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Inhibitors of inflammatory cytokine transcription derived from hcmv protein IE2

A technology of human cytomegalovirus and cytomegalovirus, which is applied in the treatment of inflammation and inflammatory diseases, and can solve the problems of side effects and high production costs

Inactive Publication Date: 2008-12-03
UNIVERSITY OF PITTSBURGH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because many anti-inflammatory drugs are only short-lived, often have severe side effects (eg, glucocorticoids), and / or are expensive to produce (eg, monoclonal antibodies), there is a need for new therapeutic agents

Method used

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  • Inhibitors of inflammatory cytokine transcription derived from hcmv protein IE2
  • Inhibitors of inflammatory cytokine transcription derived from hcmv protein IE2
  • Inhibitors of inflammatory cytokine transcription derived from hcmv protein IE2

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0100] IE2 fragments inhibit Spi-1 function on IL-1β

[0101] The functional inhibition of Spi-1 on IL-1β promoter by IE2 291-364 was detected by gene reporter assay. In this system, the IL-1β promoter is cut in front of the firefly luciferase reporter gene. When this promoter is activated by Spi-1, the cells will produce firefly luciferase. This enzyme activity is measured by how the cells light up. This general technique was employed because it is an easier and more sensitive method of measuring promoter function than gene products such as IL-1[beta].

[0102] When Spi-1 and C / EBPβ were transfected into HeLa-S3 cells, the reporter showed a titratable response (Fig. 1B and C). However, when full-length wild-type IE2 was added to the transfection of cells, the activity of the gene was increased by 4-10 fold (Fig. 1D). This demonstrates the efficacy of IE2. However, if the inhibitor peptide was added dropwise, the activity of the reporter was reduced both in the absence ...

Embodiment 2

[0106] IE2 Fragment Expression in Transfection Assay

[0107] In order to verify the IE2 fragments expressed in the transfection experiments, these fragments were inserted into the GFP expression vector to detect whether they were localized in the nucleus ( Figure 4A ). The results indicate the expression of the protein and the function of the putative nuclear localization sequence located in the IE2 fragment.

[0108] 24 hours after transfection, GFP 291-364 fragments were found in both cytoplasm and nucleus. The GFP 291-364 fragment inhibits the endogenous transactivation of the HT reporter gene by Spi-1 and C / EBPβ. To control transfection efficiency, GFP-expressing cells were first purified by FACS. Equal numbers of cells were then used to prepare lysates for reporter assays. These data show that both GFP fusion products retain the dominant negative function ( Figure 4B ). This function is specific to the inserted IE2 fragment, since the reporter gene activity was...

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Abstract

The present invention provides novel inhibitors of inflammation and methods for treating inflammation by using these inhibitors. More specifically, the present invention provides transcription inhibitors, i.e., peptide fragments derived from internal regions of the Cytomegalovirus (CMV) IE2 protein that can inhibit production of inflammatory cytokines, e.g., Interleukin 1 beta (IFN-l beta) and the methods for treating inflammatory diseases and CMV infection and related disorders, by using the IE2 fragments. An pharmaceutical composition comprising the transcription inhibitor are also provided.

Description

[0001] related application [0002] This application claims priority to US Provisional Patent Application Serial No. 60 / 721.769, filed September 29, 2005, the expression of which is incorporated herein. field of invention [0003] The present invention relates at least in part to novel inhibitors of inflammation and methods of using these inhibitors to treat inflammation. More specifically, the present invention relates to peptide fragments derived from cytomegalovirus (CMV) IE2 protein capable of inhibiting the production of inflammatory cytokines interleukin 1β (IL-1β) and other inflammatory cytokines, DNA encoding these peptides, peptide mimetics Drugs and small molecules, and methods of administering such peptide fragments to treat inflammatory diseases. Background of the invention [0004] Inflammation is a complex process characterized by a series of histological changes mediated by different forms of tissue injury, including bodily and infectious injuries. The defen...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/00
CPCA61K38/16A61P1/00A61P1/02A61P1/04A61P11/06A61P11/08A61P17/00A61P17/06A61P19/02A61P25/00A61P25/18A61P27/06A61P29/00A61P3/04A61P31/00A61P31/12A61P31/20A61P35/00A61P35/04A61P37/02A61P37/06A61P37/08A61P43/00A61P7/02A61P7/04A61P9/10A61K38/00
Inventor P·E·奥隆J·李斯特曼
Owner UNIVERSITY OF PITTSBURGH
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