CN115920006B - Application of ABCF1 or agonist thereof in preparation of anti-DNA virus preparation - Google Patents
Application of ABCF1 or agonist thereof in preparation of anti-DNA virus preparation Download PDFInfo
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- CN115920006B CN115920006B CN202211136878.9A CN202211136878A CN115920006B CN 115920006 B CN115920006 B CN 115920006B CN 202211136878 A CN202211136878 A CN 202211136878A CN 115920006 B CN115920006 B CN 115920006B
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention relates to application of ABCF1 or an agonist thereof in preparation of an anti-DNA virus preparation. The research of the invention verifies that the novel cccDNA interaction protein ABCF1 (ATP-binding cassette sub-family Fpmber 1) can bind cccDNA, and inhibits the cccDNA transcription through phase separation, thereby inhibiting the HBV replication, further defining that the combination of the N-terminal domain of ABCF1 and cccDNA has a key effect, and providing the application of ABCF1 or an agonist thereof in the research and development of anti-HBV infection related medicaments, and having important medical development prospect.
Description
Technical Field
The invention belongs to the technical field of HBV virus inhibition active ingredients, and particularly relates to application of ABCF1 or an agonist thereof in preparation of an anti-DNA virus preparation.
Background
The disclosure of this background section is only intended to increase the understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art already known to those of ordinary skill in the art.
Hepatitis B virus (Hepatitis B virus, HBV) is a hepadnavirus, chronic infection of which is closely related to liver cirrhosis and liver cancer, is an important causative factor for liver cancer occurrence, and seriously threatens human health. The HBV replication process is complex, the viral particles bind to the NTCP receptor on the surface of the hepatocyte and enter the hepatocyte, their genomic DNA (RC-DNA) enters the nucleus, and covalent closed circular DNA (covalently closed circular DNA, cccDNA) is formed through a series of repair mechanisms. cccDNA serves as the only template for viral transcription, and forms a minute chromosome in combination with host cell histones, viral core proteins, etc. to mediate long-lasting presence of viruses, and interactions between host proteins and cccDNA are critical for their formation, stability and transcriptional activity. cccDNA has stable structure and long half-life, is not easy to degrade, is a reservoir of in vivo viruses, and is also an important reason for the persistence and difficulty in clearing after HBV chronic infection. However, it is not clear how host proteins recognize cccDNA and regulate HBV replication. Therefore, the in-depth research of the interaction protein of HBV cccDNA and the molecular mechanism of the HBV cccDNA for regulating and controlling the activity of the cccDNA has important significance for discovering new HBV replication intervention targets and strategies.
Innate immune cells and hepatocytes recognize HBV through Pattern Recognition Receptors (PRRs), induce interferon production, and are important preconditions for the body to stimulate effective immune responses and clear HBV. Therefore, determining the regulatory factor of the inherent immune response of the targeted HBV is very important for HBV prevention and treatment, and is a hot spot and a difficult problem in the current field of HBV research. Based on the cccDNA-hepatocyte nuclear protein interaction screening model established earlier, this study identified an important innate immune regulator, ABCF1.ABCF1 was first discovered in 1998 as a tnfα -stimulatory gene and belongs to a member of the ABCF subfamily of ATP-binding cassette (ABC) transporter superfamily. Unlike other subfamily members, ABCF1 lacks a transmembrane domain and is expressed in the nuclear cytoplasm. ABCF1 consists of 804 amino acids and comprises an N-terminal domain (ND) and 2 nucleic acid binding domains (NBD). Studies have shown that ABCF1 can interact with ISD to regulate the interferon signaling pathway, playing an important role in recognizing the natural immune response of DNA. In addition, studies have shown that ABCF1 is identified as a co-activator of OCT4 and SOX2, activating the pluripotency gene by phase separation occurs, which is important for self-renewal of stem cells. However, whether ABCF1 recognizes cccDNA and regulates HBV replication has not been reported so far.
Disclosure of Invention
Against the background of the research, the invention confirms that ABCF1 as the interactive protein of cccDNA can participate in regulating and controlling the interferon response, and inhibits cccDNA transcription and virus replication through phase separation, thereby having very positive significance on the theoretical research and clinical treatment of HBV infection regulation and pathogenesis.
