PROTAC compound of targeted virus vRNP compound, preparation method and application

Abstract

The invention provides a PROTAC compound of a targeted virus vRNP compound, a preparation method and application. The compound comprises a conserved sequence which is specifically targeted and combined with a vRNA5'terminal untranslated region, a connector and a ligand which is responsible for recruiting a cell ubiquitin-proteasome system, the connection mode of the compound is as follows: a conserved sequence-linker-ligand responsible for recruiting a cell ubiquitin-proteasome system in specific targeted combination with a vRNA5'terminal untranslated region; wherein the virus is influenza A virus. According to the compound, by simultaneously degrading a plurality of core components of the influenza virus ribonucleoprotein complex, the limitation of a traditional single-target drug is broken through, and the drug resistance risk is remarkably reduced; a conserved sequence of an untranslated region at the 5'end of virus RNA is used as a target spot to design an oligonucleotide ligand, so that broad-spectrum coverage of different influenza subtypes is realized, and virus mutation and immune escape are effectively coped with.

Description

Technical Field

[0001] The present invention belongs to the field of biotechnology, and specifically relates to a PROTAC compound targeting a viral vRNP complex, a preparation method and an application thereof. Background Art

[0002] Influenza A virus (IAV) remains a persistent and formidable challenge to global public health due to its rapid mutation rate and ability to evade host immune responses. Structurally, IAV is characterized by an outer envelope laced with hemagglutinin (HA) and neuraminidase (NA) glycoproteins, a matrix protein layer (M1 and M2), and a core composed of eight viral ribonucleoprotein (vRNP) complexes. Each vRNP complex consists of a single-stranded viral RNA (vRNA) segment bound to a nucleoprotein (NP) and polymerase complex (PA, PB1, and PB2), which are essential for viral replication and transcription. Current pharmacological interventions against IAV, such as uminovir, oseltamivir, and amantadine, inhibit viral entry, progeny virus release, and uncoating by disrupting key viral proteins, including HA, NA, and M2. Inhibitors targeting vRNPs are also promising, primarily aiming to neutralize key components, including NP and polymerase subunits (PB1, PB2, and PA).

[0003] Protein degradation targeting chimeras (PROTACs) are becoming a transformative technology in the field of targeted protein degradation. PROTACs use a bifunctional design that combines specific proteins and E3 ubiquitin ligases to precisely eliminate unwanted proteins using the ubiquitin-proteasome system. Recent antiviral research has made significant progress in PROTACs, developing specific degraders for influenza A virus (IAV), hepatitis C virus (HCV), and SARS-CoV-2 proteins. Strategies that simultaneously target multiple viral components can reduce the risk of drug resistance and produce synergistic effects by disrupting replication at different stages, thereby improving efficacy. Therefore, PROTAC-mediated multi-target degradation provides a promising avenue for the development of potent and resistant antiviral therapies.

[0004] Therefore, the development of broad-spectrum, highly effective, and low-resistance anti-influenza drugs has become a key strategic requirement.

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

[0006] The first objective of the present invention is to provide a PROTAC compound that targets the viral vRNP complex. This compound utilizes sequences in the highly conserved 5' untranslated region of viral RNA to integrate an oligonucleotide targeting ligand with an E3 ligase recruitment element, precisely binding to and degrading vRNP components. This multi-target approach disrupts viral replication at multiple levels, establishes a high genetic barrier to drug resistance, and exhibits broad-spectrum activity against all lAV strains.

[0007] The second object of the present invention is to provide a method for preparing the above-mentioned PROTAC compound targeting the viral vRNP complex. The preparation method rapidly generates a stable 1,2,3-triazole structure through a highly selective cycloaddition between an azide group (-N3) and an alkyne group (-C≡C-), with very few by-products, high specificity and simplicity, high selectivity, good biocompatibility, mild reaction conditions, stable yield, and high connection stability.

[0008] A third object of the present invention is to provide the use of the PROTAC compound targeting the viral vRNP complex, which is used to prepare products for the targeted degradation of the vRNP complex; and to prepare anti-influenza virus drugs, especially drugs for the treatment of influenza A virus, providing a promising approach for related drug research and development.

