Cyclic Polypeptides Inhibit PCSK9 to Reduce LDL Cholesterol

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

There is a need for compounds that inhibit the binding of PCSK9 to LDLR to treat or prevent hypercholesterolemia, as current methods do not effectively address the high levels of LDL cholesterol leading to cardiovascular diseases.

Innovation Solution

Cyclic polypeptide compounds are developed to inhibit the interaction between PCSK9 and the EGF-A domain of LDLR, reducing LDL cholesterol levels and treating hypercholesterolemia and associated diseases.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current treatment methods are used for hypercholesterolemia, then LDL cholesterol levels remain high, but cardiovascular diseases progress

Engineering Contradiction:

Improveeffectiveness of treatmentVSAvoidhigh LDL cholesterol levels

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent introduces PCSK9 as an intermediary molecule that mediates the degradation of LDLR. By inhibiting PCSK9 with cyclic polypeptides, the harmful degradation of LDLR is blocked, thereby reducing LDL cholesterol levels without directly targeting LDLR itself. This intermediary approach resolves the contradiction by providing a new therapeutic target that indirectly controls LDL cholesterol.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent extracts and isolates the catalytic domain of PCSK9 as a specific therapeutic target. By focusing on this extracted portion of the PCSK9 protein, the invention develops targeted inhibitors that specifically block PCSK9's harmful function while leaving other physiological processes intact, thereby effectively reducing LDL cholesterol levels.

Inventive Principle:

Principle #2Taking out (Extraction)

2Quantity of substance

If PCSK9 binds to LDLR, then LDLR is directed to lysosomes for degradation, but LDL cholesterol levels increase

Engineering Contradiction:

ImproveLDL cholesterol levelsVSAvoidLDLR cell surface presence

Core Design Contradiction:

Quantity of substanceVSStability of the object's composition

Solution Approach 1:

The patent applies preliminary anti-action by developing cyclic polypeptide inhibitors that preemptively block PCSK9's binding to LDLR before degradation can occur. These inhibitors are designed to bind to PCSK9's catalytic domain in advance, preventing the harmful interaction between PCSK9 and LDLR, thereby maintaining LDLR stability and reducing LDL cholesterol levels.

Inventive Principle:

Principle #9Preliminary anti-action

3Quantity of substance

If inhibition compounds are administered, then LDL cholesterol levels decrease, but treatment complexity increases

Engineering Contradiction:

ImproveLDL cholesterol levelsVSAvoidtreatment regimen

Core Design Contradiction:

Quantity of substanceVSDevice complexity

Solution Approach 1:

The patent employs parameter changes by modifying the cyclic polypeptide structure to optimize its binding affinity and specificity for PCSK9. By adjusting parameters such as amino acid sequence, ring size, and stereochemistry, the invention achieves potent inhibition of PCSK9 with a relatively simple cyclic polypeptide structure, thereby effectively reducing LDL cholesterol levels without overly complex treatment regimens.

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentEP3810177B1Cyclic polypeptides for PCSK9 inhibition

Publication Date: 2024.12.04 UCB HOLDINGS 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.