CN113143930B - Use of compound in preparing SARS-Cov-2E protein inhibitor - Google Patents
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Abstract
The invention discloses an application of a compound in preparing SARS-Cov-2E protein inhibitor. In a first aspect of the present application there is provided the use of a compound, or a pharmaceutically acceptable salt thereof, of the formula a-L-B; the product has at least one function of a1 to a 3: a1. inhibiting ion channel activity of SARS-Cov-2E protein; a2. reducing the pathogenicity of SARS-Cov-2; a3. preventing and/or treating SARS-Cov-2 caused coronavirus pneumonia. According to the application of the embodiment of the application, at least the following beneficial effects are achieved: the applicant finds that the compound with the structure or the pharmaceutically acceptable salt thereof has good effect on inhibiting the ion channel activity of SARS-Cov-2E protein in the experimental process, and can be used for preparing products with corresponding functions.
Description
Technical Field
The application relates to the technical field of antiviral drugs, in particular to application of a compound in preparation of SARS-Cov-2E protein inhibitor.
Background
The novel coronavirus pneumonia covd-19 is pneumonia caused by novel coronavirus SARS-CoV-2 infection, and in addition to the development of diagnostic reagents and vaccines, drugs capable of directly treating covd-19 are needed at present. A plurality of highly pathogenic viruses code small molecular membrane proteins with ion channel activity, and the ion channel of the viruses is critical to the pathogenicity of the viruses, so that the viruses can be used as ideal drug targets, such as amantadine which is an anti-influenza A virus drug, and is an ion channel antagonist. The results of the prior studies show that all coronaviruses, including SARS-CoV-2, encode a hydrophobic small envelope (E) protein, the ion channel activity of which is critical to the pathogenicity and pathogenesis of the severe acute respiratory syndrome coronavirus (SARS-CoV) as an example. The E protein sequences of SARS-CoV and SARS-CoV-2 have high homology. In view of this, the E protein of SARS-CoV-2 is likely to also possess ion channel activity and play a vital role in viral pathogenicity. Therefore, SARS-CoV-2E protein inhibitors targeting the E protein of SARS-CoV-2 are highly likely to play an important role in the treatment of COVID-19. At present, no effective novel E protein inhibitor of coronavirus SARS-CoV-2 has been found.
Disclosure of Invention
The present application aims to solve at least one of the technical problems existing in the prior art. For this reason, the application proposes the use of a compound in the preparation of SARS-Cov-2E protein inhibitor.
In a first aspect of the present application there is provided the use of a compound, or a pharmaceutically acceptable salt thereof, of the formula a-L-B;
wherein A is
R 1 Any one selected from hydrogen, substituted or unsubstituted hydrocarbon groups, substituted or unsubstituted acyl groups;
R 2 ～R 5 each independently selected from any one of carbonyl, substituted or unsubstituted methylene;
l is at least one selected from the group consisting of a substituted or unsubstituted alkylene group, a substituted or unsubstituted heteroalkylene group, a substituted or unsubstituted alkenylene group, a substituted or unsubstituted heteroalkenylene group, a substituted or unsubstituted alkynylene group, a substituted or unsubstituted carbocyclylene group, a substituted or unsubstituted heterocyclylene group, a substituted or unsubstituted arylene group, and a substituted or unsubstituted heteroarylene group;
b is
R 6 Selected from hydrogen, halogen, cyano, nitro, azido, substituted OR unsubstituted alkyl, substituted OR unsubstituted alkenyl, substituted OR unsubstituted alkynyl, substituted OR unsubstituted aryl, -OR 7 、-SR 8 、-NR 9 R 10 Any one of R 7 ～R 10 Each independently selected from any one of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl; />
The product has at least one function of a1 to a 3:
a1. inhibiting ion channel activity of SARS-Cov-2E protein;
a2. reducing the pathogenicity of SARS-Cov-2;
a3. preventing and/or treating SARS-Cov-2 caused coronavirus pneumonia.
According to the application of the embodiment of the application, at least the following beneficial effects are achieved:
the applicant finds that the compound with the structure or the pharmaceutically acceptable salt thereof has good effect on inhibiting the ion channel activity of SARS-Cov-2E protein in the experimental process, and can be used for preparing products with corresponding functions.
Wherein pathogenicity refers to the ability of a virus to cause infection in a host, and indicators of the degree of infection of the host by the virus include pathogenicity (pathogenicity) and virulence (virus). The existing research shows that the ion channel protein of the virus has very important influence on the replication and release of the virus. Thus, inhibition of the ion channel activity of a particular protein of a virus is also an important approach to inhibiting the pathogenicity of a virus. In particular to the scheme, the compound can influence the ion channel activity of SARS-Cov-2E protein to a great extent, naturally can also have important influence on pathogenicity of the SARS-Cov-2 protein, and further can prevent and/or treat novel coronavirus pneumonia caused by SARS-Cov-2 to a certain extent.
In some embodiments of the present application, R 1 Any one selected from hydrogen, substituted or unsubstituted hydrocarbon groups and substituted or unsubstituted acyl groups, wherein the number of carbon atoms of the hydrocarbon groups or the acyl groups is 1 to 20; further, the number of carbon atoms is 1 to 10; further, the number of carbon atoms is 1 to 5 or 1 to 3; non-limiting examples of substituents for hydrocarbyl or acyl groups include halogen, cyano, nitro, and the like.
In some embodiments of the present application, R 2 ～R 5 Non-limiting examples of substituents for the methylene group include halogen, cyano, nitro, hydrocarbyl, halocarbyl, and the like.
In some embodiments of the present application, R 2 ～R 5 Each independently selected from any one of carbonyl, methylene and methyl-substituted methylene.
In some embodiments of the present application, a is selected from any one of the following:
in some embodiments of the present application, a is selected from any one of the following:
in some embodiments of the present application, non-limiting examples of substituents on the groups of L include halogen, cyano, nitro, hydrocarbyl, halocarbyl, and the like.
In some embodiments of the present application, the number of carbon atoms in L is from 1 to 40; further, the number of carbon atoms is 1 to 30; further, the number of carbon atoms is 1 to 20 or 1 to 15.
In some embodiments of the present application, L is
Wherein L is 1 Any one selected from alkylene, haloalkylene, alkyleneoxy, haloalkyleneoxy, nitrogen-containing heterocyclylene, and halogen-containing nitrogen-containing heterocyclylene is or is not present.
In some embodiments of the present application, L is selected from any one of the following:
in some embodiments of the present application, R 6 Non-limiting examples of substituents for alkyl, alkenyl, alkynyl, aryl groups on the radical include halogen, cyano, nitro, hydrocarbyl, halocarbyl, and the like.
In some embodiments of the present application, R 6 Any one selected from alkyl, haloalkyl, alkoxy and haloalkoxy.
In some embodiments of the present application, R 6 Is one of trifluoromethyl and methoxy.
In some embodiments of the present application, the compound has the formula:
in some embodiments of the present application, the compound is selected from any one of the following:
in some embodiments of the present application, the pharmaceutically acceptable salt is hydroxynaphthoate. Non-limiting examples of hydroxynaphthoates include 1-hydroxy-2-naphthoate, 3-hydroxy-2-naphthoate, 4-hydroxy-2-naphthoate, 5-hydroxy-2-naphthoate, 6-hydroxy-2-naphthoate, 7-hydroxy-2-naphthoate, 8-hydroxy-2-naphthoate, and the like.
Additional aspects and advantages of the application will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the application.
Drawings
FIG. 1 shows the results of measuring the ion channel activity of SARS-CoV-2E protein in example 1 of the present application.
FIG. 2 shows the results of the measurement of the inhibitory effect of a salt of the compound AZD5153 in example 2 of the present application on the ion channel activity of SARS-CoV-2E protein.
FIG. 3 is a model of the binding of a salt of the compound AZD5153 to SARS-CoV-2E protein in example 2 of the present application.
FIG. 4 is a graph showing the results of measurement of the inhibitory effect of compound ABBV-075 in example 3 of the present application on the ion channel activity of SARS-CoV-2E protein.
Detailed Description
The conception and technical effects produced by the present application will be clearly and completely described below in connection with the embodiments to fully understand the objects, features and effects of the present application. It is apparent that the described embodiments are only some embodiments of the present application, but not all embodiments, and that other embodiments obtained by those skilled in the art without inventive effort based on the embodiments of the present application are within the scope of the present application.
The following detailed description of embodiments of the present application is exemplary and is provided merely for purposes of explanation and not to be construed as limiting the application.
In the description of the present application, the meaning of a number is one or more, the meaning of a number is two or more, and greater than, less than, exceeding, etc. are understood to exclude the present number, and the meaning of a number above, below, within, etc. are understood to include the present number. The description of the first and second is for the purpose of distinguishing between technical features only and should not be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated or implicitly indicating the precedence of the technical features indicated.
In the description of the present application, a description with reference to the terms "one embodiment," "some embodiments," "illustrative embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present application. In this specification, schematic representations of the above terms do not necessarily refer to the same embodiments or examples. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.
