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Compounds accelerating duplication of herpes simplex virus and application

A herpes simplex virus and compound technology, applied in the direction of drug combination, medical preparations containing active ingredients, organic active ingredients, etc., can solve problems such as repeated infection and reinfection, and achieve the effect of promoting virus replication and clear mechanism of action

Active Publication Date: 2017-04-05
NANJING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

During the latent process, there is no obvious viral gene replication and virus particle formation, but the latently infected virus can be reactivated, which is the main cause of recurrent infection
We don't know much about the mechanism of virus reactivation, but low immunity, fatigue or external stress, and environmental factors such as strong ultraviolet radiation can reactivate the virus in the latent state, making it enter a replicative infection state, leading to reinfection

Method used

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  • Compounds accelerating duplication of herpes simplex virus and application
  • Compounds accelerating duplication of herpes simplex virus and application
  • Compounds accelerating duplication of herpes simplex virus and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034]Example 1 Epigenetic Small Molecular Compounds Promote HSV-1 and HSV-2 Infection Experiment

[0035] (1) Small molecule compound library screening

[0036] The day before infection, Vero cells were cultured in 96-well plates, 3x10 per well 3 cell. A small-molecule library containing 129 compounds with less than their cytotoxicity (IC 50 ) 3 times the concentration is the maximum screening concentration (for example, product description marked A compound IC 50 300nM, then the initial maximum concentration is set to 100nM), with DMEM medium as the dilution system, 3-fold dilution to 5 concentrations (take A compound as an example, the test concentration is 100, 33.3, 11.1, 3.7 and 1.2nM ), Vero cells were treated two hours before infection, and the wells were replicated in triplicate. At the same time, a normal control group without drug treatment and a compound toxicity control (using a maximum test concentration of 100 nM as a sample) were set up. Cells were infecte...

Embodiment 2

[0048] Example 2 Determination of Compound JQ-1 Promoting Herpes Simplex Virus Infection Concentration and Time Curve

[0049] (1) Determination of concentration and dosing time

[0050] EC determined according to the above 20 For the data, we selected JQ-1 as a representative, treated Vero cells with 50, 100, 300 and 500nM JQ-1 2 hours before virus infection, and then infected with 1MOI virus in parallel with untreated control. Samples were collected after 36 hours and titrated for virus. The results showed that JQ-1 could promote both HSV-1 and HSV-2 infection at the above concentrations.

[0051] In addition, we also added JQ-1 (300nM) 2 hours before virus infection (-2), at the same time as infection (0), and 1, 3, 6, 12 and 24 hours after virus addition in a similar manner, Cell samples were collected 36 hours after infection, and virus titers were titrated with secondary infections. Adding the compound before infection or in the first 6 hours of infection can signifi...

Embodiment 3

[0054] Example 3 JQ-1 promotes the infection efficiency of HSV-1 (HSV-1 / EGF) carrying the GFP reporter gene.

[0055] HeLa cells were grown overnight in 6-well plates. The cells were treated with JQ-1 (JQ1, 300nM) or (-) JQ-1 without bromodomain inhibitory activity as a control for 2 hours, and then the cells were infected with HSV-1 / GFP (MOI=0.3 and 1.0), and the wells were replicated. Samples were collected 36 hours after infection, the fluorescence intensity of GFP was detected by flow cytometry (FACS), and the mean fluorescence intensity (MFI) was calculated as the effect of JQ-1 on the expression of genes carried by HSV-1. The results showed that JQ-1, but not (-)JQ-1 without bromodomain inhibitory activity, could promote the expression of reporter gene carried by HSV-1.

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Abstract

The invention belongs to the technical field of bio-pharmaceuticals and relates to compounds accelerating duplication of a herpes simplex virus and an application. 9 known compounds are found capable of accelerating HSV duplication process, comprising JQ-1 (PubChem CID 46907787), PFI-1 (PubChem CID 71271629), I-BET-762 (PubChem CID 46943432), TG101348 (PubChem CID 16722836), Quisinostat (PubChem CID 11538455), CUDC-907 (PubChem CID 54575456), CUDC-101 (PubChem CID 24756910), Givinostat (PubChem CID 9804992) and HDAC-42 (PubChem CID 6918848). The compounds can increase virus infection to different extents and can be classified into histone deacetylase inhibitors (HDACi) or BET bromine domain proteins, for example BRD4 protein (Genbank accession NP_490597) bromodomain (bromodomain proteins) inhibitors. The compounds are drugs with ability of independently killing tumors and can be combined with HSV oncolytic viruses for tumor treatment and research.

Description

technical field [0001] The invention belongs to the technical field of biopharmaceuticals, and in particular relates to a compound for promoting the replication of herpes simplex virus and its application. Background technique [0002] Human herpes simplex virus (HSV), including HSV-1 and HSV-2, is the main pathogen causing human diseases. HSV-1 infection mainly causes gingivitis, pharyngitis, herpetic keratitis, skin herpetic eczema, etc. About 2 / 3 of the adults in the world have been infected with this virus. HSV-2 infection is a sexually transmitted disease (STD) that affects more than 10% of the sexually active population. As one of the STD pathogens, HSV-2 infection can also significantly increase the spread of HIV. Drugs for the treatment of HSV infection are mainly nucleotide derivatives, which have a certain curative effect. [0003] The biggest characteristic of herpes simplex virus infection includes two forms of cytolytic infection and latent infection. Once a...

Claims

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Application Information

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IPC IPC(8): A61K31/551A61K31/517A61K31/506A61K31/5377A61K31/325A61K31/167A61P35/00
CPCA61K31/167A61K31/325A61K31/506A61K31/517A61K31/5377A61K31/551
Inventor 李尔广任科王子润达王晶晶
Owner NANJING UNIV
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