CN110898043B - Medical application of (3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) methanone - Google Patents
Medical application of (3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) methanone Download PDFInfo
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Abstract
The invention discloses a medical application of (3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) ketone. The inventor researches and discovers that (3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) ketone is an ideal microbicide which can effectively inhibit the formation of seminal amyloid fibers, break the morphology of the seminal amyloid fibers and inhibit the seminal amyloid fiber from binding viruses, thereby blocking the effect of the seminal amyloid fibers on promoting the sexual propagation of HIV-1, ebola viruses and the like.
Description
Technical Field
The invention relates to a new application of a pharmaceutical compound, in particular to an application of (3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) ketone in preparation of a microbicide for inhibiting seminal amyloid fiber.
Background
A class of amyloid fibrils exist in human semen that can significantly contribute to the infection by a number of sexually transmitted pathogens, including HIV-1, ebola, cytomegalovirus, and the like. Most studied is the promotion of HIV-1 infection. Professor Munch, university of Ulm, germany, found that some degraded polypeptide fragments were present in semen and these hydrolyzed polypeptide fragments were able to form amyloid deposits, thereby promoting HIV-1 infection of target cells. They named this amyloid fiber that enhanced viral Infection as a Semen-derived viral Infection Enhancer (SEmen-derived Enhancer of Virus Infection, SEVI). The mechanism of action of SEVI in promoting virus infection is mainly related to the extremely strong cationic property of SEVI, and SEVI can assist viruses to interact with host cells by capturing viruses, thereby enhancing infection. SEVI promotes viral infection while reducing the efficacy of antiviral drugs, and thus SEVI has become one of the targets of microbicides in recent years.
In recent years, researches show that the semen-derived amyloid fibers can also obviously enhance the infection of the Ebola virus, so that the probability of sexual transmission of the Ebola virus is greatly improved, and on the other hand, the existence of the semen-derived amyloid fibers can reduce most of the existing antiviral drug effects, including polyanion compounds, neutralizing antibodies, reverse transcriptase inhibitors and the like. Thus, seminal amyloid is a new and important target for the development of microbicides.
Since the naturally occurring amyloid fibrillary polypeptide and amyloid fibrils, respectively, are found in seminal fluid, the amyloid fibrils are polymerized from the amyloid polypeptide and have the ability to enhance viral infection. Thus, active compounds that inhibit the immunogenic polypeptide, respectively, from aggregating to form amyloid fibrils, or target amyloid fibrils, disaggregate amyloid fibrils, and not enhance viral infection, can be developed as potential multi-effect microbicides.
Microbicides are gels, creams, suppositories, membranes or sponges containing anti-HIV components that are placed in the vagina or anus prior to sexual intercourse to prevent transmission of HIV and other sexually transmitted pathogens by directly inactivating HIV, preventing HIV from adhering to or invading target cells in the vaginal or rectal mucosa, inhibiting HIV replication in the target cells, and the like. Thus, the microbicide enables the sexual partner to avoid infection with HIV even without the use of a condom. More importantly, the use of microbicides can be controlled by women, thereby providing effective means for women to prevent sexual transmission of HIV. This is in the female aspect ratioPrevention of aids is critical in both lower developing countries (e.g. africa) and sexual workers. Recent studies have shown that the proportion of HIV transmitted in males in sexual transmission has increased year by year in recent years, and it is therefore also very urgent to develop rectal microbicides which can prevent the transmission of males in sexual love. Although the food and drug administration of the united states has recently passed through a combination of oral antiviral drugs (TDF/FTC,
gilead Science) is used to prevent HIV sexually transmission in high risk groups, but oral antiviral drugs used to prevent HIV sexually transmission have non-negligible effects, such as: the generation of drug-resistant virus strains, the systemic toxic and side effects of the medicine, the effective medicine concentration of the vaginal mucosa/rectal mucosa and the like are increased; the local microbicide has the characteristics of high local drug concentration of vaginal mucosa/rectal mucosa, no need of systemic administration and the like, and has good prospect in the aspect of preventing HIV sexual transmission
More than twenty microbicide products have been in various stages of clinical trials to date, but 7 of them have concluded phase IIb/III large-scale clinical trials (N-9, savvy, ushercell, carraguard, bufferGel, PRO-2000 and Carbopol 974P), all declared failures or were discontinued in sequence. Vaginal gel formulations containing 1% Tenofovir as candidate biocide completed phase IIb clinical trials in south Africa (CAPRISA 004 trials) and showed effective reduction of HIV infection in 39% of the population, especially in the drug-highly dependent population, by up to 54%. Yet another large-scale clinical trial by Tenofovir proved ineffective (VOICE trial). Microbicides have not been available as effective products. The reasons for this are (1) insufficient antiviral activity of the test drug, such as poor inhibition of sexually transmitted major CCR5 co-receptor dependent viral strains; single or compound combination drugs with better antiviral effect should be selected for the test; (2) The host body inflammatory reaction induced by the tested medicament limits the clinical application of the medicament, and a medicament with better safety is selected for the test; and (3) the compliance of the test drugs in use is poor.
