Micromolecule compound inhibitor for enterovirus and application of inhibitor

An enterovirus and inhibitor technology, applied in the field of enterovirus small molecule compound inhibitors

Active Publication Date: 2016-03-16
中国科学院上海免疫与感染研究所
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Hand, foot and mouth disease is still a very serious public health problem, but so far there are no effective preventive measures and treatments, so it is urgent to find antiviral drugs

Method used

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  • Micromolecule compound inhibitor for enterovirus and application of inhibitor
  • Micromolecule compound inhibitor for enterovirus and application of inhibitor
  • Micromolecule compound inhibitor for enterovirus and application of inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0099] Anti-EV71 virus activity of embodiment 1 itraconazole and its analogs

[0100] In this example, the anti-EV71 virus activity of itraconazole and its analogues and their cytotoxicity were verified. Figure 1 shows that itraconazole and posaconazole inhibit EV71 infection.

[0101] Figure 1A It shows the addition of 3-fold diluted itraconazole to RD cells, adding virus or medium and culturing for 96 hours, then using the CellTiter-Glo kit to detect cell viability, and to detect the inhibitory effect of itraconazole on EV71 and its effect on cells . Results were processed using GraphpadPrism5. The experimental results show that when the concentration of itraconazole is below 1 μM, the antiviral activity is not obvious, and when it is above 3 μM, it has significant activity of inhibiting EV71 virus.

[0102] Figure 1B It is shown that RD cells were infected with EV71 with a multiple of infection (Multiple of infections, MOI) of 0.1, and added 3-fold diluted itraconazole...

Embodiment 2

[0106] Example 2 The inhibitory effect of itraconazole on other enteroviruses

[0107] Figure 2A It shows that RD cells were infected with EV71SH036 strain (MOI=0.1), CVA16 (MOI=0.01), CVB3 (MOI=0.001), PV1 (MOI=0.01), EV68 (MOI=0.1), and added 3-fold dilution The supernatant was collected after 48, 42, 24, 42, and 48 hours of infection, and the titer of the virus was determined. The experimental results showed that itraconazole exhibited good inhibitory activity on all experimental virus strains, among which, the inhibitory degree of itraconazole on PV1, CVB3, EV71SH036 virus strains at a concentration of 25 μM was significantly better than that on CVA16 The inhibitory effect of the virus strain, but the EC of CVA16 50 lowest value, indicating that it is most sensitive to itraconazole.

[0108] Figure 2B Shown is the data processed with GraphpadPrism, and the calculated EC of itraconazole inhibiting the virus 50 .

[0109] The above experimental results show that in a...

Embodiment 3

[0114] Example 3 Itraconazole exerts antiviral activity by inhibiting the synthesis of viral RNA

[0115] The present inventors studied the mechanism of itraconazole's virus-inhibiting activity, and the experimental results are shown in FIG. 3 .

[0116] Figure 3A Dosing experiments at different time points. EV71 with an MOI of 5 was used to infect Vero cells at 4°C for 1 h, washed three times with pre-cooled medium, and then 5 μM itraconazole was added at corresponding time points, and the supernatant was collected 20 h later to measure the virus titer. In the control group, 0.25% DMSO was added at 0, 10, and 16 hours after infection. Combined with the virus infection cycle, the experimental results proved that itraconazole inhibited the synthesis of RNA.

[0117] Figure 3B Transient replicator experiments. 1 μg of replicon containing firefly luciferase reporter gene (F-Luc) was transfected into BHK-21 cells, and the transfected cells were inoculated into 12-well plate...

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Abstract

The invention provides a micromolecule compound inhibitor for enterovirus and an application of the inhibitor. Specifically, the invention provides an application of itraconazole, an itraconazole analogue, or pharmaceutically acceptable salt of itraconazole or the itraconazole analogue to preparation of a reagent, which is used for inhibiting growth or reproduction of enterovirus and/or for inhibiting synthesis of enterovirus RNA. The invention also provides an inhibitor and medicine composition containing itraconazole or the itraconazole analogue for enterovirus, and provides a method for in-vitro non-therapeutically inhibiting growth of enterovirus or killing enterovirus. Experimental results show that itraconazole and the itraconazole analogue has an excellent inhibition effect on multiple kinds of enterovirus.

Description

technical field [0001] The invention belongs to the field of biomedicine, in particular, the invention relates to a small molecular compound inhibitor of enterovirus and its application. Background technique [0002] Enterovirus, small particles, 20-hedron, 24-30nm in diameter, no lipoids, single-stranded ribonucleic acid in the core, resistant to ether and other lipid solvents, acid-resistant, resistant to various antibiotics, antivirals, and detergents There is resistance. Most viruses produce cytopathic effects in cell culture. It belongs to the picornavirus family and is a naked virus. Different enteroviruses can cause the same symptoms, and the same virus can cause different clinical manifestations. Enteroviruses are mostly recessive infections, which can cause symptoms such as mild upper flu, abdominal discomfort, and diarrhea. Occasionally invades the central nervous system, causing flaccid paralysis. [0003] Enterovirus 71 (EV71) and coxsackievirus A16 (CVA16) a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A01N43/653A01P1/00A61K31/496A61P31/14G01N33/15
CPCY02A50/30
Inventor 邹罡艾德铭高倩倩
Owner 中国科学院上海免疫与感染研究所
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