Cyclic Polypeptides Inhibit PCSK9-LDLR Binding
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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 cardiovascular diseases.
Innovation Solution
Cyclic and bicyclic polypeptide compounds with specific structures, such as those represented by Formulas (I), (II), and (III), are provided to inhibit PCSK9 activity by blocking its interaction with the EGF-A domain of LDLR, 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 LDL cholesterol levels increase in the blood
Solution Approach 1:
The patent uses cyclic polypeptide compounds as intermediary molecules that bind to PCSK9, preventing its interaction with LDLR. These compounds act as mediators that block the harmful binding interface between PCSK9 and LDLR, thereby preventing LDLR degradation while lowering LDL cholesterol levels in the blood.
Solution Approach 2:
The cyclic polypeptide compounds perform preliminary anti-action by binding to PCSK9 before it can interact with LDLR. This preemptive binding prevents the harmful cascade of events that would otherwise occur, including LDLR internalization and degradation, thereby maintaining LDLR functionality and reducing LDL cholesterol levels.
2Productivity
If PCSK9 inhibits LDLR recycling, then LDL cholesterol removal decreases, but cardiovascular disease risk increases
Solution Approach 1:
The cyclic polypeptide compounds serve as intermediaries that restore LDLR recycling by blocking PCSK9's inhibitory action. By binding to PCSK9 and preventing its interaction with LDLR, these compounds enable LDLR to recycle back to the cell surface, thereby increasing LDL removal rate and reducing cardiovascular disease risk.
Solution Approach 2:
The patent implements a feedback mechanism where the cyclic polypeptide compounds monitor and respond to PCSK9 activity. By binding to PCSK9 and preventing its harmful effects, the compounds create a feedback loop that maintains LDLR functionality and optimizes LDL cholesterol removal, thereby reducing cardiovascular disease risk.
3Object-generated harmful factors
If conventional PCSK9 inhibitors are used, then LDL cholesterol levels decrease, but compound complexity and manufacturing difficulty increase
Solution Approach 1:
The patent segments the cyclic polypeptide compounds into distinct structural modules with specific functional regions. This segmentation allows for systematic design and optimization of the compounds, reducing the complexity of synthesis and manufacturing while maintaining their ability to bind PCSK9 and lower LDL cholesterol levels.
Solution Approach 2:
The patent employs parameter changes in the cyclic polypeptide structure, such as varying amino acid sequences, cyclization patterns, and molecular weights. These parameter changes enable optimization of the compounds' binding affinity and pharmacokinetic properties, simplifying manufacturing processes while maintaining effective LDL cholesterol reduction.
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.