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NF-kappaB oligonucleotide decoy molecules

a technology of oligonucleotide decoy and kappab, which is applied in the direction of sugar derivatives, antibacterial agents, organic active ingredients, etc., can solve the problems of prolonging the survival of allografts and reducing the coronary artery disease of grafts, and achieves the effect of potent inhibitors of nf-b activity and negative gene transcription regulation

Inactive Publication Date: 2007-01-11
MCEVOY LESLIE M +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0011] The present invention concerns double-stranded NF-κB decoy oligodeoxynucleotide (NF-κB dsODN) molecules that contain a core sequence capable of specific binding to an NF-κB transcription factor. In a particular aspect, the invention concerns NF-κB decoy molecules that preferentially bind p50 / p65 and / or cRel / p50 heterodimers over p50 / p50 homodimers when p50 / p50 homodimers are present. The selective decoy molecules of the invention, by not blocking p50 / p50 homodimers, allow these homodimers to block the promoters of NF-κB regulated genes, which provides an additional level of negative regulation of gene transcription. As a result, the selective NF-κB decoy molecules are particularly potent inhibitors of NF-κB activity both in vitro and in vivo.
[0017] In another aspect, the present invention concerns NF-κB dsODN molecules that have a specificity / affinity factor of at least about 25, or at least about 30, or at least about 35, or at least about 40, or at least about 50 or at least about 60, or at least about 70, or at least about 80. In a preferred embodiment, the decoy molecules of the invention additionally show increased binding affinity to the p50 / p65 heterodimers and / or have improved stability in vivo.

Problems solved by technology

The greater inhibition of reperfusion injury, acute, and chronic rejection after transplantation results in a prolongation of allograft survival and decrease in graft coronary artery disease.

Method used

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Examples

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example 1

[0179] Design and Testing of NF-κB Decoy Molecules

[0180] Design

[0181] NF-κB dsODN decoy molecules were designed and tested for their ability to bind and / or compete for binding of NF-κB. In a particular aspect, the goal of the invention was to design NF-κB decoy molecules that preferentially bind p65 / p50 and / or cRel / p50 heterodimers over p50 / p50 homodimers. As a result of not blocking p50 / p50 homodimers, the selective decoy molecules of the invention allow these homodimers to block the promoters of NF-κB regulated genes, which provides an additional level of negative regulation of gene transcription.

[0182] In designing the oligonucleotide decoys, information available from crystal structure studies and computational analysis of the known NF-κB binding sites were utilized.

[0183] As discussed above, based on study of the crystal structure of the p50 / p65 heterodimer bound to the immunoglobulin light-chain gene, which contains the consensus sequence of 5′-GGGACTTTCC-3′ (SEQ ID NO: 2)...

example 2

[0218] NF-κB Decoy Molecules Comprising a Nuclear Localization Signal

[0219] In order to determine the ability of a nuclear localization signal (NLS) containing peptide to improve the entry of an oligonucleotide decoy into the nucleus, a peptide with the NLS sequence based on the simian virus 40 large tumor antigen (PKKKRKVEDPYC) (SEQ ID NO: 93) was synthesized by Sigma Genosys and conjugated to the NF-κB 153 H3 oligonucleotide as follows. Briefly, 6.5 nmols of oligonucleotide was first incubated with 40-fold molar excess of the linker Sulfo-SMCC (Pierce) at room temperature for 2 hours. After removal of excess linker from the reaction by a NAP-10 column (Pharmacia Biotech), the activated oligonucleotide was incubated with 5-fold molar excess of the NLS peptide at room temperature overnight. To assess the percentage of oligonucleotide successfully conjugated to the NLS peptide, the reaction was analyzed by loading 1 μl onto a 20% PAGE gel (non-denaturing). The gel was stained with S...

example 3

[0221] NF-κB Decoy Reduces Ear Swelling in Murine Atopic Dermatitis

[0222] To determine the efficacy and effective dose range of NF-kB decoy in Dustmite Ag (Dp) induced contact dermatitis in NC / Nga mice.

[0223] Method

[0224] Dp Ag induced dermatitis was induced as previously described (Sasakawa, T et al., Int Arch Allergy Immunol 126:239-47 (2001); Sasakawa et al., Int Arch Allergy Immunol 133:55-63 (2004)). Briefly, Six week old male NC / Nga mice were injected intradermally with 5 μg of Dp extract (Greer Laboratories, Lenoir, N.C.) dissolved in saline on the ventral side of their right ears on days 0, 2, 4, 7, 9, and 11. Starting on day 11, the DP injected ear was topically treated 2 times a day for 10-12 days with 20 μl of vehicle, vehicle containing 0.25% or 0.1 % NF-κB decoy or betamethasone as a control. The ear thickness was measured with an ear thickness gauge (Oditest, Dyer, Inc., Lancaster, Pa.) 24 hr after each intradermal injection or treatment.

[0225] Results

[0226] To ex...

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Abstract

The present invention concerns double-stranded NF-κB decoy oligodeoxynucleotide (NF-κB dsODN) molecules that contain a core sequence capable of specific binding to an NF-κB transcription factor. In a particular aspect, the invention concerns NF-κB decoy molecules that preferentially bind p50 / p65 and / or cRel / p50 heterodimers over p50 / p50 homodimers. In another aspect, the invention concerns NF-κB decoy molecules with improved binding affinity to p65.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation application of copending U.S. application Ser. No. 11 / 368,060 filed on Mar. 3, 2006, which is a continuation-in-part of U.S. application Ser. No. 11 / 004,512 filed on Dec. 2, 2004, which claims priority under 35 U.S.C. § 119(e)(1) of U.S. provisional patent application Ser. No. 60 / 526,623, filed on Dec. 2, 2003, and U.S. Provisional patent application Ser. No. 60 / 612,029, filed on Sep. 21, 2004, the entire disclosures of which are hereby expressly incorporated by reference.BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention [0003] The present invention concerns NF-κB oligonucleotide decoy molecules, and their use in the treatment of various NF-κB related diseases and pathological conditions. [0004] 2. Description of the Related Art [0005] NF-κB is a family of inducible dimeric transcription factors composed of members of the Rel family of DNA-binding proteins that recognize a common sequence mo...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K48/00A61K9/127C07H21/04C12N15/113C12N15/115
CPCC12N15/113C12N15/115C12N2310/53C12N2310/315C12N2310/345C12N2310/13A61P1/00A61P1/04A61P1/16A61P11/00A61P11/06A61P11/08A61P13/12A61P17/00A61P17/02A61P17/04A61P17/06A61P17/12A61P19/02A61P19/06A61P19/08A61P21/00A61P25/00A61P25/02A61P25/28A61P27/02A61P29/00A61P31/04A61P35/00A61P37/02A61P37/06A61P37/08A61P43/00A61P7/08A61P9/00A61P9/02A61P9/04A61P9/10A61P9/12A61P3/10
Inventor MCEVOY, LESLIE M.PARHAM, CHRISTIZHANG, JIEEHRHARDT, ROLF
Owner MCEVOY LESLIE M
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