Lysine-Rich Cell-Penetrating Peptides for Lower-Toxicity Nucleic Acid Delivery
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Solution Overview
Problem
Current cell-penetrating peptides (CPPs) used for delivering nucleic acid therapeutics, such as PMOs, face challenges of high toxicity and low efficacy due to their arginine-rich composition, limiting their use in human treatments for genetic disorders like Duchenne muscular dystrophy (DMD).
Innovation Solution
Development of lysine-rich CPPs that do not contain arginine residues, featuring a specific structure with cationic and hydrophobic domains, which are covalently linked to therapeutic molecules to enhance delivery and reduce toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If arginine-rich cell-penetrating peptides are used for delivering nucleic acid therapeutics, then cell penetration capability and delivery efficacy are improved, but toxicity increases significantly
Solution Approach 1:
The patent changes the chemical composition parameter of the cell-penetrating peptide by substituting arginine residues with lysine residues. This parameter change maintains the cationic charge necessary for cell membrane interaction while reducing the peptide's toxicity profile, thereby resolving the contradiction between delivery efficacy and toxicity.
Solution Approach 2:
The patent creates a composite structure by combining lysine-rich cationic domains with hydrophobic domains in a single peptide molecule. This composite design enables the peptide to maintain cell penetration capability through the cationic regions while the hydrophobic regions modulate membrane interaction properties, achieving effective delivery with reduced toxicity.
2Reliability
If arginine-rich CPPs are used to enhance dystrophin production in DMD models, then therapeutic efficacy is improved, but toxicity prevents clinical application
Solution Approach 1:
The patent modifies the amino acid composition parameter by replacing arginine with lysine in the CPP sequence. This substitution maintains the positive charge density required for binding to cell membranes and facilitating nucleic acid delivery, while lysine's different chemical properties result in reduced toxicity, enabling potential clinical application.
Solution Approach 2:
The patent employs short, naturally occurring peptide sequences that can be rapidly synthesized and degraded. The lysine-rich CPPs are designed to be biodegradable, eliminating the need for long-term accumulation in the body and reducing chronic toxicity effects, thereby enabling safer therapeutic use.
3Object-affected harmful factors
If alternative basic amino acids substitute for arginine in CPPs, then toxicity is reduced, but cell penetration capability is lost
Solution Approach 1:
The patent changes the amino acid parameter from arginine to lysine, which maintains the essential cationic charge (+1 at physiological pH) necessary for electrostatic interaction with negatively charged cell membranes. This parameter change preserves cell penetration capability while reducing toxicity, as lysine's smaller size and different hydrogen bonding characteristics allow effective membrane interaction without the harmful effects of arginine-rich sequences.
Solution Approach 2:
The patent applies local quality by concentrating cationic lysine residues in specific domains of the peptide molecule rather than uniformly distributing them. This localized arrangement optimizes interaction with cell membranes at specific regions, maintaining penetration capability while the overall peptide structure (including hydrophobic domains) controls toxicity through localized structural features.
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 lysine-rich CPPs demonstrate improved biodistribution to skeletal and cardiac tissues, reduce nuclear foci by up to 100%, and induce splicing corrections of 30-90% in target tissues with significantly lower toxicity compared to arginine-rich counterparts, effectively reversing DMD phenotypes.
Implementation Method 1
the peptide comprising at least two cationic domains and at least one hydrophobic domain, wherein the at least two cationic domains each comprise a plurality of lysine residues
Implementation Method 2
at least one hydrophobic domain
Data Source
AI summary
The present invention relates to peptides, in particular cell-penetrating peptides, and to conjugates of such cell-penetrating peptides with a therapeutic molecule, wherein the peptides comprise at least two cationic domains each comprising a plurality of lysine residues and wherein the peptides do not contain arginine residues. The present invention further relates to use of such peptides or conjugates in methods of treatment or as a medicament, especially in the treatment of genetic disorders and in particular neuromuscular diseases.