Example 1
SARS-CoV-2E protein ion channel Activity assay
(1) Expression of SARS-CoV-2E protein
The SARS-CoV-2E protein gene (NCBI reference sequence: NC_ 045512.2) was synthesized by GENEWIZ and subcloned into pcDNA3.1 vector harboring IRES-GFP. The plasmid was transiently transfected into chinese hamster ovary cell line (CHO) using Lipofectamine 3000 reagent to express SARS-CoV-2E protein.
(2) Testing of ion channel Activity of SARS-CoV-2E protein
The ion channel activity of SARS-CoV-2E protein was detected by whole cell voltage clamp assay using untransfected CHO cells as a control. The specific process is as follows:
the cells were clamped at 0mV and the cells were given a step voltage of from-100 mV to 100mV in 10mV increments. The maximum current that cells were excited at different voltages was measured and the results are shown in FIG. 1.
-current magnitude of-88.5±24.4pa (n=13) for untransfected CHO cells at 100mV voltage, and-169.9±73.7pa (n=15) for CHO cells expressing SARS-CoV-2E protein; at 100mV, the current magnitude of untransfected CHO cells was 154.9±42.8pa (n=13), and that of CHO cells expressing SARS-CoV-2E protein was 300.6±136.5pa (n=15). CHO cells expressing SARS-CoV-2E protein were stimulated with significantly increased inward and outward currents under voltage stimulation compared to CHO cells not expressing SARS-CoV-2E protein, and unpaired t-test showed significant differences in current magnitude for both groups of cells under the same voltage stimulation (p < 0.05).
The experimental results show that SARS-CoV-2E protein has ion channel activity.
Example 2
A pentameric structure model of SARS-CoV-2E protein is built through homologous modeling. Because the E protein sequences of SARS-CoV and SARS-CoV-2 have very high homology (94.7%), the structural model of SARS-CoV-2E protein is obtained by homology modeling according to the protein structure of SARS-CoV. A total of 5000 compounds were virtually screened using the structural model of SARS-CoV-2E protein using the drug library, clinical drug library and natural product library listed. The screening result included 6-hydroxy-2-naphthoate (CAS No:1869912-40-2, molecular formula: C) of the compound AZD5153 36 H 41 N 7 O 6 Molecular weight: 667.7540 The structural formula of the compound is as follows:
verification of inhibition of ion channel Activity of the Compounds on SARS-CoV-2E protein
The SARS-CoV-2E protein was assayed for ion channel activity by the method of example 1 by adding a compound to the extracellular fluid at a final concentration of 40. Mu.M, and the results are shown in FIG. 2.
Under the action of the compound, under the voltage of-100 mV, the current of CHO cells expressing SARS-CoV-2E protein is-56.8+ -21.1 pA (n=13); at 100mV, CHO cells expressing the SARS-CoV-2E protein had a current magnitude of 102.4±11.6pa (n=13). The cell current was significantly reduced compared to the case without the addition of the compound, and the unpaired t-test showed a significant difference in current magnitude (p < 0.05) between the two groups of cells under the same voltage stimulus.
The experimental results show that the compound has strong inhibition effect on the ion channel activity of SARS-CoV-2E protein.
FIG. 3 is a partial schematic diagram of a model of the binding of a salt of the compound AZD5153 to SARS-CoV-2E protein in example 2 of the present application. Referring to FIG. 3, the hydrophobic pocket of SARS-CoV-2E protein is composed of the interface formed by Val25, phe26, val29 of one subunit and Phe23 and Phe26 of the adjacent subunit, wherein Phe23 and Val29 are key sites for the action of AZD5153 on E protein, the piperazine group (A in the formula of A-L-B) of AZD5153 may act with residues of Phe23, phe26, val29 etc. of the adjacent two subunits, while the triazolopyridazine group (B in the formula of A-L-B) may act with residues of Leu18, leu19, asn15 etc. of the other two subunits of pentamer, thereby inhibiting the conduction of cations therebetween by changing its steric hindrance, thereby affecting the ion channel activity of SARS-CoV-2E protein. Therefore, the compounds of the general formula A-L-B or the salts thereof meeting the requirements of the examples of the application can obviously inhibit the ion channel activity of SARS-CoV-2E protein, thereby being capable of being used for reducing the pathogenicity of SARS-Cov-2 or preventing and/or treating novel coronavirus pneumonia caused by SARS-Cov-2.