Based on the research results, the invention provides the following technical scheme:
in a first aspect of the invention there is provided the use of ABCF1 or an agonist thereof for the preparation of an anti-DNA virus formulation.
Preferably, the ABCF1 can be a commercially available recombinant ABCF1 protein preparation, and the source of the recombinant ABCF1 protein preparation is not limited to engineering bacteria expression or liquid phase synthesis, solid phase synthesis, and the like.
Further, the ABCF1 also broadly includes derived polypeptides formed by chemical or genetic modification of the above polypeptides; the modifier comprises, but is not limited to, streptavidin, biotin, a radioisotope, a fluorescent agent, an enzyme, a cytotoxic substance, an antitumor agent and the like, and also comprises a product obtained by immobilizing the protein by physical adsorption, a carrier, a resin crosslinking material and the like.
Further, the ABCF1 also includes fusion polypeptides of the ABCF1 protein and effector fragments including transmembrane peptides or fragments for extending the in vivo half-life of ABCF1, such as serum albumin or fragments thereof, polyethylene glycol, domains that bind serum albumin, and the like.
Further, the ABCF1 also includes truncations of ABCF1 that retain a portion of the sequence in ABCF1 and have substantially similar physiological activities as ABCF1.
Preferably, the agonist of ABCF1 is a compound entity, polymer, polypeptide or nucleic acid substance that includes, but is not limited to, a compound entity, polymer, polypeptide or nucleic acid substance that is capable of stimulating an increased level of ABCF1 expression in a subject's body, and also includes agents that are related to the over-expression of ABCF1 in a subject's body based on genetic engineering means, such as plasmids, lentiviruses, and the like.
The research on the mechanism of inhibiting virus replication by using ABCF1 shows that the ABCF1 can promote the expression of interferon in organisms, is expected to realize broad-spectrum antiviral effect, and the anti-DNA virus preparation is preferably used for preventing, improving or treating drugs, model drugs, detection reagents and the like of DNA virus infection related diseases; further, specific examples of the DNA virus are Hepatitis B Virus (HBV), smallpox virus, herpes virus, cytomegalovirus, EB virus, varicella-zoster virus.
In one embodiment of the present invention, the DNA virus is HBV virus, and ABCF1 or an agonist thereof as described above is used for preparing an anti-HBV viral formulation.
In the above embodiment, the ABCF1 is a truncated form of ABCF1, the truncated form comprises an N-terminal domain of ABCF1, the amino acid sequence of the truncated form is shown as SEQ ID NO. 1, and the nucleotide sequence of the truncated form is shown as SEQ ID NO. 2.
The invention verifies that the N-terminal domain of ABCF1 has good binding property with cccDNA generated in the HBV virus replication process, and can effectively reduce the replication of HBV virus in the organism through the binding effect, thereby inhibiting relevant diseases caused by HBV infection, such as hepatitis B, liver cirrhosis, liver fibrosis, liver cancer, upper gastrointestinal hemorrhage, acute renal insufficiency and the like.
In a second aspect of the invention, there is provided a pharmaceutical composition comprising an active amount of ABCF1 or an agonist thereof.
Preferably, the pharmaceutical composition further comprises a pharmaceutically necessary carrier.
Preferably, the dosage form of the pharmaceutical composition is not particularly limited, and a solid preparation or a liquid preparation is preferable; in the case of solid formulations, the carriers include, but are not limited to, excipients, lubricants, binders, disintegrants, and the like; in the case of liquid formulations, the carrier includes solvents, solubilizers, suspending agents, isotonic agents, buffers, soothing agents and the like, and preservatives, antioxidants, colorants, sweeteners and other formulation additives may be appropriately added as desired.
As preferable examples of the excipient, for example, lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid, and the like can be used.
As preferable examples of the lubricant, for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like can be used.
As preferable examples of the binder, for example, crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, and the like can be used.
As preferable examples of the disintegrant, for example, starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, and the like can be used.
As preferable examples of the solvent, water for injection, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil and the like can be used.
As preferable examples of the solubilizing agent, for example, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, triaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like are used.
Suitable examples of suspending agents include, for example, surfactants (stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerol monostearate, etc.), hydrophilic polymers (polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, etc.) may be used.
As suitable examples of the tonicity agent, for example, sodium chloride, glycerin, D-mannitol and the like can be used.
