Modified Aminoglycosides for Stop Codon Readthrough with Reduced Toxicity
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Solution Overview
Problem
Current aminoglycosides used to treat genetic disorders associated with stop codon mutations are limited by high toxicity and antimicrobial activity, which leads to adverse effects and resistance issues, and have low bioavailability and poor permeability in mammalian cells.
Innovation Solution
Development of a new class of pseudo-disaccharide and pseudo-trisaccharide aminoglycosides with modifications to the paromomycin core, including hydroxyl groups, monosaccharide moieties, and (S)-4-amino-2-hydroxybutyryl moieties, to enhance read-through activity while reducing toxicity and antimicrobial activity, improving bioavailability and cell permeability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current aminoglycosides are used to treat genetic disorders with stop codon mutations, then read-through activity is achieved, but toxicity and antimicrobial activity increase causing adverse effects and resistance
Solution Approach 1:
The patent segments the aminoglycoside molecule into a core structure (Rings I and II of paromomycin) and variable substituent positions (R1-R6). By dividing the molecule into functional regions, the invention allows optimization of read-through activity in the core while modifying peripheral groups to reduce toxicity and antimicrobial activity.
Solution Approach 2:
The patent applies local quality by making specific positions (R1-R6) optional for substitution while keeping the core structure intact. This allows localized modification of chemical properties at specific sites to reduce harmful effects while preserving the essential read-through function of the core aminoglycoside structure.
2Reliability
If current aminoglycosides are administered, then some therapeutic effect is achieved, but bioavailability and cell permeability remain low
Solution Approach 1:
The patent changes chemical parameters by introducing various substituents (alkyl, cycloalkyl, aryl, heteroaryl groups with specific properties) at positions R1-R6. These parameter changes in molecular structure are designed to improve lipophilicity and cell membrane permeability while maintaining read-through activity.
Solution Approach 2:
The patent creates composite molecular structures by combining the paromomycin core with various organic substituent groups. This composite approach allows integration of the essential pharmacological activity with improved pharmacokinetic properties through carefully selected substituent combinations.
3Object-affected harmful factors
If aminoglycoside structure is modified to reduce toxicity, then safety improves, but read-through activity may be compromised
Solution Approach 1:
The patent applies partial action by modifying only specific positions (R1-R6) of the molecule while leaving the core structure unchanged. This selective modification approach ensures that essential read-through activity is preserved while only the necessary changes for toxicity reduction are implemented.
Solution Approach 2:
The patent uses parameter changes by selecting substituents with specific chemical properties (lipophilicity, molecular weight, steric bulk) that are optimized to reduce toxicity while maintaining or enhancing read-through activity through structure-activity relationship optimization.
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
These modified aminoglycosides exhibit high premature stop codon mutations read-through activity with low toxicity in mammalian cells and improved bioavailability, effectively treating genetic disorders like cystic fibrosis and muscular dystrophy with minimal adverse effects.
Implementation Method 1
the binding of certain aminoglycosides to the ribosomal A-site probably induce conformational changes that stabilize near-cognate mRNA-tRNA complexes
Data Source
AI summary
Novel pseudo-disaccharide and pseudo-trisaccharide aminoglycosides, represented by Formulae I or Ia, as defined in the instant specification, designed to exhibit stop codon mutation readthrough activity, are provided. Also provided are pharmaceutical compositions containing the same, and uses thereof in the treatment of genetic diseases and disorders, such as diseases and disorders associated with stop codon mutations.