Peptide-Oligonucleotide Conjugates for Low-Toxicity Cellular Delivery
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Solution Overview
Problem
Existing antisense technologies face challenges with oligonucleotides that have high toxicity, poor affinity for DNA and RNA, compromised sequence selectivity, inadequate pharmacokinetics, and unreliable in vivo distribution.
Innovation Solution
Development of peptide-oligonucleotide-conjugates with peptides that enhance oligonucleotide affinity for DNA and RNA, reduce toxicity, improve pharmacokinetics, and ensure controlled in vivo distribution, while maintaining sequence selectivity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If traditional oligonucleotides are used for antisense therapy, then sequence specificity is achieved, but toxicity is high and cellular delivery is poor
Solution Approach 1:
The patent applies composite materials by creating peptide-oligonucleotide conjugates that combine the sequence-specific binding capability of oligonucleotides with the cell-penetrating properties of peptides. This composite structure resolves the contradiction by integrating two different material types to simultaneously achieve low toxicity and high cellular delivery efficiency
Solution Approach 2:
The peptide component acts as an intermediary that facilitates cellular delivery of the oligonucleotide without compromising its sequence-specific function. The peptide mediates the entry into cells while the oligonucleotide maintains its target-binding capability, thus resolving the contradiction between delivery efficiency and functional reliability
2Strength
If oligonucleotide length is increased to improve affinity for DNA and RNA, then binding strength increases, but pharmacokinetics deteriorate
Solution Approach 1:
The patent applies parameter changes by optimizing the oligonucleotide length to a specific range (8-40 nucleotides) that balances binding affinity with pharmacokinetic properties. This parameter optimization resolves the contradiction by finding the optimal length that provides sufficient affinity while maintaining acceptable pharmacokinetics
Solution Approach 2:
The patent applies local quality by concentrating the binding strength in a compact oligonucleotide region while using the peptide component to handle pharmacokinetic functions. This spatial separation of functions allows the oligonucleotide to be short enough for good pharmacokinetics while still providing sufficient local binding affinity through optimized sequence design
3Quantity of substance
If oligonucleotide concentration is increased to improve in vivo distribution, then target coverage increases, but toxicity increases
Solution Approach 1:
The peptide component serves as an intermediary that enables effective in vivo distribution at lower oligonucleotide concentrations. By facilitating cellular uptake and tissue penetration, the peptide allows the oligonucleotide to reach targets more efficiently, thus achieving good distribution without requiring high concentrations that would cause toxicity
4Productivity
If peptide-oligonucleotide conjugates are designed with longer peptides to improve cellular delivery, then uptake efficiency increases, but molecular weight increases affecting pharmacokinetics
Solution Approach 1:
The patent applies parameter changes by optimizing the peptide length to a specific range that maximizes cellular delivery efficiency while maintaining acceptable molecular weight for pharmacokinetics. This parameter optimization resolves the contradiction by finding the optimal peptide length that provides sufficient delivery capability without excessive molecular weight
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 peptide-oligonucleotide-conjugates demonstrate stronger affinity for DNA and RNA, lower toxicity, improved cellular delivery, and reliable in vivo distribution, addressing the limitations of traditional oligonucleotides.
Implementation Method 1
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 oligonucleotides, peptides, and peptide-oligonucleotide-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 oligonucleotides, peptides, and peptide-oligonucleotide-conjugates described herein.