Neutralizing PCSK9 Variant Blocks LDLR Degradation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current methods fail to effectively manage the regulation of low density lipoprotein receptor (LDLR) levels, leading to elevated serum cholesterol due to the degradation of LDLR by PCSK9, which reduces LDL binding and increases serum LDL levels.
Innovation Solution
Development of a neutralizing PCSK9 variant that includes an active Pro/Cat domain and an inactive V domain, allowing it to bind to LDLR without degrading it, thereby blocking native PCSK9 from binding and degrading LDLR, thus maintaining or increasing LDLR availability and reducing serum LDL levels.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If PCSK9 binds to LDLR, then PCSK9 regulates LDLR levels, but LDLR is degraded and serum cholesterol increases
Solution Approach 1:
The PCSK9 protein is divided into separate functional domains: the Pro/Cat domain that binds to LDLR and the V domain that mediates degradation. By separating these functions, the invention creates a variant that can bind without degrading, resolving the contradiction between regulation function and harmful degradation.
Solution Approach 2:
The harmful V domain responsible for degradation is extracted or inactivated in the PCSK9 variant, while retaining the beneficial Pro/Cat domain binding function. This extraction eliminates the harmful effect while preserving the regulatory function.
2Reliability
If a neutralizing PCSK9 variant binds to LDLR, then LDLR availability increases, but the variant structure becomes more complex
Solution Approach 1:
The invention creates a modified copy of PCSK9 that replicates the beneficial binding function while eliminating the harmful degradation function. This copy approach allows retention of the regulatory mechanism without the adverse effects.
Solution Approach 2:
The variant introduces localized changes specifically in the V domain region while maintaining the overall PCSK9 structure and Pro/Cat domain integrity. This localized modification approach minimizes structural complexity changes while achieving the desired functional outcome.
Data Source
AI summary
Neutralizing PCSK9 variants that interact with low density lipoprotein receptor (LDLR) are described. Methods and compositions for treating disorders by administering a pharmaceutically effective amount of a neutralizing PCSK9 variant are described.