[0009] In order to achieve the above-mentioned purpose of the present invention, the following technical solutions are adopted:

[0010] The present invention provides a PROTAC compound targeting the viral vRNP complex, which specifically targets and binds to the conserved sequence of the vRNA 5' terminal untranslated region, the linker, and the ligand responsible for recruiting the cellular ubiquitin-proteasome system;

[0011] The compound is linked in a manner that specifically targets and binds to a conserved sequence in the 5' terminal untranslated region of vRNA - a linker - a ligand responsible for recruiting the cellular ubiquitin-proteasome system;

[0012] Wherein, the virus is influenza A virus.

[0013] Preferably, as a further specific embodiment, the sequence of the conserved sequence that specifically targets and binds to the 5' terminal untranslated region of vRNA is: TCATCTTTGTTCC.

[0014] In the present invention, the nucleotide sequence can target the conserved sequence at the 5' end of vRNA and can specifically recognize the eight vRNPs of IAV, so that the prepared complex has a broad spectrum and can produce activity against different IAV strains, thereby forming a higher drug resistance gene barrier.

[0015] Preferably, as a further specific embodiment, the ligand responsible for recruiting the cellular ubiquitin-proteasome system is any one of a VHL ligand, a CRBN ligand, an IAP ligand, an MDM2 ligand or a DCAF series ligand;

[0016] Preferably, the ligand is any one of a VHL ligand or a CRBN ligand;

[0017] Preferably, the ligand is a VHL ligand;

[0018] Preferably, the VHL ligand is a (S,R,S)-AHPC ligand.

[0019] The ligand has strong degradation selectivity, reliability and good structural regulation.

[0020] Preferably, as a further specific embodiment, the general structural formula of the connector is

[0021]

[0022] Wherein, L' is any one of an alkyl chain, an aromatic ring chain, a triazole chain, a PEG series, or a flexible heterocyclic chain;

[0023] Preferably, L' is an alkyl chain or any one of the PEG series.

[0024] PEG1-PEG5 have stable degradation rates, taking into account both water solubility and spatial freedom; C5-C8 alkyl chains have stable degradation efficiency, improve cell membrane permeability, and are especially suitable for hydrophobic target proteins.

[0025] Preferably, as a further specific embodiment, the L' is any one of PEG1-PEG5;

[0026] Preferably, L' is any one of PEG1, PEG3 or PEG4;

[0027] Preferably, the L' is PEG3.

[0028] The length of the linker plays a key role in the efficacy of PROTAC. Both too long and too short PEG will affect the functional groups connected on both sides to varying degrees: when PEG is too short, the E3 ligase-recruiting groups may have less access to the complex, resulting in poor degradation of vRNPs proteins; and when PEG is too long, the excessively long chain may cause the molecular size to be too large, affecting cellular uptake or the stability of the ternary complex.

[0029] Preferably, as a further specific embodiment, the molecular formula of the PROTAC compound targeting viral vRNP is:

[0030]

[0031] or,

[0032]

[0033] or,

[0034] Any of the following;

[0035] Preferably, the molecular formula is

[0036]

[0037] The present invention also provides an anti-influenza virus drug comprising the aforementioned PROTAC compound and a pharmaceutically acceptable carrier or excipient.

[0038] The present invention also provides a method for preparing the PROTAC compound targeting viral vRNP, comprising the following steps:

[0039] The synthesized DBCO-modified oligonucleotide fragment was dissolved in ddH2O, enabling it to specifically target and bind to the conserved 5' untranslated region of vRNA, to obtain solution a;

[0040] The ligand L'-azide compound that recruits the cellular ubiquitin-proteasome system is dissolved in dimethyl sulfoxide to obtain solution b;

[0041] The solution a and the solution b are mixed and stirred for more than 12 hours to obtain;

[0042] Wherein, L' is any one of an alkyl chain, an aromatic ring chain, a triazole chain, a PEG series, or a flexible heterocyclic chain;

[0043] Preferably, L' is an alkyl chain or any one of the PEG series;

[0044] Preferably, L' is any one of PEG1-PEG5;

[0045] Preferably, L' is any one of PEG1, PEG3 or PEG4;

[0046] Preferably, the L' is PEG3.

