Method and peptide for regulating cellular activity
Inventors
Hefeneider, Steven H. • McCoy, Sharon L.
Assignees
Oregon Health and Science University • US Department of Veterans Affairs
Publication Number
US-8445449-B2
Publication Date
2013-05-21
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 present invention relates to a method and peptides derived from the vaccinia virus A52R protein for regulating cellular activity, specifically by inhibiting or enhancing cellular activity, including toll-like receptor (TLR) induced cytokine secretion. The invention identifies peptides that have biological effects on cellular activity modulation, with potential applications in reducing and/or inhibiting, or initiating and/or enhancing inflammatory responses in a subject.
The problem addressed arises from the role of TLRs in recognizing pathogen-associated molecular patterns (PAMPs) leading to intracellular signaling that triggers pro-inflammatory cytokine secretion and immune responses. Excessive or prolonged TLR activation contributes to inflammatory diseases such as otitis media with effusion (OME), sepsis, and autoimmunity, presenting a challenge for controlling inflammation initiated by bacterial or viral infections. Current treatments do not effectively address inflammation sustained by TLR activation in absence of live pathogens.
The invention overcomes this by identifying specific peptides, notably peptide P13 derived from A52R, that inhibit TLR-dependent cytokine secretion in vitro and reduce bacterial-induced inflammation in vivo, demonstrated in mouse models. The peptides act intracellularly, likely by interfering with TIR signaling upstream of IκB phosphorylation, thus selectively targeting TLR pathways to modulate inflammation without affecting non-TLR mediated cytokine secretion. A panel of peptides from A52R is characterized for both inhibitory and enhancing effects on cytokine secretion, enabling tailored regulation of immune responses.
Claims Coverage
The patent contains multiple independent claims covering isolated polypeptides and methods of inhibiting TLR-induced cytokine secretion and inflammation using specific peptides derived from vaccinia virus A52R protein.
Isolated polypeptides comprising defined A52R-derived sequences with or without cell transduction sequence
Isolated polypeptides consisting of amino acid sequences set forth as SEQ ID NO: 14, SEQ ID NO: 8, or SEQ ID NO: 6, optionally covalently linked to a nine-arginine transducing sequence (SEQ ID NO: 22), with optional fluorescent labeling.
Methods of inhibiting TLR-induced cytokine secretion in subjects
Methods involve administering effective amounts of the specified peptides (SEQ ID NO: 14, SEQ ID NO: 8, or SEQ ID NO: 6, alone or linked to the transducing sequence SEQ ID NO: 22) to subjects in need thereof, thereby inhibiting cytokine secretion triggered by TLR activation.
Methods of reducing or inhibiting TLR-induced inflammation
Methods include administering effective amounts of the peptides (as above) to reduce or inhibit inflammation induced by TLRs in subjects, specifically including bacterial-induced inflammation such as that caused by Streptococcus pneumoniae, as well as treatment of conditions like otitis media.
The independent claims collectively cover specific A52R-derived peptides with or without a cell transduction sequence, their use in pharmaceutical compositions, and their therapeutic application to inhibit TLR-activated cytokine secretion and inflammation, especially bacterial-induced inflammation in subjects.
Stated Advantages
Peptides selectively inhibit intracellular TIR signaling pathways triggered by TLR activation, thus reducing pro-inflammatory cytokine secretion without affecting non-TLR mediated cytokine secretion.
Effective inhibition of multiple TLR ligands and cytokines, including LPS, CpG-ODN, Poly(I:C), flagellin, and zymosan, demonstrating broad applicability in modulating immune responses.
Peptides reduce bacterial-induced inflammation in vivo, notably in a mouse model of otitis media with effusion, by decreasing fluid accumulation, cellular infiltration, and tissue thickening.
Peptides remain effective even when administered after TLR activation has begun, indicating potential for therapeutic intervention in ongoing inflammatory responses.
The identification of both inhibitory and enhancing peptides allows potential for targeted control of inflammatory responses depending on clinical need.
Documented Applications
Use as therapeutic agents to reduce and/or inhibit pathogen-associated inflammation, including inflammation caused by bacteria such as Streptococcus pneumoniae.
Treatment of inflammatory diseases involving TLR activation, exemplified by applications in otitis media with effusion.
Potential application in treatment of viral-induced inflammation and septic shock where TLR pathways mediate inflammatory cytokine secretion.
Use in diagnostic, therapeutic, or other applications related to cellular activity regulation via modulation of TLR-dependent signaling pathways.
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