Fused in sarcoma (FUS) nuclear translocation inhibitors for preventing fibrosis
Inventors
POZZI, Ambra A. • CHIUSA, Manuel • Hawiger, Jack J. • Zienkiewicz, Jozef
Assignees
US Department of Veterans Affairs
Publication Number
US-12060396-B2
Publication Date
2024-08-13
Expiration Date
2034-04-11
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Abstract
Disclosed herein are compositions and methods for inhibiting collagen production mediated by the Fused in Sarcoma (FUS) ribonucleoprotein. As disclosed herein, the C terminal domain of FUS contains an uncommon nuclear localization sequence (NLS) motif called PY-NLS that binds the nuclear import receptor transportin. Phosphorylation of FUS leads to its association with transportin and nuclear translocation with consequent increased in collagen production. Therefore, disclosed herein is an isolated peptide having a transportin-binding moiety, which inhibits FUS from binding transportin, linked to a membrane translocating motif. These compositions and methods can be used to inhibit FUS-mediated collagen production, and treat fibrotic disease involving FUS-mediated collagen accumulation in kidneys and other organs displaying fibrotic diseases.
Core Innovation
The invention provides compositions and methods for inhibiting collagen production mediated by the Fused in Sarcoma (FUS) ribonucleoprotein. It is disclosed that the C terminal domain of FUS contains an uncommon nuclear localization sequence (NLS) motif called PY-NLS, which binds the nuclear import receptor transportin. Phosphorylation of FUS leads to its association with transportin and nuclear translocation, resulting in increased collagen production.
The disclosed compositions include isolated peptides comprising a transportin-binding moiety that inhibits FUS from binding transportin, linked to a membrane translocating motif. These peptides are designed to inhibit FUS-mediated collagen production and thereby treat or prevent fibrotic diseases involving FUS-mediated collagen accumulation in the kidney and other organs.
The background identifies that end stage glomerular disease, characterized by excessive collagen deposition and glomerulosclerosis, is a major cause of chronic kidney failure with limited therapeutic options. There is a need to identify key factors in the initiation or progression of glomerulosclerosis and fibrosis in other organs, with the goal of slowing or suppressing fibrotic responses. The invention addresses this problem by targeting FUS nuclear translocation which promotes collagen production, offering a potential therapeutic avenue for fibrotic diseases.
Claims Coverage
The claims disclose several inventive features centered on isolated peptides that inhibit FUS nuclear translocation by targeting transportin binding and incorporating membrane translocating motifs.
Isolated peptide inhibiting FUS binding to transportin
An isolated peptide comprising a transportin-binding moiety that inhibits Fused in Sarcoma (FUS) ribonucleoprotein from binding transportin, linked to a membrane translocating motif with a specific amino acid sequence (AAVALLPAVLLAVLAP). The transportin-binding moiety comprises a C-terminal fragment of FUS with the sequence SRGEHRQDRRERPY.
Specific peptide sequence comprising transportin-binding and membrane translocating motifs
A peptide comprising the amino acid sequence as set forth in SEQ ID NO: 9, which fuses the defined membrane translocating motif to the transportin-binding moiety, optionally including glycine and/or serine linkers for flexibility.
Linkers for joining motifs in isolated peptides
Use of glycine and/or serine linkers joining the membrane translocating motif to the transportin-binding moiety, where the linker is a polyglycine, a polyserine, or a combination thereof, to provide flexibility and proper folding.
Targeted delivery of the peptide to specific organs or cells
An agent comprising the peptide fused to an organ-specific or cell-specific homing peptide (e.g., sequences set forth in SEQ ID NO: 12, 13, 14, or 15) or containing a Fab antibody fragment that recognizes an organ- or cell-specific epitope, enabling targeted delivery.
The claims cover isolated peptides that inhibit FUS nuclear translocation by blocking binding to transportin, incorporating membrane translocating motifs for cell entry, optionally linked by flexible linkers, and further include targeting moieties for organ or cell-specific delivery.
Stated Advantages
Inhibition of FUS nuclear translocation reduces excessive collagen production implicated in fibrotic diseases.
Targeting FUS provides a novel therapeutic approach to treat fibrosis in multiple organs such as kidney, liver, and lung.
Use of peptides linked to membrane translocating motifs enhances intracellular delivery and efficacy of the inhibitory agents.
Documented Applications
Treatment and prevention of fibrotic diseases including kidney glomerulosclerosis, liver cirrhosis, pulmonary fibrosis, retroperitoneal fibrosis, and skin fibrosis (scleroderma).
Inhibition of collagen production by tumors such as fibrosarcoma or osteosarcoma.
Potential use in combination with corticosteroids, non-steroidal anti-inflammatory agents, or nuclear transport modifiers for fibrosis management.
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