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Inhibition of nonsense mediated mRNA decay by drugs that prevent hypusination of eukaryotic initiation factor 5a

a technology of eukaryotic initiation factor and mrna decay, which is applied in the direction of pharmaceutical active ingredients, organic active ingredients, medical preparations, etc., can solve the problems of no biological activity, low biological activity of prematurely terminated proteins, and even harmful to biological functions

Active Publication Date: 2017-11-09
RUTGERS THE STATE UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a pharmaceutical composition that combines a hydrazaline compound and at least one other inhibitor of NMD (NMDA) at low concentrations where each ingredient alone would not inhibit NMD. This combination achieves a synergistic effect, resulting in effective inhibition of NMD. In addition, the hydrazaline compound can be combined with more than two, three, or four additional NMD inhibitors at low non-inhibitory concentrations to achieve a synergistic effect.

Problems solved by technology

Depending on the gene affected and the mutation, prematurely terminated proteins may have low biological activity, no biological activity, or may even be harmful to biological functions.

Method used

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  • Inhibition of nonsense mediated mRNA decay by drugs that prevent hypusination of eukaryotic initiation factor 5a
  • Inhibition of nonsense mediated mRNA decay by drugs that prevent hypusination of eukaryotic initiation factor 5a
  • Inhibition of nonsense mediated mRNA decay by drugs that prevent hypusination of eukaryotic initiation factor 5a

Examples

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Effect test

example 1

Prevention of Maturation of eIF5A by Inhibition of DOHH

[0177]To examine the effect of compounds on the synthesis of modified eIF5A, 293T cells transfected with a FLAG-tagged eIF5A expression vector were simultaneously treated with ciclopirox (“CPX”) or deferiprone (“DEF”).

[0178]FLAG-eIF5A was monitored using NIH-353 and anti-FLAG antibodies (FIGS. 2A and 2B). FIG. 2A illustrates inhibition of eIF5A modification in 293T cells. Cells transfected with FLAG-tagged eIF5A were untreated or treated with increasing concentrations of CPX as indicated, or with agent P2. FIG. 2B illustrates cells transfected with FLAG-tagged eIF5A that were untreated or treated with increasing concentrations of DEF as indicated, or with DFOX. At 24 hours post-transfection, whole cell extract (“WCE”) was analyzed by immunoblotting with the NIH-353 anti-eIF5A antibody (upper panel) and anti-actin antibody (lower panel). The NIH-335 antibody reacts preferentially with post-translationally modified eIF5A. CPX redu...

example 2

NMD Decreases Gene Expression at Both the RNA and Protein Levels, an Effect Relieved by Inhibitors of NMD

[0184]Human 293 cells were co-transfected with a test plasmid (construct I) that is sensitive to NMD and a matched control plasmid (construct II). The constructs contain firefly luciferase (FF) reporter genes and are based on studies in the HIV-1 system (Hoque M, Hanauske-Abel H M, Palumbo P, Saxena D, D'Alliessi Gandolfi D, Park M H, Pe'ery T, Mathews M B. Retrovirology. 2009 Oct. 13; 6:90). A plasmid expressing Renilla luciferase (Ren) directed by the CMV promoter was included as a reference and internal control. RNA was analyzed by Rnase protection assay and an autoradiograph of the results is shown. More FF RNA was generated from the NMD-insensitive construct pLTRAintron (construct II) than from the NMD-sensitive construct pGL2TAR (construct I) (FIG. 4A). Similar observations were made at the protein level. Luciferase proteins were analyzed by dual luciferase assay kit (Prome...

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PUM

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Abstract

Provided are methods for treating a NAD comprising administering to a patient suffering from a NAD an inhibitor of NMD and a nonsense suppressor, whereby degradation of NMD susceptible mRNA is decreased and translation termination at a misplaced nonsense codon is blocked.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]The instant application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 61 / 496,378, filed Jun. 13, 2012, and is also a continuation-in-part of U.S. application Ser. No. 12 / 840,270, filed Jul. 20, 2010, which claims 35 U.S.C. §119(e) priority to U.S. Provisional Application No. 61 / 271,409, filed Jul. 20, 2009, all of which are incorporated by reference in their entirety.FIELD OF THE INVENTION[0002]The present invention relates to methods of treating nonsense-associated diseases and inhibiting nonsense-mediated mRNA decay by administering an inhibitor of NMD and a nonsense suppressor.BACKGROUND OF THE INVENTION[0003]Nonsense-mediated decay (“NMD”) is a cellular mechanism that selectively degrades faulty messenger RNA (“mRNA”) containing an out-of-place stop (nonsense) codon. If translated, such mRNAs would produce a shortened version of the encoded protein. The NMD surveillance mechanism reduces or prevents the f...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/7105A61K31/4418A61K31/7036A61K31/7048A61K31/4412A61K31/5025A61K45/06A61K31/7064A61K31/4375A61K31/502
CPCA61K31/7105A61K31/4375A61K31/4418A61K31/7036A61K31/502A61K31/4412A61K31/5025A61K45/06A61K31/7064A61K31/7048
Inventor PE'ERY, TSAFIMATHEWS, MICHAEL B.HOQUE, MAINULHANAUSKE-ABEL, HARTMUT M.
Owner RUTGERS THE STATE UNIV
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