Cross-Linked HNA Nucleosides for Nuclease Resistance and Lower Toxicity

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Solution Overview

Problem

Existing artificial nucleic acids, such as 2′,4′-BNA, suffer from low enzyme resistance and hepatotoxicity, while HNA analogues have improved binding affinity but require enhancements for therapeutic applications.

Innovation Solution

A cross-linked nucleoside with an HNA backbone, represented by specific structural formulas, offering improved nuclease resistance and potential as a substitute for phosphorothioate-modified nucleic acids.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If 2′,4′-BNA is used to improve binding affinity for ssRNA, then binding affinity is improved, but nuclease resistance deteriorates and hepatotoxicity increases

Engineering Contradiction:

Improvebinding affinityVSAvoidnuclease resistance and hepatotoxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent combines HNA backbone structure with modified sugar moieties (arabino, erythro, or xylo configurations) to create a composite artificial nucleic acid that integrates the advantages of both HNA (nuclease resistance) and BNA/LNA (high binding affinity), while avoiding the toxicities associated with BNA

Inventive Principle:

Principle #40Composite materials

Solution Approach 2:

The patent systematically varies the stereochemical parameters of the sugar moiety (arabino, erythro, xylo configurations) to optimize the balance between binding affinity and nuclease resistance, demonstrating that specific stereochemical configurations yield superior therapeutic properties

Inventive Principle:

Principle #35Parameter changes

2Object-affected harmful factors

If HNA is used to improve nuclease resistance, then nuclease resistance is improved, but binding affinity requires enhancement for therapeutic applications

Engineering Contradiction:

Improvenuclease resistanceVSAvoidbinding affinity

Core Design Contradiction:

Object-affected harmful factorsVSReliability

Solution Approach 1:

The patent creates a composite structure by combining the HNA backbone (providing nuclease resistance) with modified sugar moieties that mimic the N-conformation of natural nucleic acids, thereby achieving both high nuclease resistance and high binding affinity simultaneously

Inventive Principle:

Principle #40Composite materials

Data Source

PatentUS12473299B2Cross-linked nucleoside and nucleotide using same

Publication Date: 2025.11.18 OSAKA UNIVERSITY

AI summary

A cross-linked nucleoside of the present invention is a compound represented by the formula (I) below. The cross-linked nucleoside of the present invention is usable as a substitute for a phosphorothioate-modified nucleic acid, which has a risk of, for example, accumulation in a specific organ. The cross-linked nucleoside also has excellent industrial productivity.