Chemokine derived peptides that bind with chemokine receptor CXCR3 and uses for chronic wound and angiogenesis inhibition treatments
Inventors
Yates-Binder, Cecelia C. • Jaynes, Jesse • Turner, Timothy • Wells, Alan • Bodnar, Richard J.
Assignees
US Department of Veterans Affairs • Tuskegee University
Publication Number
US-8734775-B2
Publication Date
2014-05-27
Expiration Date
2031-08-26
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Abstract
Disclosed are peptides having activity against receptor CXCR3 are disclosed that exhibit activity in preventing the formation of new vessels and activity in mediating the dissociation of newly-formed vessels and resolving of wounds in the later stages of wound healing. Preferred peptides are derived from the α-helix portion IP-10 (CXCL10) or from IP-9 (CXCL11), are nontoxic, and smaller than naturally occurring peptides, making them useful in therapies against diseases or disease states marked by unwanted angiogenesis, including tumorogenic diseases such as cancers, and in healing of chronic wounds.
Core Innovation
The invention discloses peptides having activity against receptor CXCR3 that exhibit activity in preventing the formation of new vessels, mediating the dissociation of newly-formed vessels, and resolving wounds in the later stages of wound healing. Preferred peptides are derived from the α-helix portion of IP-10 (CXCL10) or from IP-9 (CXCL11), are nontoxic, and smaller than naturally occurring peptides, making them useful in therapies against diseases marked by unwanted angiogenesis, including tumorogenic diseases such as cancers, and in healing of chronic wounds.
The problem being solved relates to the need for improved therapeutics for inhibition of angiogenesis that are highly effective in promoting cancer remission, preventing tumor malignancy and metastases, and preventing progression of the disease to more advanced stages. Current understanding of CXCL10's mechanism was imperfect, and there was a need for small peptide agonists that activate the CXCR3-B receptor to inhibit angiogenesis and treat diseases associated with excessive angiogenesis or chronic wounds.
Claims Coverage
The independent claims of the patent describe methods and uses of peptides related to SEQ ID NO: 1 that bind and activate the chemokine receptor CXCR3 to inhibit endothelial cell motility, vessel formation, and induce vessel dissociation, particularly in the context of chronic wound treatment via topical formulations.
Method for inhibiting endothelial cell motility and vessel formation with CXCR3-activating peptide
A method comprising administering to a mammal an effective amount of a compound with a peptide at least 95% identical to SEQ ID NO: 1, wherein the peptide binds to and activates CXCR3, thereby inhibiting endothelial cell motility and vessel formation and inducing vessel dissociation.
Topical application for chronic wounds with CXCR3-activating peptide
The compound comprising the CXCR3-activating peptide is applied directly to the chronic wound in a topical formulation containing two or more CXCR3 ligand compounds in a topical carrier.
Method for mediating regression of vascular vessels to inhibit angiogenesis
Administering a compound comprising a peptide at least 95% identical to SEQ ID NO: 1 that binds and activates CXCR3 to mediate regression of vascular vessels to inhibit angiogenesis, applied to chronic wounds in a topical formulation containing multiple CXCR3 ligands.
The claims collectively cover methods of treating chronic wounds and inhibiting angiogenesis by applying peptides closely related to SEQ ID NO: 1 that specifically bind and activate CXCR3, with a focus on topical formulations containing multiple CXCR3 ligands to inhibit endothelial cell functions critical to angiogenesis.
Stated Advantages
The peptides are nontoxic and smaller than naturally occurring peptides, making them suitable for therapeutic use.
They effectively inhibit endothelial cell motility and vessel formation and induce vessel dissociation via activation of CXCR3, similar or superior to full-length IP-10.
The peptides are useful in treating diseases marked by unwanted angiogenesis, such as cancers, and in healing chronic wounds.
Documented Applications
Treatment of tumorogenic diseases including cancers such as breast and prostate cancer by inhibiting angiogenesis and preventing tumor growth and metastases.
Treatment of chronic wounds by promoting wound resolution and healing through topical application of CXCR3-activating peptides.
Use in pharmaceutical compositions administered orally, intravenously, parenterally, or topically for anti-angiogenic therapy or chronic wound treatment.
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