Allosteric PCSK9 Inhibitors for Dyslipidemia Treatment
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Solution Overview
Problem
Current approaches to inhibit PCSK9, particularly small molecule inhibitors, face challenges due to the protein-protein interaction involved in LDL-R degradation, which is independent of PCSK9's proteolytic activity, leading to high false positive rates in assays and non-specific molecule inhibition.
Innovation Solution
Design and development of compounds that bind allosterically to the catalytic site of PCSK9, using in silico docking studies and specific pharmaceutical compositions, to effectively inhibit PCSK9 activity and reduce LDL cholesterol levels.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If small molecule inhibitors are used to inhibit PCSK9, then LDL cholesterol levels are reduced, but false positive rates increase and non-specific inhibition occurs
Solution Approach 1:
The patent uses a cell-based assay system with secreted PCSK9 as an intermediary to specifically measure PCSK9 activity. The assay employs a fusion protein containing PCSK9 and a detection domain that specifically interacts with PCSK9, allowing differentiation between specific PCSK9 inhibition and non-specific effects on protein secretion or cell viability.
Solution Approach 2:
The patent changes the measurement parameter from general protein secretion levels to specific PCSK9 activity levels. By using a detection system that specifically recognizes PCSK9 (through the fusion protein approach), the assay measures the actual PCSK9 functional activity rather than general cellular health or protein secretion, thereby reducing false positives.
2Reliability
If compounds are designed to inhibit PCSK9 catalytic site, then binding potency is achieved, but the protein-protein interaction between LDLR and PCSK9 remains difficult to target
Solution Approach 1:
The patent extracts the detection function from the catalytic site of PCSK9 and places it in a separate fusion protein. The secreted PCSK9 contains a specific detection domain that can be independently targeted, allowing small molecules to inhibit PCSK9 catalytic activity without needing to directly interfere with the complex LDLR-PCSK9 protein-protein interaction.
Solution Approach 2:
The fusion protein acts as an intermediary that separates the measurement of PCSK9 activity from the complex protein-protein interaction. By detecting PCSK9 through its fusion partner rather than through direct observation of LDLR-PCSK9 binding, the assay simplifies the target for small molecule inhibition while maintaining measurement accuracy.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The compounds demonstrate therapeutically effective binding to PCSK9, as shown by SPR binding and in vitro potency, providing a proof of concept for treating hypercholesterolemia by reducing LDL cholesterol levels.
Implementation Method 1
Design and development of compounds that bind allosterically to the catalytic site of PCSK9
Implementation Method 2
The compounds demonstrate therapeutically effective binding to PCSK9, as shown by SPR binding
Data Source
Figure 1
AI summary
The present invention relates to compounds of the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, methods for their preparation, use of these compounds in medicine and the intermediates involved in their preparation '