Ebola hemorrhagic fever (EBHF) is an acute hemorrhagic, zoonotic infectious disease caused by infection with a filovirus. In 1976, ebola hemorrhagic fever is fulminated in Sudan and Zaire in Africa, and the fatality rate reaches 50% -90%. Ebola virus is the causative agent of fatal ebola virus disease and can be transmitted by contact with patients with ebola hemorrhagic fever, including sexual contact with survivors of ebola hemorrhagic fever. In 2014, the scale of the west africa ebola epidemic situation was unprecedented, infecting 2.8 thousands of people, resulting in the death of 1.1 thousands of people. During this outbreak, multiple cases of ebovirus sexual transmission were reported, including ebola hemorrhagic fever patients who had healed several months prior to transmission. Since there are no approved vaccines and treatments available today, there is an urgent need to develop microbicides that can be used to prevent the sexual transmission of ebola.
The discovery has important theoretical guiding significance for the development of future microbicides, and provides a new action target for the development of novel clinical microbicides. Candidate drugs with the ability to antagonize SEVI and enhance microbial infection are likely one of the future development directions for clinical microbicides that may be used to prevent sexual transmission of HIV-1, ebola virus. This also provides a theoretical basis for the study of candidate microbicides of the present invention.
(3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) methanone is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT). The chemical name is: (3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) -methanone,
the structural formula is as follows: (3, 4-dihydroxy-5-nitrophenyl) (p-tolyl) methanone. Clinically used for the adjuvant therapy of primary Parkinson disease by the combined therapy of levodopa and carbidopa, and no research shows that the compound has the efficacy of inhibiting seminal amyloid fibers and mediated Eporax or HIV-1 sexual transmission.
Disclosure of Invention
The invention aims to provide a new application of (3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) ketone.
The technical scheme adopted by the invention is as follows:
in a first aspect of the present invention, there is provided:
application of (3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) ketone and pharmaceutically acceptable derivatives thereof in preparation of microbicide for inhibiting seminal amyloid fibers.
In some examples of applications, the microorganism is a microorganism transmitted via sexual contact.
In some examples of use, the microorganism is HIV-1, ebola virus, zika virus.
In some examples of applications, the formulation of the microbicide is an external preparation.
In some examples of applications, the external preparation is selected from the group consisting of a gel, a vaginal ring, a cream, a film, a tablet, a suppository, and an enema.
In some examples of applications, the external preparation is used for rectum or vagina.
In a second aspect of the present invention, there is provided:
the application of (3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) ketone and pharmaceutically acceptable derivatives thereof in preparing seminal amyloid fibril formation inhibitors.
In a third aspect of the present invention, there is provided:
3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) ketone and application of pharmaceutically acceptable derivatives thereof in preparation of a preparation for breaking seminal amyloid fiber structures.
In some examples of the first to third aspects of the invention, the seminal amyloid fibrils are the polypeptide fragment PAP248-286, SEM1 86-107, which synthetically produces SEVI amyloid fibrils, and seminal endogenous amyloid fibrils and polypeptides.
In some examples of the first to third aspects of the invention, the pharmaceutically acceptable derivative is a pharmaceutically acceptable ester, a pharmaceutically acceptable ether or a pharmaceutically acceptable amide of (3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) methanone. In particular to a medicinal ester, a medicinal ether or a medicinal amide of (3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) ketone which can be hydrolyzed under the using environment.
In some embodiments of the invention, the pharmaceutically acceptable ester or ether is a C1-C6 pharmaceutically acceptable ester or ether of (3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) methanone; the medicinal amide is formed by (3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) ketone and natural amino acid.