[0047] Utilizing SPAAC (strain-triggered copper-free click reaction), a highly selective cycloaddition between an azide group (–N3) and an alkyne group (–C≡C–) is used to rapidly generate a stable 1,2,3-triazole structure with minimal by-products, high specificity, and simplicity. The approach also exhibits high selectivity, good biocompatibility, mild reaction conditions, stable yields, and high connection stability.

[0048] The present invention also provides the use of the above-mentioned PROTAC compound in preparing a product for targeted degradation of the vRNP complex.

[0049] The present invention also provides the use of the above-mentioned PROTAC compound in the preparation of anti-influenza virus drugs;

[0050] Preferably, the anti-influenza virus is influenza A virus.

[0051] Compared with the prior art, the present invention has the following beneficial effects:

[0052] (1) Adopting a multi-target degradation strategy: by simultaneously degrading multiple core components (NP, PB1, PB2, PA) of the influenza virus ribonucleoprotein (vRNP) complex, the limitations of traditional single-target drugs are broken and the risk of drug resistance is significantly reduced; using the conserved sequence of the 5'-terminal untranslated region of the viral RNA as a target, oligonucleotide ligands are designed to achieve broad coverage of different influenza subtypes and effectively respond to viral mutations and immune escape.

[0053] (2) By systematically adjusting the linker length and combining the strain-promoted azide-alkyne cycloaddition (SPAAC) reaction, PROTAC molecules are efficiently constructed and their stability and ternary complex formation efficiency are optimized; for the first time, PROTAC technology is combined with oligonucleotide targeting, providing a new paradigm for the development of multi-target degradation therapies against other RNA viruses. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Figure 1 :Gel electrophoresis images of PROTAC1, PROTAC2 and PROTAC3;

[0055] Figure 2 :Western Blot analysis confirmed that the three PROTAC compounds successfully degraded vRNP protein;

[0056] Figure 3 : Comparison of the degradation effects of three PROTAC compounds;

[0057] Figure 4 : Western blot analysis after IAV treatment with PBS, VHLL, or TRL;

[0058] Figure 5 : Representative immunofluorescence images and quantitative analysis of MDCK cells after treatment with PBS, VHLL, TRL, and PROTAC2 for 24 hours;

[0059] Figure 6 : Measure NP mRNA levels in IAV-infected cells at different time points and evaluate the antiviral efficacy of PROTAC2 and ribavirin;

[0060] Figure 7 : Measure NP mRNA levels in IAV infection culture supernatants at different time points to evaluate the antiviral efficacy of PROTAC2 and ribavirin;

[0061] Figure 8 : Recovery of cell viability 48 hours after virus infection;

[0062] Figure 9 : Evaluate the antiviral effects of PROTAC2 and ribavirin at different stages of viral infection;

[0063] Figure 10 :Western blotting validates the efficacy of PROTAC2 against multiple IAV strains;

[0064] Figure 11 : relative mRNA expression level of IL-1β gene;

[0065] Figure 12 : Relative mRNA expression level of TNF-α gene. DETAILED DESCRIPTION

[0066] The technical scheme of the present invention will be clearly and completely described below in conjunction with specific embodiments, but it will be understood by those skilled in the art that the following described embodiments are part of embodiments of the present invention, rather than all embodiments, and are only used to illustrate the present invention, and should not be considered as limiting the scope of the present invention. Based on the embodiments in the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative work premise belong to the scope of protection of the present invention. Those who do not specify specific conditions in the embodiments are carried out according to normal conditions or the conditions recommended by the manufacturer. Those whose reagents or instruments are not specified by the manufacturer are conventional products that can be purchased commercially.

[0067] Example 1: Preparation of PROTACs capable of simultaneously degrading multiple IAV proteins in a vRNPs complex. Preparation method of PROTAC1: (S,R,S)-AHPC-PEG1-azide (Sigma Aldrich), CAS number: 2101200-09-1, was dissolved in dimethyl sulfoxide to prepare solution A with a concentration of 100 μM.

[0068] An oligonucleotide sequence (TRL) with a base sequence of TCATCTTTGTTCC was selected, and the dibenzocyclooctyne (DBCO)-labeled TRL was dissolved in ddH2O to obtain a modified chain [the modified chain was commissioned to be synthesized by Sangon Biotech (Shanghai) Co., Ltd.], and the modified chain was prepared into a solution B with a concentration of 100 μM. Subsequently, the two were mixed in an equimolar ratio at room temperature and mechanically stirred for 16 hours to allow the azide group and the DBCO group to complete a cycloaddition reaction through copper-free click chemistry to obtain PROTAC1.

