Cyclic polypeptides for PCSK9 inhibition
Inventors
Ricardo, Alonso • Tucker, Thomas Joseph • Boyer, Nicolas Cedric • Dhamnaskar, Ketki Ashok • Ma, Zhong • Kerekes, Angela Dawn • Wu, Chengwei • Ha, Sookhee Nicole • Youm, Hyewon • Bianchi, Elisabetta • Branca, Danila • Ingenito, Raffaele • Costantini, Willy • Shahripour, Aurash • Xiong, Yusheng
Assignees
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Publication Number
US-11932705-B2
Publication Date
2024-03-19
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 relates to bicyclic polypeptide compounds selected from a defined group, or a pharmaceutically acceptable salt thereof. The compounds are described in the context of PCSK9 inhibition, PCSK9–LDLR EGF-A domain interaction inhibition, and reducing low density lipoprotein (LDL) cholesterol.
The disclosure also describes pharmaceutical compositions containing the bicyclic polypeptide compounds together with a pharmaceutically acceptable carrier. The compounds are associated with increasing LDL receptor availability and are further related to therapeutic methods for treating hypercholesterolemia, including subjects with comorbidities associated with hypercholesterolemia.
Reported characterization includes TR-FRET and ALEXA FRET/ALEXA PLUS FRET assay formats, LC/MS identification, fluorescent conjugate reagents, and IC50 categorization for inhibition of PCSK9–LDLR protein-protein interaction.
Claims Coverage
The independent claim covers a bicyclic polypeptide compound selected from a specified group, or a pharmaceutically acceptable salt thereof. The claim coverage adds five inventive features centered on PCSK9 inhibition, PCSK9–LDLR EGF-A domain interaction, LDL cholesterol reduction, a pharmaceutical composition, and comorbidity-restricted hypercholesterolemia treatment.
Bicyclic polypeptide compound selection
A bicyclic polypeptide compound selected from the group consisting of the compounds shown in the claim, or a pharmaceutically acceptable salt thereof.
Inhibiting PCSK9 activity by administration
A method for inhibiting PCSK9 activity in a subject by administering a therapeutically effective amount of the bicyclic polypeptide compound.
Inhibiting PCSK9–LDLR EGF-A domain interaction
A method for inhibiting the PCSK9–LDLR EGF-A domain interaction in a subject by administering a therapeutically effective amount of the bicyclic polypeptide compound.
Reducing LDL cholesterol by administration
A method for reducing low density lipoprotein (LDL) cholesterol in a subject by administering a therapeutically effective amount of the bicyclic polypeptide compound.
Pharmaceutical composition with pharmaceutically acceptable carrier
A pharmaceutical composition comprising the bicyclic polypeptide compound and a pharmaceutically acceptable carrier.
Comorbidity-restricted hypercholesterolemia treatment
Limiting the comorbidity associated with hypercholesterolemia to nephrotic syndrome, kidney failure, coronary artery disease, atherosclerosis, stroke, peripheral vascular disease, diabetes, and high blood pressure.
The claim set centers on a selected bicyclic polypeptide compound, or pharmaceutically acceptable salt, and covers therapeutic use by administering a therapeutically effective amount to inhibit PCSK9 activity and the PCSK9–LDLR EGF-A domain interaction, thereby reducing LDL cholesterol. Additional coverage includes a pharmaceutical composition with a pharmaceutically acceptable carrier and treatment limited to specified hypercholesterolemia comorbidities.
Stated Advantages
Inhibits PCSK9 activity in a subject.
Inhibits the interaction between PCSK9 and the EGF-A domain of LDLR in a subject.
Reduces low density lipoprotein (LDL) cholesterol in a subject.
Increases LDL receptor availability.
Treats hypercholesterolemia.
Treats diseases comorbid with hypercholesterolemia.
Provides a pharmaceutical composition comprising the bicyclic polypeptide compound with a pharmaceutically acceptable carrier.
Documented Applications
Therapeutic methods that inhibit PCSK9 activity in a subject.
Therapeutic methods that inhibit the interaction between PCSK9 and the EGF-A domain of LDLR in a subject.
Therapeutic methods that reduce LDL cholesterol in a subject.
Treatment of hypercholesterolemia.
Treatment of diseases comorbid with hypercholesterolemia, including atherosclerosis, ischemic cardiovascular disease, myocardial infarction, stroke, nephrotic syndrome, kidney failure, coronary artery disease, peripheral vascular disease, diabetes, and high blood pressure.
Pharmaceutical compositions comprising the bicyclic polypeptide compound and a pharmaceutically acceptable carrier.
Assays and compound characterization for inhibition of PCSK9–LDLR protein-protein interaction, including TR-FRET and ALEXA FRET/ALEXA PLUS FRET formats using fluorescent conjugate reagents.
Quantification reporting of IC50 categories for selected bicyclic polypeptide compounds based on inhibition of PCSK9–LDLR protein-protein interaction.
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