Peptide-based stat inhibitor
Inventors
Tarasova, Nadya I. • Timofeeva, Olga • Gaponenko, Vadim • Michejda, Christopher J. • Perantoni, Alan O. • Tarasov, Sergey G.
Assignees
US Department of Health and Human Services
Publication Number
US-9540427-B2
Publication Date
2017-01-10
Expiration Date
2028-05-30
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Abstract
A peptide or peptidomimetic comprising the amino acid sequence of the second helix of a STAT protein, or a variant of such sequence, wherein the peptide or peptidomimetic comprises about 40 or fewer amino acids and binds to a STAT protein, as well as a method of inhibiting a STAT protein in a cell, a method of treating or preventing a disease associated with STAT overexpression in a host, and related compounds, compositions, and methods.
Core Innovation
The invention provides an isolated peptide or peptidomimetic comprising the amino acid sequence of the second helix of a STAT protein, or a variant of such sequence, which is about 40 or fewer amino acids in length and binds to a STAT protein. This peptide or peptidomimetic inhibits one or more activities of STAT proteins, especially those involving the N-terminal domain. The invention also includes cells comprising the peptide or peptidomimetic, nucleic acids encoding the sequence, antibodies binding the peptide, and methods of inhibiting STAT proteins in cells by introducing the peptide or peptidomimetic.
The background identifies that aberrant activation of STAT proteins, especially STAT3, is frequent in many tumors including lymphomas, leukemias, and various solid cancers. Conventional STAT inhibitors mainly target upstream kinases, but there remains a desire for direct inhibitors of STAT proteins with greater selectivity. The invention addresses this need by providing peptides that directly bind STAT proteins to inhibit their function.
The peptide comprises approximately 12 residues corresponding to the second helix of STAT proteins' N-terminal domain, located roughly from residue 11 to residue 22. By binding to the N-terminal domain, the peptide inhibits critical functions such as STAT-STAT dimerization, tetramerization on DNA, interaction with cofactors, receptor binding, and nuclear translocation. This inhibition reduces STAT-regulated gene expression, thereby suppressing tumor cell growth and survival related to STAT overexpression.
Claims Coverage
The claims describe multiple inventive features primarily related to isolated peptides or peptidomimetics of 40 or fewer amino acids that bind to STAT proteins, including specific sequences and modifications, as well as pharmaceutical compositions containing such peptides.
Isolated peptide or peptidomimetic binding STAT proteins
An isolated peptide or peptidomimetic of 40 or fewer amino acids that binds to a STAT protein, comprising at least one of the following: (a) amino acid sequences of SEQ ID NOs: 32-34 or their reverse sequences, optionally cyclized; (b) the amino acid sequence Tyr Leu Xaa4 Gln Xaa3 Gln Xaa2 Leu Ala Xaa1 Gly Gln (SEQ ID NO: 66) with specified amino acid options at positions Xaa1 to Xaa4; or (c) the amino acid sequence of SEQ ID NO: 11 or 38.
Use of D-amino acids in peptide or peptidomimetic sequences
The peptide or peptidomimetic may comprise D-amino acids, including retro-inverso or inverse sequence versions of defined sequences, enhancing stability or activity.
Inclusion of cell-penetrating motifs
The peptide or peptidomimetic can be further modified to include a cell-penetrating motif such as a protein transduction domain or fatty acid, optionally attached via a linker sequence, to facilitate cellular uptake.
Cyclization of peptide sequences
Certain peptide sequences (SEQ ID NOs: 32-34) can be cyclized via interactions between specific cysteine and lysine residues to enhance stability or function.
Pharmaceutical compositions
Pharmaceutical compositions comprising the peptide or peptidomimetic and a pharmaceutically acceptable carrier, optionally further comprising one or more active agents or drugs, such as anticancer agents, are claimed.
Binding specificity to STAT N-terminal domain
The peptides or peptidomimetics are characterized by their binding specifically to the N-terminal domain of a STAT protein, thereby inhibiting its function.
The claims cover isolated peptides or peptidomimetics of defined sequences and variants that bind to STAT proteins, optionally containing D-amino acids, cell-penetrating motifs, and cyclization, and compositions thereof for inhibiting STAT activity with pharmaceutical applications.
Stated Advantages
The peptides and peptidomimetics directly inhibit STAT protein function with greater selectivity than upstream kinase inhibitors.
Peptides of about 40 or fewer amino acids facilitate cell entry and effective targeting of STAT activities related to tumor growth and progression.
The inhibitors can specifically target the N-terminal domain of STAT proteins without affecting phosphorylation levels, allowing selective interference with transcriptional activity.
The peptides induce cancer cell death and inhibit proliferation, with reduced toxicity toward normal cells, supporting an improved therapeutic index.
Documented Applications
Treatment or prevention of diseases associated with STAT overexpression, including various blood malignancies and solid tumors such as lymphomas, leukemias, breast, prostate, lung, head and neck, brain, and colon cancers.
Use as research tools to inhibit STAT protein activity in cells to study STAT function and regulation.
Screening assays to identify STAT inhibitors by detecting binding interactions between STAT proteins, peptides, and test compounds.
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