[0069] The reaction equation is:

[0070]

[0071] The resulting molecular formula of PROTAC1 is:

[0072]

[0073] Preparation method of PROTAC2: (S,R,S)-AHPC-PEG3-azide (Sigma Aldrich), CAS number: 1797406-80-4, was dissolved in dimethyl sulfoxide to prepare solution A with a concentration of 100 μM.

[0074] An oligonucleotide sequence (TRL) with a base sequence of TCATCTTTGTTCC was selected, and the dibenzocyclooctyne (DBCO)-labeled TRL was dissolved in ddH2O to obtain a modified chain [the modified chain was commissioned to be synthesized by Sangon Biotech (Shanghai) Co., Ltd.], and the modified chain was prepared into a solution B with a concentration of 100 μM. Subsequently, the two were mixed in an equimolar ratio at room temperature and mechanically stirred for 16 hours to allow the azide group and the DBCO group to complete a cycloaddition reaction through copper-free click chemistry, PROTAC2.

[0075] The reaction equation is:

[0076]

[0077] The resulting molecular formula of PROTAC2 is:

[0078]

[0079] Preparation method of PROTAC3: (S,R,S)-AHPC-PEG4-Azide (TargetMol), CAS number: 1797406-81-5, was dissolved in dimethyl sulfoxide to prepare solution A with a concentration of 100 μM.

[0080] An oligonucleotide sequence (TRL) with a base sequence of TCATCTTTGTTCC was selected, and the dibenzocyclooctyne (DBCO)-labeled TRL was dissolved in ddH2O to obtain a modified chain [the modified chain was commissioned to be synthesized by Sangon Biotech (Shanghai) Co., Ltd.], and the modified chain was prepared into a solution B with a concentration of 100 μM. Subsequently, the two were mixed in an equimolar ratio at room temperature and mechanically stirred for 16 hours to allow the azide group and the DBCO group to complete a cycloaddition reaction through copper-free click chemistry to obtain PROTAC3.

[0081] The reaction equation is:

[0082]

[0083] The resulting molecular formula of PROTAC3 is:

[0084]

[0085] The three PROTAC compounds prepared were subjected to gel electrophoresis, and the electrophoresis results were as follows Figure 1 As shown in the figure, the mobility of the molecule changed significantly before and after coupling the target sequence with the VHL ligand, proving that the three PROTAC compounds were successfully synthesized.

[0086] Example 2: Verification that three PROTAC compounds can simultaneously degrade multiple viral proteins by utilizing the interaction between the vRNP complex and VHL

[0087] Three different PROTAC compounds were transfected one hour after infection, and viral proteins were analyzed 24 hours later. The experimental results are as follows Figure 2 As shown, Figure 2 It shows that all three PROTAC compounds successfully degraded PB2, PB1, PA and NP proteins, and at the same time, it can be shown that the degradation efficiency of the three PROTAC compounds is different. Figure 2 Combine Figure 3 It can be seen that among all four viral proteins, PROTAC2 compound has the strongest degradation effect.

[0088] PROTAC2 was subsequently subjected to cytotoxicity experiments. The results showed that PROTAC2 did not affect cell viability within the concentration range of 0-50 μM, demonstrating that PROTAC2 has good biocompatibility and can be used for further functional studies. Therefore, PROTAC2 was selected as the optimal degrader in subsequent experiments.

[0089] Example 3: Verification of the mechanism of PROTAC2 degradation of vRNPs complex (PB2, PB1, PA, NP)

[0090] The results of the experiments were as follows: PBS alone, a ligand responsible for recruiting the cellular ubiquitin-proteasome system (hereinafter referred to as VHLL), or an oligonucleotide fragment specifically targeting the conserved 5' untranslated region of vRNA (hereinafter referred to as TRL) were used to treat IAV proteins. Figure 4 As shown in the figure, it can be seen that treatment with PBS, VHLL or TRL alone has no significant effect on the level of IAV protein and cannot degrade IAV protein.

