阅读说明：本技术 噻唑类化合物用于抗鱼类病毒的新用途 (New application of thiazole compound in resisting fish virus ) 是由 贾坤同 易梅生 陈明懿 于 2019-09-19 设计创作，主要内容包括：本发明公开了噻唑类化合物用于抗鱼类病毒的新用途,所述噻唑类化合物为硝唑尼特,其结构式如式1所示：<Image he="490" wi="700" file="DDA0002206770510000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses a new application of a thiazole compound in fish virus resistance, wherein the thiazole compound is nitazoxanide, and the structural formula of the compound is shown as a formula 1:)

1. The novel application of the thiazole compound in resisting fish viruses is characterized in that the thiazole compound is nitazoxanide, and the structural formula of the compound is shown as formula 1:

2. the novel use of thiazole compounds in fish virus resistance according to claim 1, wherein said thiazole compound is tizoxanide, the structural formula of which is shown in formula 2:

3. the novel use of thiazole compounds according to any one of claims 1 to 2 against fish viruses, wherein said thiazole compounds comprise geometrical isomers of nitazoxanide/tizoxanide, and pharmaceutically acceptable salts thereof and solvates thereof or hydrates thereof.

4. The novel use of thiazole compounds for combating fish viruses as claimed in claim 3, wherein said pharmaceutically acceptable salts thereof include inorganic or organic acid salts and inorganic or organic base salts thereof.

5. The novel use of thiazole compounds as claimed in claim 4 for combating fish viruses, wherein said pharmaceutically acceptable salts thereof include sodium, potassium, calcium, lithium, meglumine, hydrochloride, hydrabamate, rosate, nitrate, sulfate, bisulfate, phosphate, biphosphate, acetate, propionate, butyrate, oxalate, pivalate, adipate, alginate, lactate, citrate, tartrate, succinate, maleate, fumarate, picrate, aspartate, gluconate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and/or pamoate.

6. The novel use of thiazole compounds according to any one of claims 1 to 5 for combating fish viruses, wherein said thiazole compounds are useful for inhibiting the proliferation of viral hemorrhagic septicemia virus in the epithelial cells of phoxinus lagowskii, eliminating cytopathic effects.

7. The novel use of thiazole compounds according to any one of claims 1 to 5 against fish virus, wherein said thiazole compounds significantly reduce CPE in cells caused by virus infection, inhibit virus proliferation on FHM cells and reduce the copy number of viral genes in cells.

8. Use of thiazole compounds according to claims 1 to 5 for combating fish viruses, characterized in that said thiazole compounds reduce the CPE level of VHSV infected cells in an in vitro antiviral assay at micromolar concentrations.

9. Novel use of thiazole compounds according to claims 1 to 5 for combating fish viruses, characterized in that said thiazole compounds reduce the viral gene copy number in VHSV infected cells at micromolar concentrations.

10. Novel use of thiazole compounds according to claims 1 to 5 for combating fish viruses, wherein said thiazole compounds are used for preventing the invasion of VHSV into FHM cells.

Technical Field

The invention relates to a novel application of thiazole compounds, in particular to a novel application of thiazole compounds in resisting fish viruses.

Background

Nitazoxanide is a thiazolidine compound, and is firstly synthesized on the frame of an antiparasitic compound niclosamide in the seventies of the twentieth century (Rosssignol 1975). Nitazoxanide was originally marketed in mexico and the united states as an active ingredient of an antiparasitic drug, and was subsequently found to have good antiviral activity in cell models, animal models, and human clinical trials. The research shows that the nitazoxanide has good treatment effect on infection of a plurality of respiratory viruses such as influenza viruses H1N1 and H7N9 and non-respiratory viruses such as liver viruses HBV and HCV. However, the antiviral effect of nitazoxanide on fish viruses is rarely reported.

Studies on antiviral mechanisms have shown that nitazoxanide can inhibit different stages of viral proliferation depending on the nature of the virus and the host cell for vaccinia virus (vaccinia virus), nitazoxanide can inhibit replication of the viral genome (Hickson, marginetantutou et al 2018.) for chikungunya virus (chikungunya), nitazoxanide inhibits the viral adsorption and viral release processes (Wang, Lu et al 2016.) while for Hepatitis C Virus (HCV), nitazoxanide activates PKR protein kinase in cells, phosphorylates the eukaryotic initiation factor eIF2 α, initiates cellular innate immune responses, inhibits viral proliferation in cells (Rossignol 2014.) but the antiviral mechanism of nitazoxanide for fish virus is still lacking in research.