As preferable examples of the buffer, for example, buffer solutions of phosphate, acetate, carbonate, citrate, and the like can be used.
As a preferable example of the soothing agent, for example, benzyl alcohol or the like can be used.
As preferable examples of the preservative, for example, paraoxybenzoate, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and the like can be used.
As preferable examples of the antioxidant, for example, sulfite, ascorbic acid, and the like can be used.
Preferably, the pharmaceutical composition further comprises other antiviral active ingredients or auxiliary antiviral ingredients, wherein the antiviral active ingredients are preferably anti-DNA virus drugs, such as acyclovir; the auxiliary antiviral components include, but are not limited to, immunomodulating drugs, antibiotics, antipyretics, and drugs for relieving respiratory distress, and specific examples include compound aminopyrine, antalgic, penicillin, streptomycin, nikomi, aminophylline, and the like.
In a third aspect, the present invention provides a therapeutic agent for a disease associated with HBV viral infection, comprising an active amount of ABCF1, a truncate of ABCF1, or an agonist of ABCF1.
In the above third aspect, the HBV viral infection-related disease is preferably hepatitis b or liver cancer (HCC).
In addition, the dosage of the above-mentioned ABCF1, ABCF1 truncations or agonists of ABCF1 belongs to a technical means that can be routinely confirmed depending on the purpose of administration of the therapeutic agent, the subject and the mode of administration, etc.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention.
FIG. 1 is an ND domain of ABCF1, which is the key domain for binding cccDNA;
a: the ability of ABCF1 to bind cccDNA in different models;
b: comparison of binding ability of different truncations of ABCF1 to cccDNA;
c: GST-Pull down experiment to analyze the binding level of ABCF1-ND protein and cccDNA;
d: in vitro Biotin-pull Down demonstrated the binding of the ABCF1-ND protein to cccDNA
FIG. 2 shows that ABCF1 inhibits HBV replication primarily in dependence on its ND domain;
a: ABCF1 inhibits HBV replication in the transfection model;
b: ABCF1 inhibits HBV replication in the virus infection model;
c: influence of different truncations of ABCF1 on HBV replication;
FIG. 3 is an IFN response of ABCF1 to promote HBV infection;
a: ABCF1 promotes IFN- β, IFN- λ, CXCL10 levels of HBV infection in the transfection model;
b: antiviral effects of ABCF1 in IFNAR-KO cell lines;
FIG. 4 shows that the lysine (K) repeat domain and glutamine (Q) repeat domain of ABCF1-ND are key regions for ABCF1 to phase separate and inhibit HBV replication;
a: in vitro analysis of the phase separation ability of GFP-ABCF1, GFP-ABCF1-ND and GFP-ABCF 1-DeltaND and the fusion ability with Cy 5-MC-HBV;
b and C: comparison of antiviral Capacity of ABCF1-ND repeat prediction (B) and ND deletion mutant (C);
d: phase separation capability level comparisons for ND, ND- Δ1KK, ND- ΔQ and ND- Δ1K/Q;
FIG. 5 shows that ABCF1 inhibits host RNA polymerase II binding to cccDNA by phase separation;
a: effects of ABCF1 on binding RNA polymerase II to cccDNA in different models;
b: the effect of ND, ND- Δ1KK, ND- ΔQ and ND- Δ1K/Q on binding of RNA polymerase II to cccDNA in different models;
FIG. 6 shows that ABCF1, an interacting protein of cccDNA, can be involved in the mechanism of regulation of interferon response.
Detailed Description
It should be noted that the following detailed description is illustrative and is intended to provide further explanation of the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the present invention. As used herein, the singular is also intended to include the plural unless the context clearly indicates otherwise, and furthermore, it is to be understood that the terms "comprises" and/or "comprising" when used in this specification are taken to specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof.
In order to enable those skilled in the art to more clearly understand the technical scheme of the present invention, the technical scheme of the present invention will be described in detail with reference to specific embodiments.
Example 1
1) ND domain of ABCF1 is the key domain for binding cccDNA
ABCF1 was found to bind cccDNA using Huh7/MC-HBV transfection model, HLCZ01/HBV viral infection model and Biotin-pull down experimental technique (A). In the Huh7/MC-HBV transfection model, by interaction of ABCF1 truncations with cccDNA, ND domain of ABCF1 was found to be the key domain for binding to cccDNA (B). In vitro prokaryotic expression and purification of ABCF1-ND protein, GST-pull down experiment proves that ABCF1-ND can be directly combined with cccDNA (C), and in vitro Biotin-pull down experiment further proves that ABCF1-ND can be combined with cccDNA (D), which indicates that ND domain is a key domain of ABCF1 combined with cccDNA.