[0091] Representative immunofluorescence images and quantitative analysis of MDCK cells were then treated with PBS, VHLL, TRL, and PROTAC2 for 24 hours. Figure 5 As shown, Figure 5 The blue signal represents the cell nucleus, and the green signal represents the viral protein PB2, PB1, PA or NP, respectively. From the experimental results, it can be seen that the fluorescence of cells treated with PROTAC2 is significantly reduced, indicating the degradation of viral proteins; while PBS, VHLL or TRL alone cannot reduce viral proteins.

[0092] This part of the experiment confirmed that the coupling of TRL and VHLL components in the PROTAC compound is essential for the degradation of multiple IAV proteins in infected cells, that is, the antiviral activity requires the coordinated action of all PROTAC components.

[0093] Example 4: In vitro evaluation of the antiviral ability of PROTAC2 to degrade the vRNP complex (PB2, PB1, PA, NP)

[0094] The antiviral efficacy and duration of PROTAC2 were compared with those of ribavirin, a drug that inhibits IAV RNA polymerase.

[0095] Cells infected with IAV at different time points were treated with PROTAC2 and ribavirin, and the viral load in MDCK cells was analyzed by real-time quantitative PCR (RT-qPCR) 8 hours after treatment. The experimental results are shown in Figure 2. Figure 6 As shown in the figure, the results showed that PROTAC2 can effectively reduce viral mRNA levels within 4 hours, and this effect can last for at least 48 hours. In contrast, although ribavirin can also reduce viral mRNA levels within 4 hours, its efficacy quickly weakened after 8 hours.

[0096] The viral mRNA in the supernatant was further detected, and the experimental results were as follows Figure 7 As shown, the experimental results show that the antiviral effect of PROTAC2 is more lasting and more obvious, thus proving the powerful antiviral effect of PROTAC2 by completely degrading viral components.

[0097] Subsequently, the antiviral effects of PROTAC2 and ribavirin at different stages of viral infection were evaluated. Traditional anti-influenza drugs such as ribavirin usually face a major challenge: the time window for effective treatment is relatively narrow, especially in the late infection, and its antiviral effect is often significantly weakened. Ribavirin can effectively inhibit the expression of viral mRNA in the early stages of infection (within 6 hours after infection). However, as the infection time prolongs, the inhibitory effect of ribavirin gradually weakens. In contrast, PROTAC2 can effectively inhibit viral replication even in cells where the infection lasts for 10 hours, and its effective treatment window is almost twice that of ribavirin. In addition, after 24 hours of treatment with the two drugs in the infected cell model, RT-qPCR results showed that ribavirin lost its therapeutic effect in almost all infection models, while PROTAC2 can still effectively inhibit viral replication in cells infected for 10 hours. The experimental results are as follows Figure 9 shown.

[0098] At the same time, CCK-8 cell viability assay was performed to evaluate the effect of PROTAC2 on the recovery of cell function after infection. The experimental results are as follows Figure 8 As shown, after 48 hours of PROTAC2 treatment, the cell viability was significantly increased to 93%, which was significantly higher than that of the ribavirin-treated group and the virus-infected control group. This proves that PROTAC2 can provide long-lasting and effective antiviral protection, effectively disrupting the viral life cycle and alleviating virus-induced cell damage.

[0099] The above research results show that PROTAC2 has a longer-lasting antiviral effect than traditional antiviral drugs in treating influenza virus infection, suggesting that it has the potential to become a more effective treatment option.

[0100] Example 5: Verification of PROTAC2's broad-spectrum anti-IAV activity in vitro and its potential to alleviate the inflammatory response induced by IAV infection

[0101] PROTAC2 was evaluated for efficacy against multiple IAV strains, including H1N1, H9N2, and H3N2, which are representative models of influenza infection. Western blot analysis of enriched NPs showed that after PROTAC2 treatment, the experimental results were as follows: Figure 10 As shown, it can be seen that the NP levels of all tested IAV subtypes were significantly reduced, demonstrating the broad-spectrum antiviral activity of PROTAC2.

