreated with hydroxycamptothecin (10μM) for 24h, and then IFNɑ (60U / ml) was added to stimulate the cells for 24h, followed by VSV virus (MOI=0.5) to infect the cells for 24h, and finally Trizol was added to collect the cells, and the whole genome RNA was extracted. After reverse transcription into cDNA, the level of interferon-stimulated genes (ISGs) that play an antiviral function in the cells was detected by real-time fluorescence quantitative PCR (RT-qPCR). The RT-qPCR detection program was: 95℃, 10min; 95℃, 15s, 60℃, 1min, and 40 cycles. The RT-qPCR reaction system was: SYBR Green: 10μL; template: 2μL; Forward primer (10μM): 0.3μL; Reverse primer (10μM): 0.3μL; ddH2O: 7.4μL.

[0068] The detection primers are as follows:

[0069] human Ifit1:

[0070] Forward:5'-GCCTTGCTGAAGTGTGGAGGAA-3'(SEQ ID NO.1)

[0071] Reverse:5'-ATCCAGGCGATAGGCAGAGATC-3'; (SEQ ID NO.2)

[0072] human Isg15:

[0073] Forward:5'-CTCTGAGCATCCTGGTGAGGAA-3'(SEQ ID NO.3)

[0074] Reverse:5'-AAGGTCAGCCAGAACAGGTCGT-3'; (SEQ ID NO.4)

[0075] human Viperin:

[0076] Forward:5'-CCAGTGCAACTACAAATGCGGC-3'; (SEQ ID NO.5)

[0077] Reverse:5'-CGGTCTTGAAGAAATGGCTTCC-3'; (SEQ ID NO.6)

[0078] Internal reference gene

[0079] β-actin:

[0080] Forward:5'-ACCAACTGGGACGACATGGAGAAA-3'; (SEQ ID NO.7)

[0081] Reverse: 5'-ATAGCACAGCCTGGATAGCAACG-3' (SEQ ID NO. 8).

[0082] The results are as follows Figure 2 As shown, HCPT significantly increased the transcription levels of interferon-induced ISGs (Ifit1, Viperin, Isg15) in a time-dependent manner.

[0083] In addition, HEK293T and HT1080 cells were cultured at 1 × 10 6 The cells were seeded in a 6-well plate. The next day, after the cells adhered to the wall, they were pretreated with hydroxycamptothecin (10 μM) for 24 h, and then stimulated with IFNɑ (1000 U / ml) for 30 or 60 min, and then RIPA lysis buffer was added to collect the cells; or after hydroxycamptothecin pretreatment for 24 h, VSV virus (MOI=0.5) was directly added to infect the cells, and RIPA lysis buffer was added to collect the cells 24 h later, and the cells were lysed on ice for 30 min, the protein supernatant was taken and the protein was quantified by the BCA method, and the effect of hydroxycamptothecin on the phosphorylation level of STAT1, a key protein of IFN signaling, and the level of VSV protein was detected by WB.

[0084] The results are as follows Figure 3 As shown, HCPT significantly enhanced the interaction between STAT1 and IFNAR2, promoted the IFNɑ-induced STAT1 Y701 phosphorylation level, and downregulated the VSV protein level in a dose-dependent manner, indicating that HCPT can inhibit the replication of VSV virus in cells by enhancing IFN signaling.

[0085] Example 3

[0086] Construction and functional testing of hydroxycamptothecin antiviral mouse model.

[0087] Twelve C57BL / 6 mice were prepared and divided into two groups. One group was injected with hydroxycamptothecin control reagent, and the other group was intraperitoneally injected with hydroxycamptothecin at a dose of 3 mg / kg per day, once a day for 3 consecutive days. After that, 1x10 8 Vesicular stomatitis virus (VSV) was intraperitoneally injected into mice at a dose of 100 PFU / g. After 24 hours, the heart, liver, spleen, lung, and kidney tissues of the mice were collected. Figure 4 To build a roadmap for the model, the mouse heart, liver, spleen, lung, kidney and other tissues were collected, and steel beads were added to the grinder for grinding and centrifugation.

[0088] Part of the tissue homogenate was added with Trizol to extract the whole genome RNA, which was reverse transcribed into cDNA and then detected by RT-qPCR for the expression of ISGs and VSV in mouse heart, liver, spleen, lung, kidney and other tissues (detection primers are as follows):

[0089] mouse Ifit1:

[0090] Forward:5'-TACAGGCTGGAGTGTGCTGAGA-3'; (SEQ ID NO.9)

[0091] Reverse:5'-CTCCACTTTCAGAGCCTTCGCA-3'; (SEQ ID NO.10)

[0092] mouse Rsad2(Viperin):

[0093] Forward:5'-CAGGCTGGTTTGGAGAAGATCAAC-3'; (SEQ ID NO.11)

[0094] Reverse:5'-TACTCCCCATAGTCCTTGAACCATC-3'; (SEQ ID NO.12)

[0095] mouse Isg15:

[0096] Forward:5'-CATCCTGGTGAGGAACGAAAGG-3'; (SEQ ID NO.13)

[0097] Reverse:5'-CTCAGCCAGAACTGGTCTCGT-3'; (SEQ ID NO.14)

[0098] The results showed that HCPT could upregulate the levels of ISGs (Ifit1, Viperin, Isg15) in the heart, liver, spleen, lung and kidney of mice. Figure 5 ) and inhibited the transcription of VSV in the heart, liver, spleen, lung and kidney of mice ( Figure 6 ).

