Cyclic Polypeptides Inhibit PCSK9-LDLR Interaction
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Solution Overview
Problem
There is a need for compounds that inhibit the binding of proprotein convertase subtilisin/kexin type 9 (PCSK9) to the low-density lipoprotein receptor (LDLR) to treat or prevent hypercholesterolemia, a condition characterized by high levels of low-density lipoprotein (LDL) cholesterol, which can lead to atherosclerosis and associated cardiovascular diseases.
Innovation Solution
Cyclic polypeptide compounds, specifically those with structures represented by Formulas (I) and (II), or their pharmaceutically acceptable salts, are administered to inhibit PCSK9 activity, thereby reducing LDL cholesterol levels and treating hypercholesterolemia and related diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If PCSK9 binds to LDLR, then LDLR is directed to lysosomes for degradation, but this leads to high LDL cholesterol levels and atherosclerosis
Solution Approach 1:
The patent uses cyclic polypeptide compounds as intermediary substances that bind to PCSK9 and prevent its interaction with LDLR. These compounds act as mediators that block the harmful binding pathway while allowing LDLR to remain on the cell surface and perform its cholesterol removal function.
Solution Approach 2:
The cyclic polypeptide compounds are administered to preemptively block PCSK9 before it can bind to and degrade LDLR. By introducing these inhibitory compounds in advance, the pathway leading to LDLR degradation is prevented before the harmful effect occurs.
2Object-affected harmful factors
If cyclic polypeptide compounds are administered to inhibit PCSK9, then LDL cholesterol levels decrease, but the complexity of treatment increases
Solution Approach 1:
The patent employs cyclic polypeptide compounds with specific structural parameters (amino acid composition, cyclic conformation, molecular weight range) that optimize their binding affinity to PCSK9. By carefully controlling these physical and chemical parameters, the compounds achieve effective inhibition with minimal dosage and treatment complexity.
Data Source
AI summary
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.