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Assignees
Member
Oklahoma Medical Research FoundationFounded in 1946, this independent nonprofit biomedical research institute conducts basic, translational, and clinical research in critical areas such as heart disease, cancer, autoimmune, and neurodegenerative diseases. Its mission focuses on understanding biological mechanisms and advancing diagnostics and therapeutics. Activities include conducting clinical trials, managing a patent portfolio, commercializing biotechnologies, and supporting the biotech community. Research efforts are funded by grants and philanthropy, and the institute hosts advanced facilities, interdisciplinary research teams, and collaborations with academia and industry.
Founded in 1946, this independent nonprofit biomedical research institute conducts basic, translational, and clinical research in critical areas such as heart disease, cancer, autoimmune, and neurodegenerative diseases. Its mission focuses on understanding biological mechanisms and advancing diagnostics and therapeutics. Activities include conducting clinical trials, managing a patent portfolio, commercializing biotechnologies, and supporting the biotech community. Research efforts are funded by grants and philanthropy, and the institute hosts advanced facilities, interdisciplinary research teams, and collaborations with academia and industry.
Publication Number
US-11084852-B2
Publication Date
2021-08-10
Expiration Date
Abstract
The present disclosure describes the use peptides of comprising ubiquitin interacting motifs (UIMs) alone or in combination with other agents to treat conditions such as cancer, atherosclerosis and obesity.
Core Innovation
The invention describes a chimeric ubiquitin-interacting-motif (UIM)-containing peptide termed UPI, comprising an epsin UIM motif linked to a cyclic iRGD tumor-homing sequence and a Lyn H4 plasma-membrane anchoring peptide, synthesized with D-amino acids for stability. UPI selectively binds VEGFR2 (not EGFR/FGFR/PDGFR), competitively disrupts epsin–VEGFR2 interaction, stabilizes activated VEGFR2 at the plasma membrane, enhances VEGF signaling including increased VEGFR2 phosphorylation, PLCγ and ERK, and impairs VEGFR2 endocytosis/degradation. This induces non-productive, hyper-leaky tumor angiogenesis that inhibits tumor growth and metastasis and improves survival in multiple murine and human tumor models [procedural detail omitted for safety].
The disclosure extends modulation of epsin and UIM peptides to atherosclerosis, obesity, and metabolic regulation. Endothelial or global epsin deletion and UIM peptides reduce atherosclerotic lesions [procedural detail omitted for safety] by stabilizing IP3R1 and reducing ER stress and inflammation, and support protection against high-fat diet-induced obesity with improved insulin sensitivity. Molecular modeling and [procedural detail omitted for safety] identify key interacting residues [procedural detail omitted for safety]; a triple-mutant UPI-Mut shows reduced binding and loses therapeutic efficacy, and sequences such as SEQ ID NO:6 are disclosed.
Claims Coverage
The independent claim covers administration of a ubiquitin-interactive motif (UIM)-containing peptide comprising SEQ ID NO:6 [procedural detail omitted for safety] to achieve cardiovascular and metabolic therapeutic outcomes. The claim set includes two main inventive features.
UIM-containing peptide comprising SEQ ID NO:6
A ubiquitin-interactive motif (UIM)-containing peptide comprising SEQ ID NO:6 [procedural detail omitted for safety].
Therapeutic indications
Methods comprising administering the UIM-containing peptide to reduce the risk of myocardial infarction, treat heart disease, reduce atherosclerotic plaque rupture, reduce the risk of restenosis, inhibit atherosclerosis, reduce vascular inflammation, or reduce weight in a subject.
The independent claim covers administration of the defined UIM-containing peptide sequence to address multiple cardiovascular outcomes and weight reduction; dependent claims further refine [procedural detail omitted for safety].
Stated Advantages
Reduces primary tumor growth and metastasis and extends survival in multiple murine and human tumor models [procedural detail omitted for safety].
Minimal systemic toxicity as indicated by toxicity biomarker values.
Protects against high-fat diet-induced obesity and improves insulin sensitivity.
Reducing the risk of myocardial infarction, treating heart disease, reducing atherosclerotic plaque rupture, reducing the risk of restenosis, inhibiting atherosclerosis, reducing vascular inflammation, and reducing weight in a subject.
Documented Applications
Cancer therapy: homing to tumor endothelium and UPI-induced non-productive/hyper-leaky tumor angiogenesis to inhibit tumor growth and metastasis and improve survival in murine and human tumor models [procedural detail omitted for safety].
Cardiovascular disease therapy: reducing risk of myocardial infarction, treating heart disease, reducing atherosclerotic plaque rupture, reducing the risk of restenosis, inhibiting atherosclerosis, and reducing vascular inflammation by administration of a UIM-containing peptide (SEQ ID NO:6) [procedural detail omitted for safety].
Atherosclerosis treatment and atheroma reduction, including reduction of atherosclerotic lesions [procedural detail omitted for safety] using UIM peptides or epsin deletion.
Obesity and metabolic regulation: protection against high-fat diet-induced obesity, improvement of insulin sensitivity, and reduction of weight gain [procedural detail omitted for safety].
Combination therapy and formulation use cases [procedural detail omitted for safety].
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