2-amino-2,7-dideoxy-alpha-D-glycero-D-gluco-heptopyranosyl inhibitors of positive sense single-stranded RNA envelope viruses

A dideoxy, amino technology, applied in sugar derivatives, organic chemistry, drug combinations, etc., can solve the problem of inability to identify targeted viruses

Inactive Publication Date: 2010-07-07
INST FOR HEPATITIS & VIRUS RES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, because replicons do not undergo a complete replication cycle, drug screening programs and mechanisms of action based on these assays alone may not identify targets for viral replication cycles early (virion attachment, entry, uncoating) or late (virion assembly, export) stage compound
Furthermore, it is possible that drugs that could negatively affect neomycin resistance would also inhibit viral replication of the HCV RNA replicon without affecting any viral machinery, necessitating additional screening to filter out false positives

Method used

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  • 2-amino-2,7-dideoxy-alpha-D-glycero-D-gluco-heptopyranosyl inhibitors of positive sense single-stranded RNA envelope viruses
  • 2-amino-2,7-dideoxy-alpha-D-glycero-D-gluco-heptopyranosyl inhibitors of positive sense single-stranded RNA envelope viruses
  • 2-amino-2,7-dideoxy-alpha-D-glycero-D-gluco-heptopyranosyl inhibitors of positive sense single-stranded RNA envelope viruses

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Effect test

example 1

[0085] Raw materials and methods

[0086] chemical

[0087] All cell culture supplies were obtained from Invitrogen (Carlsbad, CA, USA). All other reagents were provided by SigmaAldrich (St. Louis, MO, USA) unless otherwise stated.

[0088] cells and viruses

[0089] MDBK cells (ATCC-CCL22) were grown in Dale Burke's Modified Medium (DMEM) containing 4.5 g of Glucose 4.5 and 10% Horse Serum, or in Minimal Essential Medium (MEM) with 10% irradiated fetuses without BVDA antibodies bovine serum. Monolayers of 50 to 70% confluent cells were infected with plaque-purified cpBVDV strain NADL or ncpBVDV strain NY-1 in cell culture or in mock-infected cell culture only. The titers of cpBVDV used in our study were sufficient to generate an input multiplicity of infection (MOI) of 0.1 to 0.5. After a preliminary incubation with virus in cell culture for 1 hour (5% carbon dioxide, 37° C.), the medium has been changed to a new virus-free medium. For aminoglycoside or interferon exper...

example 2

[0101] figure 2 showed that geneticin suppresses viral load in MDBK cells infected with NADL or NY-1. Panel A shows the effect of geneticin, 6, 12 and 25 μg / ml, on active virus titers in NADL at 24, 48 and 72 hours post-infection. Panel B shows the effect of geneticin, 6, 12 and 25 μg / ml, on the active virus titer of NY-1 at 24, 48 and 72 hours post infection. Determination of virus titers according to Reed-Münch (Spector, S. and Lonz, G., 1986, Handbook of Clinical Virology, Elsevier Scientific Publishing Ltd., New York, pp.194, Snyder, M.L., Stewart, W.C., Kresser, J.1, PRV and TGE Miniaturized Neutralization Assays, 1981, Serum Miniaturized Technology, NVSL, USDA, Ames, Iowa, pp.44-45), respectively CPE or NS3 Mab 20.10.6 with NADL or NT-1. Error bars represent the standard error for each time point and indicated concentration of Geneticin (n=3).

example 3

[0103] image 3 Shows geneticin-mediated cytoprotection against NADL, compared to kanamycin and gentamicin. Panel B shows that only geneticin provided cytoprotection against NADL. All aminoglycosides used 6, 12 and 25 μg / ml. Cell viability was assessed in 96-well plates using the resazurin (Allmar blue) indicator dye (22). Quantitative analysis of dye conversion The assay was measured with a fluorescent plate reader with excitation / emission = 550 / 580 nm. Error bars show standard error for each aminoglycoside and indicated concentrations.

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Abstract

The present invention is directed to compounds, compositions and methods comprising the aminoglycoside moiety represented by Formula (II) for treating and preventing the spread of positive sense single-stranded RNA envelope viral infections. One embodiment of the present invention uses geneticin or its analogs, including 2-amino-2,7-dideoxy-alpha-D-glycero-D-gluco-heptopyranose, as the antiviral agent. The compounds, compositions and methods of the present invention are applicable to infections resulting from Hepatitis C virus, West Nile virus, Yellow Fever virus, Dengue virus, Bovine Viral Diarrhea virus, Equine Arteritis virus, and / or Sindbis virus.

Description

[0001] Cross reference to related applications [0002] This application claims priority to US Provisional Application No. 60 / 933,529, filed June 7, 2007. field of invention [0003] The present invention relates to the treatment of virus infection, specifically refers to positive sense single-stranded RNA enveloped virus infection. Background of the invention [0004] Sense single-stranded RNA enveloped viruses, eg, members of the Flaviviridae family, present health-related problems in human and animal populations. For example, hepatitis C virus (HCV) is a major cause of chronic liver disease, leading to cirrhosis and liver cancer (1). It is the major pathogenic infection of approximately 170 million individuals worldwide (1, 2). [0005] Another example of a positive-sense single-stranded RNA enveloped virus is dengue virus. Dengue virus (DV) infection encompasses a spectrum of disease caused by infection with one of four serotypes of DV (types 1-4), occurring in many t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/70
CPCC07H15/23C07D309/14A61P31/00
Inventor 亚历山大·V·贝克爱德华·J·杜博维黑兹尔·H·司徒
Owner INST FOR HEPATITIS & VIRUS RES
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