Functional and therapeutic effects of PAR4 cleavage by cathepsin G
Inventors
Bray, Paul F. • Campbell, Robert A. • Stoller, Michelle
Assignees
University of Utah • University of Utah Research Foundation Inc
Publication Number
US-12077607-B2
Publication Date
2024-09-03
Expiration Date
2042-09-23
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Abstract
Disclosed herein are a synthetic peptide mimetic and compositions comprising the synthetic peptide mimetic that induce activation of and signaling through PAR4. Also disclosed herein are methods of treating a bleeding disorder comprising administering the synthetic peptide.
Core Innovation
The invention relates to a synthetic peptide mimetic comprising an amino acid sequence of SEQ ID NO: 1, which is designed to induce activation and signaling through Protease-Activated Receptor 4 (PAR4). The peptide mimetic is described as an 11mer PAR4 agonist peptide, shown to be a more potent activator of PAR4 compared to shorter sequences such as 10-mer, 8-mer, or 6-mer mimetics. The composition can include the peptide alone or with a pharmaceutically acceptable carrier.
The problem addressed by this invention is the need for effective therapeutic agents that can activate PAR4 and induce platelet activation, granule release, and aggregation, which are crucial for clot formation and hemostasis. This need arises particularly in the context of bleeding disorders or conditions where current therapies may be insufficient, ineffective, or have undesirable side effects. Previous studies have highlighted the importance of PAR4 over PAR1 in terms of causing sustained increases in intracellular Ca2+, which promotes thrombosis under shear stress and is implicated in both hemostatic and pathologic contexts.
The synthetic peptide mimetic of SEQ ID NO: 1 activates PAR4 by mimicking the action of cathepsin G cleavage at the PAR4 N-terminal extracellular sequence. This activation leads to PAR4-dependent calcium flux, platelet aggregation, and platelet activation. The invention further discloses methods for treating bleeding disorders through administration of this peptide, providing an approach for enhancing platelet function in conditions such as hemophilia A, hemophilia B, von Willebrand disease, thrombocytopenia, and bleeding due to qualitative platelet dysfunction or caused by factors such as liver cirrhosis, leukemia, or certain medications.
Claims Coverage
There are three main inventive features outlined in the independent claims of the patent.
Synthetic peptide mimetic for PAR4 activation
A synthetic peptide mimetic consisting of SEQ ID NO: 1 that induces activation of and signaling through PAR4. - The peptide is specifically defined by the sequence SEQ ID NO: 1. - The inventive concept is centered on this mimetic's ability to activate the PAR4 receptor pathway.
Composition comprising the synthetic peptide mimetic
A composition that includes the synthetic peptide mimetic of SEQ ID NO: 1. - The composition may consist of the peptide alone or in combination with a pharmaceutically acceptable carrier. - This feature covers formulations that deliver the PAR4-activating peptide for potential administration.
Method of treating a bleeding disorder using the peptide mimetic
A method for treating a bleeding disorder by administering a therapeutically effective amount of the synthetic peptide mimetic consisting of SEQ ID NO: 1. - The method encompasses the treatment of various bleeding disorders by inducing platelet aggregation and activation via PAR4 activation. - The treatment can be applied to bleeding disorders including hemophilia A, hemophilia B, von Willebrand disease, thrombocytopenia, and conditions caused by liver disease, leukemia, vitamin K deficiency, or specific medications.
The inventive features collectively cover the synthetic peptide for PAR4 activation, its compositions, and therapeutic methods for treating bleeding disorders by harnessing the unique properties of the SEQ ID NO: 1 peptide.
Stated Advantages
The synthetic peptide mimetic induces potent activation of PAR4, resulting in enhanced platelet activation, granule release, and aggregation.
The CatG-generated PAR4 tethered ligand (SEQ ID NO: 1) is a more potent activator of PAR4 than the thrombin-generated tethered ligand, requiring lower concentrations to induce maximal platelet aggregation.
The peptide mimetic provides a new therapeutic approach for treating bleeding disorders, especially where enhancing platelet reactivity is beneficial.
Documented Applications
Treatment of bleeding disorders, including hemophilia A (factor VIII deficiency), hemophilia B (factor IX deficiency), von Willebrand disease, thrombocytopenia, or bleeding due to qualitative platelet dysfunction.
Treatment of bleeding disorders resulting from cirrhosis of the liver, leukemia, vitamin K deficiency, or administration of aspirin, heparin, or warfarin.
Methods of inducing platelet activation or aggregation by administering the synthetic peptide mimetic to cells or subjects.
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