Modified Oligonucleotides Avoiding Off-Target AMPA Receptor Binding
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Solution Overview
Problem
Current strategies for modulating RNA function, such as antisense oligonucleotides, face challenges in effectively inhibiting microRNA activity without promoting RNA degradation or causing off-target effects like AMPA receptor antagonism.
Innovation Solution
Development of modified oligonucleotides with specific nucleobase sequences and sugar moieties that are complementary to microRNAs, avoiding hydrogen bond acceptors at position 6 of purine nucleobases to minimize AMPA receptor binding, thereby inhibiting microRNA activity effectively.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antisense oligonucleotides are designed to bind to microRNA through Watson-Crick base pairing, then microRNA activity is inhibited, but off-target effects such as AMPA receptor antagonism occur
Solution Approach 1:
The patent applies local quality by making specific positional modifications to nucleobases within the oligonucleotide sequence. Purine nucleobases at positions complementary to positions 1 and/or 2 of the microRNA are specifically modified to remove hydrogen bond acceptors at position 6, while other positions may use standard Watson-Crick base pairing. This localized modification approach maintains target binding efficacy while eliminating off-target AMPA receptor antagonism.
Solution Approach 2:
The patent changes the chemical parameter of the purine nucleobase structure by removing hydrogen bond acceptor groups at position 6. This parameter change prevents the formation of inappropriate hydrogen bonds with AMPA receptors while preserving the ability to bind to the target microRNA through complementary base pairing at the relevant positions.
2Reliability
If modified oligonucleotides are used to inhibit microRNA activity, then therapeutic effects are achieved, but RNA degradation may be promoted
Solution Approach 1:
The patent applies local quality by implementing sterically hindering modifications at specific positions within the oligonucleotide sequence, particularly at the 3' end. These localized modifications create physical barriers that prevent RNase H from accessing and degrading the bound microRNA, while still allowing the oligonucleotide to effectively inhibit microRNA function through steric hindrance of the seed region.
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 modified oligonucleotides achieve therapeutically effective inhibition of microRNA activity, reducing cyst growth in ADPKD models and avoiding central nervous system toxicity associated with AMPA receptor antagonism.
Implementation Method 1
antisense oligonucleotides that are designed to bind to the RNA target through Watson-Crick base pairing
Implementation Method 2
mechanisms that involve binding of the modified oligonucleotide to the target RNA and interference with its function without promoting degradation of the RNA (e.g., steric hindrance)
Data Source
AI summary
Provided herein are compounds comprising modified oligonucleotides targeted to microRNAs, wherein the modified oligonucleotides are designed to avoid off-target effects.