[0102] The relative mRNA expression levels of IL-1β and TNF-α genes in the PROTAC2 and PBS-treated control groups were determined, and the experimental results were as follows: Figure 11 and Figure 12As shown in the experimental results, PROTAC2 can effectively degrade vRNP protein, inhibit viral RNA synthesis, reduce the production of proinflammatory cytokines, and inhibit the production of progeny viruses, which highlights its potential as a candidate drug for the treatment of influenza infection. Therefore, designing PRTAC2 molecules by targeting the conserved 5'UTR of IAV RNA can produce potent and broad-spectrum antiviral activity against multiple IAV subtypes.

[0103] As can be seen from Examples 1 to 5, the novel PROTAC molecules designed in the present invention integrate heterotropically targeted binding to conserved sequences in the untranslated region of the 5' terminal of vRNA, ligands responsible for recruiting the cellular ubiquitin-proteasome system, and linkers. This multi-target strategy can simultaneously degrade the vRNP complex (PB2, PB1, PA, NP), disrupt viral replication, and establish a high-resistance genetic barrier, with strong antiviral ability; in addition, the selection of nucleotide fragments gives the PROTAC molecule a strong broad-spectrum activity, which can effectively respond to viral mutations and immune escape, and more effectively target viral resistance, providing a promising approach for the development of potent drug-resistant antiviral therapies.

[0104] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the above embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A PROTAC compound targeting a viral vRNP complex, characterized in that The compound includes: a conserved sequence that specifically targets and binds to the 5' terminal untranslated region of vRNA, a linker, and a ligand responsible for recruiting the cellular ubiquitin-proteasome system; The compound is linked in a manner that specifically targets and binds to a conserved sequence in the 5' terminal untranslated region of vRNA - a linker - a ligand responsible for recruiting the cellular ubiquitin-proteasome system; Wherein, the virus is influenza A virus.

2. The PROTAC compound targeting the viral vRNP complex according to claim 1, characterized in that The sequence of the conserved sequence that specifically targets and binds to the 5' terminal untranslated region of vRNA is: TCATCTTTGTTCC.

3. The PROTAC compound targeting the viral vRNP complex according to claim 1, characterized in that The ligand responsible for recruiting the cellular ubiquitin-proteasome system is any one of a VHL ligand, a CRBN ligand, an IAP ligand, an MDM2 ligand or a DCAF series ligand; Preferably, the ligand is any one of a VHL ligand or a CRBN ligand; Preferably, the ligand is a VHL ligand; Preferably, the VHL ligand is a (S,R,S)-AHPC ligand.

4. The PROTAC compound targeting the viral vRNP complex according to claim 1, characterized in that The general structural formula of the linker is Wherein, L' is any one of an alkyl chain, an aromatic ring chain, a triazole chain, a PEG series, or a flexible heterocyclic chain; Preferably, L' is an alkyl chain or any one of the PEG series.

5. The PROTAC compound targeting the viral vRNP complex according to claim 4, characterized in that The L' is any one of PEG1-PEG5; Preferably, L' is any one of PEG1, PEG3 or PEG4; Preferably, the L' is PEG3.

6. The PROTAC compound targeting the viral vRNP complex according to claim 5, characterized in that The molecular formula of the PROTAC compound is: or, or, Any of the following; Preferably, the molecular formula is 7. An anti-influenza virus drug, characterized in that: Also included is a PROTAC compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier or excipient.

8. A method for preparing a PROTAC compound according to any one of claims 1 to 6, characterized in that: The steps include: The synthesized DBCO-modified oligonucleotide fragment was dissolved in ddH2O, enabling it to specifically target and bind to the conserved 5' untranslated region of vRNA, to obtain solution a; The ligand L'-azide compound that recruits the cellular ubiquitin-proteasome system is dissolved in dimethyl sulfoxide to obtain solution b; The solution a and the solution b are mixed and stirred for more than 12 hours to obtain; Wherein, L' is any one of an alkyl chain, an aromatic ring chain, a triazole chain, a PEG series, or a flexible heterocyclic chain; Preferably, L' is an alkyl chain or any one of the PEG series; Preferably, L' is any one of PEG1-PEG5; Preferably, L' is any one of PEG1, PEG3 or PEG4; Preferably, the L' is PEG3.

9. Use of the PROTAC compound according to any one of claims 1 to 6 in the preparation of a product for targeted degradation of a vRNP complex.

10. Use of the PROTAC compound according to claim 9 in the preparation of an anti-influenza virus drug; Preferably, the anti-influenza virus is influenza A virus.

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