2) Inhibition of HBV replication by ABCF1 is primarily dependent on its ND domain
By using a HepG2/MC-HBV transfection model and a HepaRG/HBV virus infection model, the over-expression of ABCF1 is found to remarkably inhibit the levels of HBsAg, HBeAg, pgRNA, HBV DNA and HBc of HBV, and the interference of the ABCF1 can remarkably promote the replication level (A, B) of HBV. Through antiviral experiments on HBV with ABCF1 truncations, it was found that ND domain of ABCF1 is a key domain (C) that inhibits HBV replication.
3) ABCF1 promotes HBV infection mediated IFN response
In the HepG2/MC-HBV transfection model, ABCF1 was found to significantly promote IFN- β, IFN- λ, CXCL10 levels when HBV was present (a). Using the IFNAR-KO cell line, it was found that the inhibitory effect of ABCF1 on HBV was still present when IFN receptor was knocked out (B), indicating that ABCF1 was able to promote IFN response to HBV infection, but its antiviral effect might not be entirely dependent on IFN.
4) The lysine (K) repeat domain and glutamine (Q) repeat domain of ABCF1-ND are critical regions for ABCF1 to phase separate and inhibit HBV replication
In vitro prokaryotic expression purified GFP-ABCF1-FL, GFP-ABCF1-ND, GFP-ABCF1- ΔND proteins, it was found that GFP-ABCF1 protein could be fused to Cy 5-labeled MC-HBV, phase separated, and ND formed phase separation more than ABCF1 (A). And (3) constructing ND deletion mutants by using repeated sequences in the ND fragment predicted by the website, and finding that the antiviral effects of ND-delta 1KK and ND-delta Q are obviously weakened (B). In vitro prokaryotic expression purified GFP-ND, GFP-ND- Δ1KK, GFP-ND- ΔQ and GFP-ND- Δ1K/Q proteins, the phase separation levels and antiviral effects of ND- Δ1KK, ND- ΔQ and ND- Δ1K/Q were found to be significantly reduced compared to ND (C, D), indicating that the lysine (K) and glutamine (Q) repeat domains of ABCF1-ND are critical regions for phase separation and inhibition of HBV replication of ABCF1.
5) ABCF1 inhibits host RNA polymerase II binding to cccDNA by phase separation
Using Huh7/MC-HBV transfection model and HLCZ01/HBV viral infection model, ABCF1 was found to inhibit host RNA polymerase II binding to cccDNA and was dependent on ND (a). Using the above model, it was found that when the lysine (K) repeat domain and glutamine (Q) repeat domain of ND are deleted, namely ND- Δ1KK, ND- ΔQ and ND- Δ1K/Q inhibit RNA pol II binding to cccDNA is reduced (B), it was demonstrated that ABCF1 inhibits host RNA polymerase II binding to cccDNA by phase separation.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (5)
- Use of the atp-binding cassette transporter ABCF1 for the preparation of an anti-DNA virus formulation, said virus being HBV virus.
- 2. The use of ABCF1 as claimed in claim 1 for the preparation of an anti-DNA virus preparation, wherein said ABCF1 is a commercially available recombinant ABCF1 protein preparation derived from engineering bacteria expression or liquid phase synthesis, solid phase synthesis.
- 3. The use of ABCF1 for the preparation of an anti-DNA virus preparation according to claim 1, wherein said ABCF1 further comprises a polypeptide formed by chemical or genetic modification of ABCF 1; the modifier is selected from streptavidin, biotin, a radioisotope or a fluorescent agent.
- 4. Use of ABCF1 according to claim 3 for the preparation of an anti-DNA virus preparation, wherein said use is of a truncate of ABCF1 having the amino acid sequence shown in SEQ ID No. 1.
- 5. The use of ABCF1 as claimed in claim 4 for the manufacture of an anti-DNA virus preparation, wherein said DNA virus infection-associated disorder is hepatitis b, cirrhosis, liver fibrosis or liver cancer.
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