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 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

VSEngineering Contradiction Analysis

1Reliability

If PCSK9 binds to LDLR, then LDLR is directed to lysosomes for degradation, but LDL cholesterol removal from extracellular fluid is reduced

Engineering Contradiction:

ImproveLDLR functionalityVSAvoidPCSK9 binding to LDLR

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent uses cyclic polypeptide compounds as intermediary substances that bind to PCSK9, preventing its interaction with LDLR. These compounds act as mediators that block the harmful binding interaction between PCSK9 and LDLR, thereby preserving LDLR functionality and preventing PCSK9-induced degradation of LDLR to lysosomes.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Quantity of substance

If PCSK9 inhibits LDLR recycling, then LDL cholesterol levels increase, but treatment effectiveness is reduced

Engineering Contradiction:

ImproveLDL cholesterol levelVSAvoidLDLR recycling

Core Design Contradiction:

Quantity of substanceVSReliability

Solution Approach 1:

The patent applies preliminary anti-action by administering cyclic polypeptide compounds before PCSK9 can bind to and inhibit LDLR recycling. These compounds preemptively block PCSK9 binding sites or interfere with PCSK9-LDLR interaction, preventing the harmful effect before it occurs and thereby maintaining LDLR recycling functionality and reducing LDL cholesterol levels.

Inventive Principle:

Principle #9Preliminary anti-action

3Object-generated harmful factors

If LDLR is degraded in lysosomes, then PCSK9 binding is confirmed, but cell surface LDLR presence is reduced

Engineering Contradiction:

ImprovePCSK9-LDLR interactionVSAvoidCell surface LDLR

Core Design Contradiction:

Object-generated harmful factorsVSQuantity of substance

Solution Approach 1:

The cyclic polypeptide compounds serve as intermediary agents that interfere with the PCSK9-LDLR interaction pathway. By binding to PCSK9 or blocking its binding site on LDLR, these compounds prevent the degradation process and thereby maintain higher levels of functional LDLR on the cell surface, reducing the harmful interaction between PCSK9 and LDLR.

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS11505575B2Cyclic polypeptides for PCSK9 inhibition

Publication Date: 2022.11.22 RA PHARMACEUTICALS INC

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.