Peptide-based inhibitor of interleukin-10 or interferon-gamma signaling
Inventors
Tarasova, Nadya I. • Trinchieri, Giorgio • Young, Howard A. • Stewart, C. Andrew • Cardone, Marco A. • Perantoni, Alan O.
Assignees
US Department of Health and Human Services
Publication Number
US-9475839-B2
Publication Date
2016-10-25
Expiration Date
2031-05-11
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Abstract
A peptide or peptidomimetic comprising an amino acid sequence based on conserved regions of IL10 or IFN-gamma receptor sequences, and related compounds and compositions, as well as methods for the use thereof to inhibit cytokine signaling.
Core Innovation
The invention provides isolated or purified peptides or peptidomimetics comprising amino acid sequences based on conserved regions of IL10 or IFN-gamma receptor sequences, particularly sequences of SEQ ID NOs: 1-75 and 110 or their inverse sequences, with peptides comprising about 35 or fewer amino acid residues. These peptides and peptidomimetics inhibit cytokine signaling, including IL10 signaling or STAT3 activation and IFN-gamma signaling or STAT1 activation in cells. Methods of inhibiting these signaling pathways using such peptides and methods of treating or preventing diseases associated with cytokine signaling by administering these peptides or peptidomimetics to cells or hosts are also provided.
The problem solved by the invention arises from the crucial roles of IL10 and IFN-gamma cytokine signaling in inflammation, cancer growth, autoimmune, and infectious diseases. Aberrant IFN-gamma expression is linked to various autoimmune and autoinflammatory diseases, as well as cancers, and plays a critical role in graft-versus-host disease (GVHD), a major cause of morbidity after bone marrow transplantation. IL10 controls immune response to prevent exaggerated inflammation but also disarms innate and adaptive responses, facilitating pathogen persistence. Several viruses and pathogens exploit IL10 signaling to evade immune elimination. Current selective inhibitors of cytokine signaling are limited to antibodies, thus creating a need for selective inhibitors of IFN-gamma and IL10 signaling.
The peptides and peptidomimetics provided mimic conserved receptor intracellular domains involved in cytokine receptor signaling. They are believed to act by interfering with the formation of signaling complexes, such as the heterodimeric receptor assemblies with associated JAK kinases that lead to phosphorylation and activation of STAT proteins. The invention includes various peptides based on conserved receptor motifs that inhibit cytokine binding to receptors and STAT activation, thereby blocking downstream gene regulation and cell growth signaling associated with diseases.
Claims Coverage
The claims include two independent claims covering peptides or peptidomimetics and their therapeutic methods, focusing on IL10 signaling inhibition, with several dependent claims providing additional features.
Peptides or peptidomimetics comprising specific conserved receptor sequences
The invention covers peptides or peptidomimetics comprising amino acid sequences of any of SEQ ID NOs: 3-37, 72, and 74-75, with 35 or fewer amino acids. Specific sequence motifs are defined (e.g., SEQ ID NO: 20 as Fx2GYx5x6QTR with x5 as L; SEQ ID NO: 25 as AxGYLKQ with x as K or T; SEQ ID NO: 36 as Px2HLKEx7L where x2 is E or Q and x7 is Y or F).
Inhibition of IL10 signaling or STAT3 activation by the peptides
The peptides or peptidomimetics as defined inhibit IL10 signaling or STAT3 activation, providing a mechanism of action for therapeutic use.
Peptidomimetics comprising D-amino acids and cell-penetrating motifs
Peptides or peptidomimetics may include D-amino acids and can be further modified with cell-penetrating motifs such as protein transduction domains or fatty acids, optionally attached via a linker.
Terminal modifications of peptides
The peptides or peptidomimetics may comprise terminal modifications including acetyl or palmitoyl groups, specifically ε-palmitoyl modified lysine residues.
Pharmaceutical compositions comprising the peptides
Pharmaceutical compositions comprising the described peptides or peptidomimetics and pharmaceutically acceptable carriers are covered.
Methods of inhibiting IL10 signaling in cells and treating related diseases
Methods include introducing the peptides or peptidomimetics into cells to inhibit IL10 signaling or STAT3 activation and administering them to hosts to treat diseases associated with aberrant IL10 signaling or STAT3 activation, including infectious, inflammatory, autoimmune diseases, and cancers.
The independent claims disclose peptides or peptidomimetics based on conserved IL10 receptor sequences that inhibit IL10 signaling or STAT3 activation, as well as methods of therapeutic application. The dependent claims provide modifications enhancing stability, cell penetration, and pharmaceutical formulation, and specify treatment uses.
Stated Advantages
Selective inhibitors of IFN-gamma and IL10 signaling without relying on antibodies.
Potent inhibition of cytokine signaling pathways involved in inflammation, autoimmune diseases, infectious diseases, and cancer.
Peptides are small and modified for enhanced cell penetration and stability, facilitating therapeutic use.
Ability to inhibit STAT protein activation and downstream gene regulation, affecting cell growth and survival.
Documented Applications
Treatment or prevention of diseases associated with IL10 signaling or STAT3 activation, including infectious diseases mediated by viruses such as Epstein-Barr virus, Orf virus, or cytomegaloviruses.
Treatment of autoimmune diseases such as lupus nephritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, type I diabetes, and inflammatory bowel disease.
Treatment of cancers associated with aberrant IL10 or IFN-gamma signaling, including prostate, breast, ovarian, colon, liver, lung, stomach, renal, pancreatic, thyroid, skin cancers, lymphoma, and leukemia.
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