Formula I Compounds for Stabilizing Mutant PAH Proteins
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Solution Overview
Problem
Current treatments for phenylketonuria (PKU), such as Phe-restricted diets and existing medications like Kuvan and Pegvaliase, are inadequate for all patients and face challenges with adherence and effectiveness, particularly in maintaining therapeutically effective amounts of protein in vivo.
Innovation Solution
Development of compounds that stabilize mutant phenylalanine hydroxylase (PAH) proteins, including specific compounds of Formula I and their pharmaceutically acceptable salts, which can be administered to reduce phenylalanine levels in PKU patients.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If Pegvaliase enzyme substitution therapy is used to treat PKU, then phenylalanine levels can be reduced, but the infused protein is rapidly degraded or inactivated making it difficult to maintain therapeutically effective amounts
Solution Approach 1:
The patent uses PEGylation as an intermediary approach, where polyethylene glycol chains are attached to the phenylalanine ammonia lyase enzyme. This PEG intermediary layer protects the protein from rapid degradation and inactivation by the immune system and other proteolytic mechanisms, thereby extending the duration of action and maintaining therapeutically effective phenylalanine levels in patients.
Solution Approach 2:
The patent modifies the physical and chemical parameters of the protein by attaching PEG chains of various molecular weights and configurations. This parameter change transforms the protein's properties, including its hydrodynamic radius, charge distribution, and immunogenicity, to achieve prolonged circulation half-life and sustained therapeutic effect.
2Reliability
If numerous costly high dose injections are administered to overcome protein degradation, then phenylalanine levels can be controlled, but the treatment complexity and cost increase
Solution Approach 1:
The PEGylation modification is performed in advance during drug manufacturing, creating a pre-stabilized protein formulation. This preliminary action of stabilizing the protein before administration eliminates the need for frequent dose adjustments and complex administration regimens, allowing for simpler, less frequent injections while maintaining reliable phenylalanine level control.
3Adaptability or versatility
If Kuvan (sapropterin dihydrochloride) is used as a BH4 cofactor, then some PKU patients can benefit, but it is not effective for all PKU patients particularly those with two null mutations
Solution Approach 1:
The PEGylated phenylalanine ammonia lyase therapy is designed to be universally applicable across all PKU patient populations, including those with null mutations who do not respond to BH4 cofactor therapy. The enzyme substitution approach bypasses the need for functional PAH enzyme or BH4 cofactor responsiveness, providing a multi-functional treatment that addresses both classic PKU and severe null mutation cases.
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 effectively stabilize mutant PAH proteins, allowing for reduced phenylalanine levels and enabling patients to increase their natural protein intake without the limitations of current treatments.
Implementation Method 1
The compounds effectively stabilize mutant PAH proteins
Data Source
AI summary
The disclosure relates to compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein, m, R1-R5, R5A, and L are defined herein. These compounds are useful in methods for stabilizing a mutant PAH protein or reducing blood phenylalanine concentration in a subject suffering from phenylketonuria. In some embodiments, the mutant PAH protein contains at least one R408W, R261Q, R243Q, Y414C, L48S, A403V, I65T, R241C, L348V, R408Q, or V388M mutation. In other embodiments, the mutant PAH protein contains at least one R408W, Y414C, I65T, F39L, R408Q, L348V, R261Q, A300S, or L48S mutation.