The invention has the beneficial effects that:
the (3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) ketone is an ideal microbicide which can effectively inhibit the formation of seminal amyloid fibers, break the form of the seminal amyloid fibers and inhibit the seminal amyloid fiber from binding viruses, thereby blocking the function of the seminal amyloid fibers for promoting the sexual transmission of HIV-1, ebola viruses and the like.
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FIG. 1 is a graphical representation of the data for the in vitro inhibition of PAP248-286, SEM1, seminal fluid formation of amyloid fibrils by (3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) methanone;
FIG. 2 is a graphical representation of data for the in vitro inhibition of SEVI binding to Ebola virus, HIV-1, by (3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) methanone;
FIG. 3 is a graphical representation of data for the in vitro disruption of seminal amyloid fibrils by (3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) methanone.
Detailed Description
In vitro experiments are carried out to verify that (3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) ketone inhibits SEVI formation, inhibits SEVI from binding to virus particles, breaks fiber morphology, and thereby antagonizes SEVI's ability to promote virus infection.
Effect of (3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) methanone on SEVI formation
Congo red dyeing method: polypeptide PAP 248-286 (220. Mu.M) was mixed with each concentration of (3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) methanone (5X, 7.5X, 11X) or PBS, reacted at 1400rpm in a 37 ℃ shaker at various time points (2h, 4h,8h,12h,24h, 48h) 10. Mu.L of the sample was taken out and mixed with 90. Mu.L of Congo Red solution (Sigma), reacted in the dark for 15min, centrifuged at 12000rpm, the supernatant was removed, the precipitate was dissolved in 50. Mu.L of DMSO, and assay was performedAbsorbance value at 490nm, referenced to a wavelength of 650nm.
Virus infection enhancement experiment: the polypeptide and (3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) ketone or PBS are mixed uniformly and reacted (as described above), samples are taken at different time points (2h, 4h,8h,12h,24h and 48h), centrifugation is carried out for 10min at room temperature at 5000rpm, precipitates are suspended in a culture medium and incubated with viruses into target cells (HIV-1 is added into TZM-bl cells and Ebola viruses are added into HuH-7 cells), fresh culture medium is replaced after 16h, and chemiluminescence values are detected by a luciferase detection kit after 72h, so that the promotion effect of the samples on virus infection is judged.
The results of the experiment are shown in FIG. 1. As can be seen in FIG. 1, (3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) methanone inhibits the formation of SEVI fibers by PAP248-286 and also inhibits the formation of fibers by SEM 1-107, while antagonizing the SEVI-mediated effects of enhancing HIV-1 and Ebola infections, respectively.
Effect of (3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) methanone on SEVI-binding Virus
Determination of the surface potential of the SEVI amyloid fibrils: mixing amyloid fiber SEVI (110M) and (3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) methanone at different concentrations, incubating at 37 deg.C for 30min, centrifuging at room temperature for 10min, and discarding the supernatant; the pellet was resuspended in 1mM KCl solution at a total volume of 1ml per sample, and the prepared samples were loaded into a dedicated potentiometric cell and tested three times per sample using a Zetasizer Nano ZS90 analyzer.
Virus infection enhancement experiment: SEVI is mixed with (3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) ketone or PBS, incubated for 15min at 37 ℃, centrifuged for 10min at 5000rpm at room temperature, the precipitate is resuspended in a culture medium and incubated with viruses to be added into target cells (HIV-1 is added into TZM-bl cells, ebola viruses are added into HuH-7 cells), the culture medium is replaced with fresh culture medium after 16h, and chemiluminescence values are detected by a luciferase assay kit after 72h, so that the promotion effect of the sample on virus infection is judged.
The results of the experiment are shown in FIG. 2. As can be seen from fig. 2, (3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) methanone binds to the surface of the SEVI fiber, changing its potential; (3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) methanone is effective in blocking the ability of SEVI to increase Ebola virus and HIV-1 infection.
(3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) methanone to disrupt the morphology of SEVI fibers
Amyloid SEVI (110. Mu.M) was mixed with (3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) methanone at various concentrations, incubated at 37 ℃, sampled at various time points (2h, 4h,8h,12h,24h, 48h), centrifuged at 5000rpm for 10min at room temperature, the pellet resuspended in PBS, and then ThT solution was added. The fluorescence value was measured.