Example 3
Previous studies have shown that the compound AZD5153 binds to the bromodomain of BET (bromodomain and extraterminal domain) protein BRD4 (bromodomain protein 4), i.e. bromodomain protein 4, in a way that prevents protein-protein interactions between BET proteins and acetylated histones and transcription factors from targeted inhibition of BRD4 protein, delays tumor cell proliferation and even induces tumor cell apoptosis, thus achieving an antitumor effect (Expert Opinion on Therapeutic Patents,2014,24 (2): 185-199;Nature Structural&Molecular Biology,2014,21 (12): 1047-1057). For this reason, the inventors further investigated whether inhibition of ion channel activity of SARS-CoV-2E protein could equally well be achieved, taking as an example other known BRD4 inhibitors. In the verification process, a pyridone compound ABBV-075 is adopted, and the structural formula is as follows:
the results of the test performed by the method of example 2 are shown in FIG. 4. The experimental results showed no significant decrease in cell current compared to the no added compound ABBV-075, and no significant difference in current magnitude (p > 0.05) in the two groups of cells under the same voltage stimulus as demonstrated by the unpaired t-test.
Example 4
1-hydroxy-2-naphthoate, 3-hydroxy-2-naphthoate and 6-hydroxy-2-naphthoate of a compound having the following structural formula were taken, respectively, and the inhibition effect on the ion channel activity of SARS-CoV-2E protein was verified by the method of example 2, and the preparation of the compound was found in Journal of Medicinal Chemistry,2016,59 (17): 7801-7817:
the results show that there is a significant decrease in cell current after addition compared to when no corresponding compound was added, indicating that these compounds also have a significant inhibitory effect on the ion channel activity of SARS-CoV-2E proteins.
It can be seen from the above experiments that the compounds with specific structures provided in the examples of the present application can be used as inhibitors of ion channel activity of SARS-CoV-2E protein. In addition, studies with various coronaviruses have shown that ion channel proteins have a very important effect on viral replication and release. Therefore, the compound and the salt thereof can have important influence on the pathogenicity of SARS-CoV-2, and further can prevent and/or treat the novel coronavirus pneumonia caused by SARS-CoV-2 to a certain extent.
The present application has been described in detail with reference to the embodiments, but the present application is not limited to the embodiments described above, and various changes can be made within the knowledge of one of ordinary skill in the art without departing from the spirit of the present application. Furthermore, embodiments of the present application and features of the embodiments may be combined with each other without conflict.
Claims (2)
1. Use of a compound or a pharmaceutically acceptable salt thereof in the manufacture of a product, wherein the compound is selected from any one of the following:
the product has at least one function of a 1-a 3:
a1. inhibiting ion channel activity of SARS-Cov-2E protein;
a2. reducing the pathogenicity of SARS-Cov-2;
a3. preventing and/or treating SARS-Cov-2 caused coronavirus pneumonia.
2. The use according to claim 1, wherein the pharmaceutically acceptable salt is hydroxynaphthoate.
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| WO2017216772A2 (en) * | 2016-06-16 | 2017-12-21 | The University Of Chicago | Methods and compositions for treating breast and prostate cancer |
| CN110575455A (en) * | 2018-06-07 | 2019-12-17 | 中国科学院上海药物研究所 | Application of benzoic acid derivative in preparation of antibacterial drugs |
| CN111182917A (en) * | 2017-09-29 | 2020-05-19 | J·梅利埃夫 | Immunogenic compositions for the treatment of cancer |
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| IL278921A (en) * | 2018-05-24 | 2021-01-31 | Univ Virginia Patent Foundation | Combination therapies for treating cancer |
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| CN111727189B (en) * | 2017-12-01 | 2023-10-03 | 伊利诺伊大学董事会 | Pyridone-based epigenetic modifiers and uses thereof |
| WO2020007322A1 (en) * | 2018-07-04 | 2020-01-09 | 清华大学 | Compound targeted to degrade bet protein and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2017216772A2 (en) * | 2016-06-16 | 2017-12-21 | The University Of Chicago | Methods and compositions for treating breast and prostate cancer |
| CN111182917A (en) * | 2017-09-29 | 2020-05-19 | J·梅利埃夫 | Immunogenic compositions for the treatment of cancer |
| CN111788203A (en) * | 2018-01-10 | 2020-10-16 | 里科瑞尔姆Ip控股有限责任公司 | Benzamide compounds |
| CN111801320A (en) * | 2018-01-10 | 2020-10-20 | 里科瑞尔姆Ip控股有限责任公司 | Benzamide compounds |
| IL278921A (en) * | 2018-05-24 | 2021-01-31 | Univ Virginia Patent Foundation | Combination therapies for treating cancer |
| CN110575455A (en) * | 2018-06-07 | 2019-12-17 | 中国科学院上海药物研究所 | Application of benzoic acid derivative in preparation of antibacterial drugs |
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