Ribose-GalNAc Oligonucleotide Conjugates With ASGPR Affinity Tuning

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Solution Overview

Problem

There is a need to enhance the liver-targeted delivery efficiency of nucleic acid drugs, particularly for PCSK9 inhibitors, using GalNAc ligands to address hypercholesterolemia and related diseases.

Innovation Solution

Development of novel GalNAc compounds conjugated with oligonucleotides through solid-phase synthesis, enhancing liver-targeted delivery efficiency by binding to the asialoglycoprotein receptor (ASGPR).

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional GalNAc compounds are used for liver-targeted delivery, then basic delivery function is achieved, but delivery efficiency is insufficient

Engineering Contradiction:

Improveliver-targeted delivery efficiencyVSAvoidgene silencing activity

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent modifies the chemical structure of GalNAc compounds by changing parameters such as the number of antennae (mono-, bi-, tri-, tetra-antennary structures), linker types, and conjugation positions to optimize binding affinity to ASGPR and improve delivery efficiency. This directly addresses the contradiction by systematically varying structural parameters to enhance both delivery efficiency and gene silencing activity.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates composite structures by conjugating GalNAc ligands with oligonucleotide drugs (siRNA, ASO, aptamers) through various linkers. This composite approach combines the target-specific binding capability of GalNAc-ASGPR interaction with the therapeutic function of oligonucleotides, achieving improved liver-targeted delivery efficiency and enhanced gene silencing activity simultaneously.

Inventive Principle:

Principle #40Composite materials

2Reliability

If GalNAc conjugation technology is applied to oligonucleotides, then liver targeting is achieved, but delivery efficiency needs further enhancement

Engineering Contradiction:

Improveliver targeting capabilityVSAvoiddelivery efficiency

Core Design Contradiction:

ReliabilityVSManufacturing precision

Solution Approach 1:

The GalNAc oligonucleotide conjugate is segmented into distinct functional modules: the GalNAc ligand portion for ASGPR binding, the linker portion for connecting ligand to oligonucleotide, and the oligonucleotide portion for therapeutic action. This segmentation allows independent optimization of each module's properties to achieve superior overall delivery efficiency while maintaining liver targeting capability.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent employs various linker molecules as intermediaries between the GalNAc ligand and the oligonucleotide drug. These linkers mediate the connection while allowing optimal spatial arrangement and conformational flexibility, thereby enhancing delivery efficiency without compromising the liver targeting capability provided by the GalNAc-ASGPR interaction.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Reliability

If tetraantennary and triantennary GalNAc compounds are used, then affinity for ASGPR is markedly higher, but structural complexity increases

Engineering Contradiction:

Improveaffinity for ASGPRVSAvoidmolecular structure complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent utilizes asymmetric structural designs in the GalNAc compounds, particularly in the arrangement of antennae and linker attachments. This asymmetry allows for optimized binding interactions with ASGPR while potentially simplifying the synthesis route compared to fully symmetric multi-antennary structures, thus achieving high affinity with manageable structural complexity.

Inventive Principle:

Principle #4Asymmetry

Solution Approach 2:

The invention employs protecting group strategies and pre-formed building blocks in the synthesis of complex multi-antennary GalNAc structures. By performing preliminary protective actions on hydroxyl groups and using pre-synthesized modular units, the patent reduces the actual complexity of the final synthesis steps while achieving the desired high-affinity tetra- and tri-antennary structures.

Inventive Principle:

Principle #10Preliminary action

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 new GalNAc compounds significantly improve liver-targeted delivery and gene silencing activity, providing effective treatment for hypercholesterolemia and related diseases.

Implementation Method 1

N-acetylgalactosamine (GalNAc) is a ligand that binds to the asialoglycoprotein receptor (ASGPR) on the liver surface. ASGPR is an endocytic receptor that is specifically expressed on the surface of hepatocytes.

Methodology Applied

Scientific EffectLigand-receptor binding:

Data Source

PatentUS20260009035A1Galnac compound containing ribose ring or its derivative structure and oligonucleotide conjugate thereof

Publication Date: 2026.01.08 HANGZHOU TIANLONG PHARM CO LTD

AI summary

Provided are a GalNAc compound containing a ribose ring or its derivative structure and an oligonucleotide conjugate thereof. The oligonucleotide conjugate can achieve efficient liver-targeted delivery and improve the efficacy of the drug.