Immunomodulator has amino acid sequence; used as therapy to reduce, inhibit, initiate, or enhance an inflammatory response; antiinflammatory agents treating the inflammation of middle ear caused by fluid accumulation; biodrugs derived from the vaccinia virus A52R protein
Inventors
Hefeneider, Steven H. • McCoy, Sharon L.
Assignees
Oregon Health and Science University • US Department of Veterans Affairs
Publication Number
US-7192930-B2
Publication Date
2007-03-20
Expiration Date
2025-07-12
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Abstract
Method and peptide for regulating cellular activity includes a panel of synthesized peptides that have biological effects on inhibiting or enhancing cellular activity. Selected peptides can be used as therapy to reduce and/or inhibit, or initiate and/or enhance, an inflammatory response in a subject.
Core Innovation
The invention relates to a method and peptides derived from the vaccinia virus A52R protein that regulate cellular activity by inhibiting or enhancing toll-like receptor (TLR) induced cytokine secretion in cells. The identified peptides have biological effects on cellular activity and can be used to modulate inflammatory responses in subjects. One specific peptide sequence, DIVKLTVYDCI (SEQ ID NO: 13), linked to a 9-arginine cell transduction sequence, effectively inhibits cytokine secretion triggered by multiple TLR ligands.
The background identifies a problem in controlling inflammation caused by TLR activation, which is implicated in chronic inflammatory diseases such as otitis media with effusion (OME). Current treatments face challenges in reducing prolonged inflammation initiated by bacterial or viral infections, especially when inflammation persists despite antibiotic treatment. The invention aims to provide therapeutic agents that target TLR-dependent intracellular signaling to reduce or modulate inflammation.
The invention addresses the need for agents that can selectively inhibit or enhance TLR-induced cytokine secretion. The peptides obtained from the vaccinia virus A52R protein effectively inhibit TLR signaling pathways, demonstrated both in vitro and in vivo. This regulation reduces inflammation exemplified by significant reduction of middle ear inflammation in a mouse model of bacterial-induced OME and decreases pro-inflammatory mediators in a septic shock model. Additional peptides from the A52R protein can also enhance cytokine secretion, broadening the therapeutic potential.
Claims Coverage
The claims include three independent claims covering specific peptides and compositions derived from the A52R protein. The main inventive features encompass peptides with defined amino acid sequences and their biological activity regarding inflammation and cytokine signaling.
Peptide consisting of amino acid sequence SEQ ID NO: 13
A synthesized peptide consisting solely of the amino acid sequence set forth in SEQ ID NO: 13, which is identified as a key immunoregulatory sequence derived from the vaccinia virus A52R protein.
Immunoregulatory peptide with specific amino acid sequence
An immunoregulatory peptide comprising the amino acid sequence set forth in SEQ ID NO: 13, which affects inflammatory response and cellular signaling in a subject.
Pharmaceutical composition including peptide SEQ ID NO: 13
A pharmaceutical composition that comprises the peptide having the amino acid sequence of SEQ ID NO: 13, intended for therapeutic use.
Peptide affecting inflammatory response in a subject
The peptide of SEQ ID NO: 13 has the functional ability to affect the inflammatory response within a subject.
Peptide affecting inflammatory cell signaling
The peptide of SEQ ID NO: 13 modulates signaling pathways within inflammatory cells, notably cytokine secretion induced by TLR activation.
Peptide comprising sequence SEQ ID NO: 20
A synthesized peptide comprising the amino acid sequence set forth in SEQ ID NO: 20, which includes the immunoregulatory sequence linked to a cell transduction domain for internalization.
The claims protect synthesized peptides derived from the vaccinia virus A52R protein, particularly sequences SEQ ID NO: 13 and SEQ ID NO: 20, as well as pharmaceutical compositions containing them, focusing on their immunoregulatory functions affecting inflammation and cellular signaling.
Stated Advantages
The peptides selectively inhibit TLR-dependent cytokine secretion, reducing inflammatory responses related to bacterial and viral infections.
They effectively reduce in vivo inflammation, demonstrated by significant reduction of middle ear inflammation in a mouse model of otitis media with effusion.
The peptides retain function even when administered after initiation of TLR activation, suggesting utility as therapeutic agents for ongoing inflammation.
By targeting a common signaling component upstream of IκB phosphorylation, these peptides can inhibit multiple TLR-dependent responses, potentially offering broad anti-inflammatory effects.
Documented Applications
Therapeutic use in reducing or inhibiting inflammation caused by bacterial and viral pathogen-associated molecular patterns, including treatment of otitis media with effusion.
Use in reducing fluid accumulation and mucosal hypertrophy in the middle ear of subjects.
Potential application in treating chronic inflammation initiated by bacterial or viral infections.
Use as immunoregulatory agents to either inhibit or enhance cytokine secretion in immune cells.
Pharmaceutical application in compositions comprising the peptides for administration to subjects in need thereof.
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