5′-Substituted Bicyclic Nucleosides for RNA Binding Affinity
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Solution Overview
Problem
Current antisense compounds face limitations in enhancing binding affinity and stability for target RNA modulation, particularly in therapeutic applications, due to their susceptibility to nuclease degradation and pharmacokinetic challenges.
Innovation Solution
Development of 5′-(S)—CH3 substituted bicyclic nucleosides with a 2′ to 4′ bridging group, which are incorporated into oligomeric compounds to enhance properties such as binding affinity, stability, and pharmacokinetics, allowing for effective hybridization with target RNA and modulation of gene expression pathways.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antisense compounds are used, then they can hybridize to target RNA, but they suffer from susceptibility to nuclease degradation and reduced binding affinity
Solution Approach 1:
The patent applies parameter changes by modifying the sugar moiety of nucleosides from conventional ribose to bicyclic structures with 2′ to 4′ bridging groups. This structural parameter change simultaneously enhances nuclease resistance and increases binding affinity to target RNA, resolving the contradiction between reliability and binding strength.
Solution Approach 2:
The invention creates composite oligomeric compounds by incorporating modified bicyclic nucleosides with specific stereochemistry (5′-(S)—CH3 substitution) into the oligonucleotide backbone. This composite approach combines the stability benefits of bicyclic structures with the binding properties of antisense sequences, achieving both nuclease resistance and high binding affinity.
2Reliability
If chemical modifications are made to enhance binding affinity, then potency increases, but pharmacokinetic challenges and toxicity may arise
Solution Approach 1:
The patent applies local quality by introducing specific chiral substitution (5′-(S)—CH3) at a particular position on the bicyclic nucleoside structure. This localized structural modification enhances potency through improved target binding while the specific stereochemistry is designed to minimize off-target effects and reduce toxicity, allowing potency enhancement without proportional increase in harmful effects.
3Stability of the object's composition
If bicyclic nucleosides with 2′ to 4′ bridging groups are incorporated, then thermal stability (Tm) increases, but structural complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the sugar moiety into distinct structural components with the 2′ to 4′ bridging group forming a separate bicyclic system. This segmentation allows the bridging structure to independently contribute to thermal stability through pre-organization of the sugar pucker, while the base and phosphate backbone remain relatively simple, thus managing overall structural complexity.
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 5′-(S)—CH3 substituted bicyclic nucleosides increase the thermal stability (Tm) of oligomeric compounds and improve their ability to hybridize with target RNA, leading to efficient modulation of gene expression and potential therapeutic benefits, including reduced toxicity and improved pharmacokinetic profiles.
Implementation Method 1
the oligomeric compounds provided herein are expected to hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA
Data Source
AI summary
Provided herein are novel 5′-(S)—CH3 substituted bicyclic nucleosides, oligomeric compounds prepared therefrom and methods of using the oligomeric compounds. More particularly, the furanose ring of each of the novel 5′-(S)—CH3 substituted bicyclic nucleosides includes a 2′ to 4′ bridging group. The 5′-(S)—CH3 substituted bicyclic nucleosides are expected to be useful for enhancing one or more properties of the oligomeric compounds they are incorporated into such as for example increasing the binding affinity. In certain embodiments, the oligomeric compounds provided herein hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA.