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Inhibitor of RNA polymerase ii

a technology of rna polymerase and inhibitor, which is applied in the field of inhibitors of rna polymerase ii to achieve the effect of reducing the expression of proteins and increasing the phosphorylation of host pol ii

Inactive Publication Date: 2019-08-08
SELECTIMMUNE PHARM AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes the identification of two closely related genes, NlpD and SN25, in a strain of E. coli. These genes are involved in the inhibition of a host protein called AmiC, which is involved in cell wall hydrolase activation and bacterial growth. Mutations in NlpD have been found to change bacterial morphology and activate other host proteases. The patent also discusses the potential mechanisms of amidase activation by LytM factors and the regulation of rpoS and rpoS-dependent genes. Ultimately, the patent suggests that disruption of the pre-initiation complex by Sigma S may affect downstream transcriptional activity.

Problems solved by technology

However, as a broad spectrum suppressor of protein expression, Pol-II inhibitors may find application in any therapy where host protein is over-expressed or problematic.

Method used

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Examples

Experimental program
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Effect test

example 2

Identification of an ABU 83972 Variant SN25 with Loss of Pol II Inhibitory Activity and its Genome Sequencing

[0057]Patients were inoculated with therapeutic doses of ABU 83972. The protocol for therapeutic bladder inoculation of patients with E. coli 83972 has been described previously (Agace, J Clin Invest, 1993; Wullt, Mol Microbiol, 2000; Sunden, J Urol, 2010). Briefly, after antibiotic treatment to remove prior infection, patients were inoculated with E. coli 83972 through a catheter (30 ml, 105 cfu / ml in saline). Blood and urine samples were obtained before and repeatedly after inoculation. Throughout the colonization period, viable bacterial counts in urine were determined, monthly urine samples were collected and analyzed for IL-6 and IL-8 as well as neutrophil infiltration. Bacteria from each urine sample were verified by PCR for presence of a kryptic plasmid unique for strain 83972 and one chromosomal marker (4.7-kb deletion in strain 83972 in the type 1 fimbrial gene clust...

example 3

Screening of Single-Gene Mutants to Identify Genes Responsible for Pol II Inhibition

[0060]To identify genetic determinants of Pol II phosphorylation, genes comprising the identified variant sequences were replaced in E. coli 83972 chromosome by homologous recombination with chloramphenicol resistance cassette. Deletions were validated (Uli). The mutants were subsequently screened for effects on Pol II (FIG. 3A). Single deletions of ΔlldD, ΔlldR, ΔnlpD, ΔrfaH and ΔcysE reduced the inhibitory effect of E. coli 83972 wt, as shown by flow cytometry and confocal microscopy (FIG. 3B-C). Statistical difference in level of Pol II phosphorylation was measured with t test.

[0061]The lldD gene is responsible for aerobic L-lactate metabolism, whose product catalyzes the interconversion of L-lactate and pyruvate, while lldR is a regulator of the lldPRD operon. It was concluded from these data that products of both lldD and lldR genes are responsible for suppression of RNA Polymerase II phosphoryl...

example 4

Secretion of Bacterial Inhibitors of Pol II Phosphorylation

[0063]In parallel with the genetic studies, a biochemical approach was taken to identify the compound responsible for the Pol II inhibitory activity. Bacteria were incubated for 4 hours in tissue culture medium (RPMI supplemented with 1 mM pyruvate). The medium was harvested after 4 hours, centrifuged at 4,000×g for 10 min and sterile filtered to remove remaining bacteria (0.2 μm filter), before addition to human kidney cells (FIG. 3D). E. coli are typically 2 μm long and 0.5 μm in diameter, and filtration through 0.2 μm syringe filters removes bacterial cells. Significant Pol II inhibitory activity (p=0.023) was identified in the ABU culture supernatants compared to uninfected, substituted RPMI, suggesting that growth in cell-free culture medium induced the secretion of the inhibitor(s).

[0064]As it was shown that supernatant of ABU bacteria have similar inhibitory effect on Pol II as ABU bacteria per se, we questioned if th...

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Abstract

An inhibitor of RNA polymerase II is described, wherein said inhibitor is selected a moiety which targets a protein selected from cyclin kinase 12 (CDK12) or its recruiting protein PAF1C. Particular examples of such inhibitors are polypeptides expressed by a gene selected from lldD, lldR, nlpD or rfaH of a bacterial species, such as a commensal bacteria or asymptomatic carrier, or a variant of said protein. Inhibitors may be based upon bacterial Sigma S or NplD proteins. These inhibitors are useful in therapies, to suppress protein expression. Thus they may be used as immunosuppressants, anti-inflammatory or anti-infection agents.

Description

[0001]The present invention relates to factors and moieties that can modulate host protein expression, for example, a factor having immunosuppressant activity, to methods of preparing the factors and moieties and to their use in therapy.BACKGROUND TO THE INVENTION[0002]The multi-subunit RNA polymerase II complex (Pol II) is essential for protein expression in eukaryotes. Transcription cycle has been extensively characterized to show that around 10% of all expressed genes are involved in transcriptional regulation, assembly and control of the Pol II complex. In eukaryotic cells, RNA polymerase II catalyzes the synthesis of mRNA and small nuclear RNA. Pol II transcription cycle consists of several stages, termed preinitiation, initiation, promoter clearance, during which Pol II pauses at the promoter proximal site, followed by escape from pausing, productive elongation and termination.[0003]For specificity, the assembly of Pol II is tightly controlled and the efficiency of transcripti...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/16A61K38/44
CPCA61K38/164A61K38/443A61K35/74G01N33/573G01N2333/91255A61P13/00A61P13/02Y02A50/30
Inventor SVANBORG, CATHARINAFILENKO, NINAAMBITE, INES
Owner SELECTIMMUNE PHARM AB
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