Viral Hemorrhagic Septicemia (VHS) is a virulent infectious disease of fish caused by VHSV (VHSV). The VHSV has wide host range, can infect economic fishes such as salmon, trout, turbot and the like, causes severe hemorrhagic septicemia, and has high mortality rate of diseased fishes. In virology research, scholars at home and abroad clearly know the genomic structure and evolutionary relationship of VHSV.

VHSV is known to belong to Rhabdoviridae (Rhabdoviridae) as a minus-strand RNA virus having a total genome length of 11kb and expressing 6 genes in the order of 3 'to 5'. VHSV can be subdivided into four classes of virus strains (Pereiro, Figueras et al.2016) depending on genomic differences. Although the virology of the virus is known to some extent through domestic and foreign research, the research on the host immune response pathway is not thorough and deep enough for the interaction mechanism of the virus and the host, which hinders the development process of novel aquatic drugs. VHS is mainly prevalent in europe, north america, japan and korea, has caused a serious economic loss, and is one of aquatic epidemic diseases that must be reported to the world animal health organization after an epidemic situation occurs. In the last decade, scientists successively discover and separate VHSV from various Pacific wild marine fishes, and detect VHSV from various cultured fishes in China, such as economic fishes like largemouth bass and the like. Although the harm of the VHSV is huge, an effective VHSV vaccine is still lacking in the current market, and epidemic disease prevention and control mainly takes strict monitoring and prevention, so that the research and development of the VHSV-resistant medicine are beneficial to improving the quality and international competitiveness of aquaculture fish in China and assisting the healthy development of the aquaculture industry.

Disclosure of Invention

The invention aims to provide a novel application of thiazole compounds in resisting fish viruses.

In order to achieve the purpose, the invention provides the technical scheme that: the thiazole compound is new application of resisting fish viruses, and is nitazoxanide, and the structural formula of the thiazole compound is shown in a formula 1:

the thiazole compound is tizoxanide, and the structural formula of the tizoxanide is shown as a formula 2:

the thiazole compound comprises geometrical isomers of nitazoxanide/tizoxanide, pharmaceutically acceptable salts thereof, solvates thereof or hydrates thereof.

The pharmaceutically acceptable salts thereof include inorganic or organic acid salts thereof, and inorganic or organic base salts thereof.

The pharmaceutically acceptable salts thereof include sodium salts, potassium salts, calcium salts, lithium salts, meglumine salts, hydrochloride salts, hydroabietate salts, rosasite salts, nitrate salts, sulfate salts, bisulfate salts, phosphate salts, hydrogen phosphate salts, acetate salts, propionate salts, butyrate salts, oxalate salts, pivalate salts, adipate salts, alginate salts, lactate salts, citrate salts, tartrate salts, succinate salts, maleate salts, fumarate salts, picrate salts, aspartate salts, gluconate salts, benzoate salts, methanesulfonate salts, ethanesulfonate salts, benzenesulfonate salts, p-toluenesulfonate salts and/or pamoate salts. But are not limited to the above salt forms.

The thiazole compounds are used for inhibiting the proliferation of Viral Hemorrhagic Septicemia Virus (VHSV) in phoxinus scaphocephala epithelial cells (FHM) cells and eliminating cytopathic effects (CPE).

The thiazole compound can obviously slow down CPE of cells caused by virus infection, inhibit virus proliferation on FHM cells and reduce the copy number of virus genes in the cells

The thiazole compounds reduce the CPE degree of VHSV infected cells in micromolar concentration in an in vitro antiviral experiment.

The thiazole compounds reduce the copy number of viral genes in VHSV infected cells at micromolar concentrations.

The thiazole compounds are used for preventing invasion of VHSV into FHM cells.

Drawings

FIG. 1 is a graph of the effect of nitazoxanide and tizoxanide at different concentrations on the protection of the activity of VHSV infected FHM cells;

FIG. 2 is a graph of the effect of ribavirin on the protection of VHSV infected FHM cell activity at different concentrations;

FIG. 3 is a graph of the effect of nitazoxanide and tizoxanide in very significantly reducing the copy number of viral genes in FHM cells infected with VHSV infection;

FIG. 4 is a graph showing the effect of nitazoxanide in inhibiting the invasion of VHSV into FHM cells and significantly reducing the copy number of viral genes in FHM cells infected with VHSV;

FIG. 5 is a graph of the effect of nitazoxanide significantly slowing CPE in FHM cells infected with VHSV; wherein A is 8 μ M nitazoxanide treated group, B is 8 μ M ribavirin treated group, and C is DMSO treated group.

Detailed Description

The following claims are provided to illustrate the present invention in a more detailed description, but not by way of limitation.