Non-canonical Peptide Conjugates for Antisense Delivery
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Despite progress in antisense technology, there is a need for oligonucleotides and antisense oligomer conjugates that can effectively modulate gene expression for therapeutic applications, particularly for neuromuscular diseases like Duchenne muscular dystrophy.
Innovation Solution
The development of antisense oligomer conjugates that covalently bind a cell-penetrating peptide, specifically containing non-canonical amino acids, to enhance delivery and efficacy in treating various diseases, including neuromuscular disorders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If conventional cell-penetrating peptides are used for antisense oligomer delivery, then delivery capability is achieved, but penetration efficiency and cellular uptake are insufficient
Solution Approach 1:
The patent modifies the chemical structure of cell-penetrating peptides by incorporating non-canonical amino acids with specific side chains (e.g., arginine, lysine, histidine, or custom-designed residues with tailored hydrophobicity and charge distributions). This parameter change in peptide composition optimizes the balance between cellular uptake efficiency and penetration capability, resolving the contradiction between delivery efficiency and penetration reliability.
Solution Approach 2:
The invention creates composite peptide structures combining multiple functional motifs: cell-penetrating domains, endosomal escape motifs, and cargo-binding regions. These composite peptides integrate the advantages of different peptide segments to achieve both efficient delivery and reliable penetration, overcoming the limitations of single-function conventional peptides.
2Reliability
If antisense oligomers are used to modulate gene expression, then therapeutic efficacy is achieved, but cellular delivery and bioavailability are limited
Solution Approach 1:
The cell-penetrating peptide acts as an intermediary carrier that facilitates the transport of antisense oligomers across cell membranes and into the cytoplasm. This intermediary function overcomes the inherent poor bioavailability of naked oligomers while preserving their therapeutic efficacy through sequence-specific binding to target mRNA, thereby resolving the contradiction between efficacy and bioavailability.
Solution Approach 2:
The conjugate system combines multiple functions in a single entity: the peptide provides cell penetration and endosomal escape functions, while the oligomer provides sequence-specific gene silencing function. This multi-functionality ensures both high bioavailability through cellular uptake and reliable therapeutic efficacy through targeted gene modulation.
3Productivity
If peptide conjugates are formed to enhance cell penetration, then delivery is improved, but conjugate stability and structural integrity may be compromised
Solution Approach 1:
The patent employs preliminary conjugation strategies where the antisense oligomer is covalently attached to the cell-penetrating peptide through stable linkers (e.g., maleimide, disulfide, or amide bonds) formed under controlled conditions. This preliminary action ensures structural integrity is established before cellular interaction, preventing degradation while maintaining penetration capability.
Solution Approach 2:
The conjugate structure incorporates local quality variations: the peptide portion maintains structural flexibility for membrane interaction, while the oligomer portion maintains sequence-specific binding capability. The linker region is designed with appropriate rigidity and chemical stability to connect these functional elements without compromising either, thus resolving the contradiction between penetration and stability.
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
These conjugates demonstrate improved antisense or antigen performance, effectively penetrating cells and modulating gene expression, thereby offering potential therapeutic benefits for neuromuscular diseases.
Implementation Method 1
an antisense oligomer covalently bound to a cell-penetrating peptide
Implementation Method 2
the cell-penetrating peptide comprises at least one non-canonical amino acid
Implementation Method 3
an antisense compound, e.g., an oligonucleotide, which hybridizes to a target nucleic acid, modulates gene expression activities
Data Source
AI summary
Provided herein are antisense oligomer conjugates. Also provided herein are methods of treating a muscle disease, a viral infection, or a bacterial infection in a subject in need thereof, comprising administering to the subject one or more of the antisense oligomer conjugates described herein.