The results of the experiment are shown in FIG. 3. As can be seen from FIG. 3, (3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) methanone was able to degrade SEVI amyloid fibrils in a time-dependent and dose-dependent manner.
Evaluation of safety of (3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) methanone
Selecting reproductive tract cell (Hela cell) and epithelial cell (Huh-7, A549 cell) with good growth state according to 3 × 10 5 The cells were seeded in 96-well plates at a density of 100. Mu.L/well. Different concentrations of (3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) methanone (1000. Mu.M, 500. Mu.M, 250. Mu.M, 62.5. Mu.M, 15.63. Mu.M, 3.91. Mu.M, 0.98. Mu.M, 0.49. Mu.M) were added to the cell culture plates, 3 replicate wells per group, 37 ℃,5% CO 2 Incubator incubation 48h, XTT method for detecting influence of (3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) ketone on cell viability, and calculating CC 50 。
The toxicity of (3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) ketone on cells and lymphocytes related to the genital tract is detected by an XTT method, and the experimental results are shown in Table 1.
TABLE 1 Effect of (3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) methanone on different cell viability
As can be seen from Table 1, (3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) methanone is less toxic to both types of cells and has better safety.
The medicinal derivatives of (3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) methanone, in particular medicinal esters, medicinal ethers and medicinal amides thereof can be hydrolyzed under the application environment to obtain the (3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) methanone, which has the same or similar activity and the function of killing microbes, can inhibit the formation of seminal amyloid fibrils, break the seminal amyloid fibrils and block the seminal amyloid fibrils from being combined with virus particles, thereby antagonizing the promotion of the virus infection of the seminal amyloid fibrils.
Claims (5)
1. The use of (3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) methanone in the preparation of a microbicide for inhibiting seminal amyloid fiber; the microorganism is HIV-1, ebola virus and Zika virus; the dosage form of the microbicide is an external preparation; the external preparation is selected from gel, vaginal ring, milk fat, film, tablet, suppository or enema.
2. Use according to claim 1, characterized in that: the external preparation is used for rectum or vagina.
3. Use of (3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) methanone in the preparation of an inhibitor of in vitro seminal fluid amyloid fibril formation.
4. Application of (3, 4-dihydroxy-5-nitrophenyl) - (4-methylphenyl) ketone in preparation of a preparation for breaking the amyloid fiber structure of in vitro seminal fluid.
5. Use according to any one of claims 1 to 4, characterized in that: the seminal amyloid fiber is polypeptide fragment PAP248-286, SEM1 86-107 which generates SEVI amyloid fiber through synthesis, and seminal endogenous amyloid fiber and polypeptide.
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Citations (2)
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| WO2014066502A2 (en) * | 2012-10-23 | 2014-05-01 | Georgetown University | Flavivirus protease inhibitors |
| CN108078971A (en) * | 2017-11-28 | 2018-05-29 | 南方医科大学 | Applications of the Suramin in SEVI formation inhibitor is prepared |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014066502A2 (en) * | 2012-10-23 | 2014-05-01 | Georgetown University | Flavivirus protease inhibitors |
| CN108078971A (en) * | 2017-11-28 | 2018-05-29 | 南方医科大学 | Applications of the Suramin in SEVI formation inhibitor is prepared |
Non-Patent Citations (4)
| Title |
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| A Sensitive In Vitro High-Throughput Screen to Identify Pan-Filoviral Replication Inhibitors Targeting the VP35-NP Interface;Gai Liu等;《ACS Infectious Diseases》;20170202(第3期);第1-32页 * |
| Gai Liu等.A Sensitive In Vitro High-Throughput Screen to Identify Pan-Filoviral Replication Inhibitors Targeting the VP35-NP Interface.《ACS Infectious Diseases》.2017,(第3期),第1-32页. * |
| Repositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicity;Ricardo Sant’Anna等;《NATURE COMMUNICATIONS》;20160223;第1-13页 * |
| Transthyretin stabilization activity of the catechol-O-methyltransferase inhibitor tolcapone (SOM0226) in hereditary ATTR amyloidosis patients and asymptomatic carriers: proof-of-concept study;Josep Gamez等;《AMYLOID》;20190523(第26期);第1-11页 * |
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