Cyclic polypeptides for PCSK9 inhibition
Inventors
Ricardo, Alonso • Boyer, Nicolas Cedric • Stringer, Joseph R. • LaPlaca, Derek M. • Jette, Kelli • Sun, Yili
Assignees
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Publication Number
US-11814445-B2
Publication Date
2023-11-14
Expiration Date
Abstract
Provided herein are cyclic polypeptide compounds that can, e.g., bind specifically to human proprotein convertase subtilisin/kexin type 9 (PCSK9) and optionally also inhibit interaction between human PCSK9 and human low density lipoprotein receptor (LDLR), and pharmaceutical compositions comprising one or more of these compounds. Also provided are methods of reducing LDL cholesterol level in a subject in need thereof that include administering to the subject one or more of the cyclic polypeptide compounds or a pharmaceutical composition provided herein.
Core Innovation
The invention provides cyclic polypeptide compounds of Formula (I), including specific cyclic peptides, stereochemical and isomeric forms, isotopically labeled variants, tautomers, racemic, optically active, regioisomeric, and stereoisomeric forms, together with pharmaceutically acceptable salts. The compounds are described with variable side-chain selections, including substituents R1 through R5, A1, A2, and P1, and specified amino-acid side-chain options and N-methylated amino acid residues.
The disclosed cyclic peptide compounds inhibit PCSK9 activity and inhibit PCSK9/LDLR EGF-A interaction. Binding interactions are characterized with TR-FRET, ALEXA FRET, and ALEXA FRET Plus formats, including reported IC50 ranges/categories and example values.
The invention also discloses pharmaceutical compositions comprising the cyclic polypeptide compounds and therapeutic methods for reducing LDL cholesterol and treating hypercholesterolemia. The therapeutic methods include treating hypercholesterolemia in subjects with comorbid conditions and are described in terms of inhibiting PCSK9/EGF-A interaction.
Claims Coverage
The independent claim coverage centers on a cyclic peptide compound selected from a group of specific cyclic peptides. The inventive features include therapeutic administration to inhibit PCSK9 activity, inhibit the PCSK9–LDLR EGF-A interaction, reduce LDL cholesterol, and treat hypercholesterolemia in defined comorbid disease contexts, with specified administration routes.
Cyclic peptide compound selection
A cyclic peptide compound selected from the group consisting of specific cyclic peptides.
Inhibiting PCSK9 activity by administration
A method for inhibiting PCSK9 activity in a subject by administering a therapeutically effective amount of the cyclic peptide compound.
Inhibiting PCSK9–LDLR EGF-A interaction
A method for inhibiting the interaction between PCSK9 and the EGF-A domain of LDLR in a subject by administering a therapeutically effective amount of the cyclic peptide compound.
Reducing LDL cholesterol by administration
A method that reduces LDL cholesterol in a subject by administering a therapeutically effective amount of a cyclic peptide compound.
Treating hypercholesterolemia with comorbidity selection
A method in which the disease showing comorbidity with hypercholesterolemia is selected from nephrotic syndrome, kidney failure, coronary artery disease, atherosclerosis, stroke, peripheral vascular disease, diabetes, and high blood pressure.
Administration route options
The method is performed with an administration route chosen from oral, intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, or intravitreal administration.
The claim coverage is directed to defined cyclic peptide compounds and their therapeutic administration to inhibit PCSK9 activity and/or the PCSK9–LDLR EGF-A interaction, reduce LDL cholesterol, and treat hypercholesterolemia, optionally within specified comorbid disease contexts and using selected administration routes.
Stated Advantages
Reducing LDL cholesterol in a subject.
Treating hypercholesterolemia.
Inhibiting PCSK9 activity in a subject.
Inhibiting the interaction between PCSK9 and the EGF-A domain of LDLR in a subject.
Treating or addressing comorbid conditions selected from diseases described as occurring with hypercholesterolemia, including nephrotic syndrome and kidney failure.
Documented Applications
Methods to reduce LDL cholesterol in a subject by administering a cyclic peptide compound.
Treatment of hypercholesterolemia and comorbid conditions described as disease comorbidity with hypercholesterolemia, including nephrotic syndrome, kidney failure, coronary artery disease, atherosclerosis, stroke, peripheral vascular disease, diabetes, and high blood pressure.
Methods to inhibit PCSK9 activity in a subject via administration of the cyclic peptide compound.
Methods to inhibit the interaction between PCSK9 and the EGF-A domain of LDLR in a subject via administration of the cyclic peptide compound.
Use of PCSK9–LDLR EGF-A interaction inhibition supported by binding-interaction assays (TR-FRET, ALEXA FRET, ALEXA FRET Plus) for characterizing activity.
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