Morpholino Oligonucleotides with Phosphorodiamidate Linkages
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Solution Overview
Problem
Current antisense oligonucleotides face challenges such as electrostatic repulsion, non-specific binding, and poor pharmacokinetics, which limit their therapeutic effectiveness and delivery efficiency.
Innovation Solution
Development of oligomers with modified intersubunit linkages and terminal groups, specifically morpholino oligonucleotides with phosphorodiamidate linkages and peptide conjugation, to enhance binding affinity, cellular uptake, and tissue distribution.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If phosphorothioate linkages are used in oligonucleotide analogues, then nuclease degradation resistance is improved, but electrostatic repulsion with DNA/RNA target increases and non-specific binding to cellular components occurs
Solution Approach 1:
The patent changes the chemical parameters of the intersubunit linkages by replacing phosphorothioate linkages with morpholino-based phosphorodiamidate linkages. This modification alters the charge distribution and steric properties of the backbone, reducing electrostatic repulsion with negatively charged DNA/RNA targets while maintaining nuclease resistance through the morpholino ring structure's geometric constraints on nuclease access.
Solution Approach 2:
The invention creates a composite molecular structure combining morpholino rings with phosphorodiamidate linkages. This composite architecture integrates the nuclease-resistant morpholino backbone with the sequence-specific binding capability of the phosphorodiamidate connections, achieving both stability and specific target recognition without the harmful non-specific binding of phosphorothioate analogues.
2Ease of operation
If methylphosphonate-linked oligonucleotide analogues are used, then cellular transport is improved through passive diffusion, but stereoisomeric complexity and poor solubility occur
Solution Approach 1:
The patent employs morpholino rings as chiral copies of the sugar-phosphate backbone, where the ring structure inherently defines the stereochemistry. This eliminates the need for multiple stereoisomeric forms to achieve the same spatial arrangement, simplifying the molecular architecture while maintaining the ability to passively diffuse into cells through the morpholino ring's hydrophobic character.
3Productivity
If peptide conjugation is added to oligonucleotides, then cellular uptake is enhanced, but molecular complexity and synthesis difficulty increase
Solution Approach 1:
The invention segments the oligonucleotide structure into distinct functional modules: morpholino rings for structural stability and nuclease resistance, phosphorodiamidate linkages for sequence-specific binding, and peptide conjugation sites for cellular uptake. This modular segmentation allows independent optimization of each function while simplifying the overall synthesis process through standardized coupling protocols.
Data Source
AI summary
Oligonucleotide analogues comprising modified intersubunit linkages and/or modified 3′ and/or 5′-end groups are provided. The disclosed compounds are useful for the treatment of diseases where inhibition of protein expression or correction of aberrant mRNA splice products produces beneficial therapeutic effects.