[0099] The detection primers are as follows:

[0100] VSV:

[0101] Forward:5'-ACGGGCTACTTCCAGATGG-3'(SEQ ID NO.15)

[0102] Reverse:5'-CTCGGTTCAAGATCCAGGT-3'; (SEQ ID NO.16)

[0103] The reference gene is GAPDH, and the primers for detecting GAPDH are as follows:

[0104] Forward:5'-CATCACTGCCACCCAGAAGACTG-3'(SEQ ID NO.17)

[0105] Reverse:5'-ATGCCAGTGAGCTTCCCGTTCAG-3'.(SEQ ID NO.18)

[0106] The RT-qPCR detection program was: 95°C, 10 min; 95°C, 15 s; 60°C, 1 min, 40 cycles. The RT-qPCR detection system was: SYBR Green: 10 μL; Template: 2 μL; Forward primer (10 μM): 0.3 μL; Reverse primer (10 μM): 0.3 μL; ddH2O: 7.4 μL.

[0107] Part of the tissue homogenate was added to RIPA lysis buffer and lysed on ice for 30 minutes. The protein supernatant was taken and the protein was quantified by BCA method. The effect of hydroxycamptothecin on VSV protein level was detected by WB. Figure 7 As shown, HCPT significantly reduced the content of VSV protein in the spleen, lung and kidney of mice.

[0108] The above experimental results show that in addition to its anti-tumor function, hydroxycamptothecin also has significant antiviral effects, which provides a new understanding of the function of hydroxycamptothecin.

[0109] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. Use of hydroxycamptothecin or its stereoisomers, derivatives and pharmaceutically acceptable salts in the preparation of antiviral drugs.

2. The use according to claim 1, characterized in that: The virus is selected from viruses that can infect humans.

3. The use according to claim 1, characterized in that: The virus is selected from at least one of a DNA virus, a segmented RNA virus and a non-segmented RNA virus.

4. The use according to claim 3, characterized in that: The virus is selected from at least one virus of the oncolytic virus, Bunyavirales and Orthomyxoviridae.

5. The use according to claim 4, characterized in that: The oncolytic virus is selected from at least one of: rhabdovirus, vaccinia virus, herpes virus, measles virus, Newcastle disease virus, adenovirus, alphavirus, parvovirus and enterovirus.

6. The use according to claim 5, characterized in that: The rhabdovirus is selected from vesicular stomatitis virus or Maraba virus.

7. The use according to claim 3, characterized in that: The segmented RNA virus is selected from at least one virus of the families Phenuiviridae, Nairoviridae and Arenaviridae under the order Bunyavirales; Preferably, the segmented RNA virus is selected from at least one virus of Severe fever with thrombocytopenia syndrome virus (SFTSV), Heartland virus (HRTV) and Guertu virus (GTV) under the family Leukoviridae; Preferably, the segmented RNA virus is selected from at least one virus selected from Songling virus (SGLV) and Crimean Congo hemorrhagic fever virus (CCHFV) under the Nairoviridae family; Preferably, the segmented RNA virus is selected from at least one virus of Lymphocytic Choriomeningitis Virus LCMV, Machupo virus (MACV) and Lassa virus under the Arenaviridae family; Preferably, the segmented RNA virus is selected from at least one virus of the genus Influenzavirus, genus Influenzavirus, genus Influenzavirus and genus Togotovirus under the family Orthomyxoviridae; Preferably, the non-segmented RNA virus is selected from the group consisting of hepatitis A virus and hepatitis C virus; Preferably, the DNA virus is selected from the group consisting of hepatitis B virus.

8. The use according to claim 1, characterized in that: The drug fights viruses by: (1) Inhibit 3-hydroxybutyrylation modification of STAT1 protein in the IFN-I signaling pathway; (2) enhance the interaction between STAT1 and IFNAR2 and promote STAT1 Y701 tyrosine phosphorylation; (3) Promote the activation of IFN-I signaling; (4) increase the expression level of interferon-stimulated genes (ISGs); (5) Inhibit viral activity; (6) inhibiting the levels of viral capsid protein, envelope protein, surface protein (SU), and transmembrane protein; Preferably, the interferon-stimulated gene is selected from Ifit1, Viperin and Isg15.

9. The use according to claim 1, characterized in that: The drug also includes a pharmaceutically acceptable carrier; Preferably, the drug is administered orally or by injection.

10. Use of hydroxycamptothecin or its stereoisomers, derivatives and pharmaceutically acceptable salts thereof in the preparation of drugs for preventing, improving or treating diseases related to viral infection, characterized in that: The viral infection-related disease is hepatitis B, liver cirrhosis or liver fibrosis.

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