Alpha-Beta-Constrained Nucleic Acid Compounds for Nuclease Resistance
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Solution Overview
Problem
Current antisense compounds face limitations in terms of nuclease resistance, pharmacokinetics, and target affinity, which affect their therapeutic efficacy and convenience of administration, particularly in achieving specific gene expression modulation.
Innovation Solution
Development of α-β-constrained nucleic acid compounds with cyclic phosphorus internucleoside linkages, such as cyclic phosphate, attached to modified nucleosides, which are incorporated into oligomeric compounds to enhance properties like nuclease resistance and binding affinity, allowing for targeted modulation of gene expression by hybridizing with target RNA.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If chemically modified nucleosides are incorporated into antisense compounds to enhance nuclease resistance and pharmacokinetics, then stability and duration of action are improved, but manufacturing complexity and cost increase
Solution Approach 1:
The patent applies parameter changes by systematically varying the chemical structure of the cyclic phosphate linkage (different ring sizes, substituent positions, and stereochemistry) to optimize the balance between nuclease resistance and manufacturability. Specific modifications at the 5′ position of the nucleoside create distinct chemical parameters that enhance stability while maintaining synthetic feasibility through established chemical transformation pathways.
Solution Approach 2:
The invention creates composite nucleic acid structures by combining modified nucleosides with cyclic phosphate linkages to form hybrid oligonucleotide compounds. These composite structures integrate multiple functional elements (nucleoside backbone, cyclic phosphate constraint, 5′ position modification) into a single molecule that achieves enhanced nuclease resistance and pharmacokinetic properties while relying on modular synthesis approaches.
2Reliability
If chemical modifications are combined in one compound to optimize efficacy, then potency and binding affinity are improved, but manufacturing precision and synthesis difficulty increase
Solution Approach 1:
The patent segments the oligonucleotide compound into distinct modular regions: modified nucleoside units with cyclic phosphate linkages, unmodified nucleotide sequences, and terminal modifications. This segmentation allows each module to be synthesized and characterized independently, then assembled into the complete compound, thereby maintaining manufacturing precision while achieving enhanced binding affinity through cumulative modifications.
Solution Approach 2:
The invention applies local quality by introducing cyclic phosphate modifications at specific positions within the oligonucleotide sequence rather than uniformly throughout. The 5′ position modification and selective placement of constrained linkages create localized enhancements in binding affinity and stability, while leaving other regions unchanged to maintain synthetic simplicity and manufacturing precision.
3Duration of action of stationary object
If modified nucleosides are used to enhance pharmacokinetics and reduce clearance, then duration of action is improved, but dosing frequency and patient convenience worsen due to complex administration protocols
Solution Approach 1:
The patent applies preliminary action by incorporating cyclic phosphate linkages and 5′ position modifications into the oligonucleotide structure during manufacturing, before administration to the patient. These pre-installed structural features provide inherent protection against nuclease degradation and optimize pharmacokinetic properties, thereby extending duration of action and reducing dosing frequency without requiring complex post-administration protocols or patient compliance measures.
4Object-affected harmful factors
If lower doses are administered to reduce toxicity, then safety and patient comfort are improved, but manufacturing cost per unit dose increases due to complex synthesis requirements
Solution Approach 1:
The patent utilizes parameter changes by optimizing the cyclic phosphate linkage structure (ring size, substitution pattern, stereochemistry) to achieve maximum therapeutic efficacy at lower doses. These parameter optimizations enhance the compound's potency and safety profile, allowing reduced dosing while the modular synthetic approach maintains cost-effectiveness through efficient use of reagents and established chemical transformations.
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 α-β-constrained nucleic acid compounds demonstrate improved stability, binding specificity, and reduced toxicity, enabling more effective modulation of gene expression and potential for less frequent dosing, thereby enhancing therapeutic outcomes.
Implementation Method 1
a constrained cyclic phosphorus internucleoside linkage such as a cyclic phosphate that is attached to an optionally modified nucleoside at its 5′ position
Implementation Method 2
the oligomeric compounds provided herein hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA
Data Source
AI summary
The present disclosure provides oligomeric compounds comprising at least one α-β-constrained nucleic acid as provided herein. More particularly, the α-β-constrained nucleic acid provided herein comprise an optionally modified nucleoside with a phosphorus containing constrained internucleoside linkage such as for example a cyclic phosphate internucleoside linkage. The α-β-constrained nucleic acid provided herein are expected to be useful for enhancing one or more properties of oligomeric compounds they are incorporated into such as for example nuclease resistance. 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.