Backbone Constrained Oligomeric Compounds for Nuclease Resistance

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Solution Overview

Problem

Current antisense technologies face limitations in enhancing the properties of oligomeric compounds such as nuclease resistance and target specificity, particularly in hybridizing with RNA and modulating gene expression effectively.

Innovation Solution

Development of novel backbone constrained nucleoside units and oligomeric compounds with modified oligonucleotides that incorporate a carbon or heteroatom-containing chain linking two adjacent phosphorus atoms, forming a macrocycle, which enhances properties like stability, binding affinity, and cellular uptake.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If chemically modified nucleosides and internucleoside linkages are used to enhance nuclease resistance and pharmacokinetics, then stability and affinity are improved, but molecular flexibility and conformational adaptability are reduced

Engineering Contradiction:

Improvenuclease resistanceVSAvoidmolecular flexibility

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The invention divides the rigid backbone into segments by introducing flexible linker regions between the modified nucleoside units. These linker segments contain rotatable bonds and flexible atoms that allow the molecule to adopt different conformations, thereby restoring adaptability while preserving the nuclease resistance provided by the modified backbone segments.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The invention changes the physical and chemical parameters of the backbone by incorporating atoms with different bond angles and rotational characteristics. This allows the backbone to transition from a rigid structure to one with controlled flexibility, enabling the molecule to adapt to target binding requirements while maintaining enhanced stability.

Inventive Principle:

Principle #35Parameter changes

2Manufacturing precision

If rigid backbone modifications are introduced to enhance target binding affinity, then specificity is improved, but molecular adaptability to different targets is reduced

Engineering Contradiction:

Improvebinding specificityVSAvoidtarget adaptability

Core Design Contradiction:

Manufacturing precisionVSAdaptability or versatility

Solution Approach 1:

The invention applies local quality by creating regions of rigidity at specific binding sites to enhance specificity, while maintaining flexible regions in other parts of the molecule. This allows the rigid portions to provide precise target recognition while the flexible portions enable adaptation to different target configurations and orientations.

Inventive Principle:

Principle #3Local quality

3Reliability

If macrocyclic structures are formed by linking phosphorus atoms to enhance stability, then nuclease resistance is improved, but synthesis complexity increases

Engineering Contradiction:

Improveoligonucleotide stabilityVSAvoidsynthesis complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The invention applies preliminary action by pre-forming the macrocyclic structure during the oligonucleotide synthesis process itself, rather than requiring post-synthesis cyclization steps. The backbone constraints are built into the synthesis pathway, allowing the macrocycle to form automatically as the chain elongates, thereby reducing overall synthesis complexity while maintaining stability benefits.

Inventive Principle:

Principle #10Preliminary action

Data Source

PatentUS20230095696A1Oligomeric compounds comprising backbone constrained macrocycles

Publication Date: 2023.03.30 IONIS PHARMACEUTICALS INC

AI summary

The present disclosure provides a trinucleotide comprising the formula below or an oligomeric compound comprising the formula below: