Small peptide compositions and uses thereof
Inventors
Yates-Binder, Cecelia C. • Jaynes, Jesse
Assignees
University of North Carolina at Chapel Hill • University of Pittsburgh • US Department of Veterans Affairs • Tuskegee University
Publication Number
US-11338017-B2
Publication Date
2022-05-24
Expiration Date
2039-03-29
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Interferon-γ-inducible protein 10 (IP-10) peptides, IP-10 peptide variants and in silico designed C-X-C chemokine receptor 3 (CXCR3) peptide agonists are described. The small peptides can be used for inhibiting pathological tissue remodeling and treating fibrosis in a subject, such as a subject with fibrosis of the heart, lung, liver, kidney or skin. The peptide agonists can also be used to treat cardiovascular disease, including myocardial infarction and ischemia-reperfusion injury. Also described are in silico designed peptide antagonists that bind CXCR3 or ligands of CXCR3. These antagonist peptides block CXCR3 signaling by disrupting interaction of CXCR3 with its ligand. Antagonist peptides can be used, for example, to treat myocarditis and atherosclerosis. In additional embodiments agonists and antagonists of CXCR4 are disclosed.
Core Innovation
The invention describes interferon-γ-inducible protein 10 (IP-10) peptides, IP-10 peptide variants, and in silico designed C-X-C chemokine receptor 3 (CXCR3) small peptide agonists and antagonists that modulate CXCR3 signaling. These synthetic peptides, typically 12 to 30 amino acids in length, can be used for inhibiting pathological tissue remodeling and treating fibrosis in various tissues such as heart, lung, liver, kidney, and skin. The peptides also have therapeutic potential for treating cardiovascular diseases including myocardial infarction and ischemia-reperfusion injury.
Additionally, antagonist peptides that bind to CXCR3 or its ligands disrupt CXCR3 signaling by blocking interaction between CXCR3 and its ligands. These antagonist peptides have potential use in treating myocarditis and atherosclerosis. The disclosure also includes synthetic peptides that act as agonists or antagonists of related chemokine receptor CXCR4, providing further therapeutic options.
The problem addressed arises from the background where pathological fibrosis and adverse tissue remodeling following myocardial infarction contribute to heart failure and increased mortality. Existing treatments inadequately prevent fibrosis and tissue stiffening. Furthermore, cardiovascular diseases, myocarditis, and atherosclerosis lack targeted therapies that effectively modulate chemokine receptor signaling to mitigate pathological inflammation, fibrosis, and tissue remodeling. Thus, there is a need for novel peptides that can selectively modulate CXCR3 and CXCR4 signaling pathways to treat these conditions.
Claims Coverage
The patent contains multiple independent claims covering synthetic peptides and compositions with specific amino acid sequences, as well as nucleic acids and vectors encoding these peptides, with a focus on agonists and antagonists of CXCR3 signaling.
Synthetic peptides antagonizing CXCR3 signaling
Synthetic peptides 12 to 30 amino acids in length comprising at least 12 consecutive amino acids of SEQ ID NOs: 5-24 and 28-29 that antagonize CXCR3 signaling by binding CXCR3 or its ligands to inhibit receptor activation.
Synthetic peptides agonizing CXCR3 signaling
Synthetic peptides 12 to 30 amino acids in length comprising at least 12 consecutive amino acids of SEQ ID NOs: 7, 9, 14, 17, 19 and 35-42 that act as agonists of CXCR3 signaling to enhance receptor activity.
Synthetic peptides comprising sequences of SEQ ID NOs: 5-42
Synthetic peptides that include or consist of the amino acid sequences of SEQ ID NOs: 5-42 functioning either as agonists or antagonists of CXCR3 signaling.
Pharmaceutical compositions comprising synthetic peptides
Compositions containing one or more of the synthetic peptides and a pharmaceutically acceptable carrier, optionally including peptides from SEQ ID NOs: 1-4.
Nucleic acid molecules and vectors encoding synthetic peptides
Isolated nucleic acid molecules encoding the synthetic peptides, operably linked to promoters, and vectors, including viral vectors, comprising these nucleic acids for expression of the peptides.
The claims collectively cover synthetic peptides that function as CXCR3 agonists or antagonists, pharmaceutical compositions comprising these peptides, and nucleic acid molecules and vectors encoding them, providing comprehensive protection for peptides designed to modulate CXCR3 signaling for therapeutic use.
Stated Advantages
The peptides inhibit pathological tissue remodeling and fibrosis, including cardiac fibrosis, which may reduce incidence or severity of heart failure.
The agonist peptides promote CXCR3 signaling to treat cardiovascular diseases, myocardial infarction, and ischemia-reperfusion injury.
The antagonist peptides disrupt CXCR3 signaling to provide therapeutic effects in myocarditis and atherosclerosis.
The peptides provide multiple mechanisms including inhibition of TGFβ-induced myofibroblast activation, migration, and extracellular matrix production.
Peptides can be chemically modified or combined in compositions tailored for specific therapeutic needs, enabling personalized medicine.
Documented Applications
Treatment and inhibition of fibrosis in subjects, including fibrosis of heart, lung, liver, kidney, or skin.
Treatment of cardiovascular diseases such as myocardial infarction, ischemia-reperfusion injury, heart failure, coronary artery disease, and aortic aneurysm.
Treatment of myocarditis and atherosclerosis by inhibiting CXCR3 signaling pathways.
Inhibition of CXCR3 signaling in vitro and in vivo to modulate cellular responses related to fibrosis and cardiovascular disease.
Interested in licensing this patent?