Dual-Hydrophobic Cell-Penetrating Peptides for Lower-Toxicity Delivery
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Solution Overview
Problem
Current cell-penetrating peptides (CPPs) used for delivering therapeutic molecules, such as antisense oligonucleotides, are inefficient and toxic at high doses, limiting their effectiveness in treating genetic disorders like Duchenne muscular dystrophy (DMD).
Innovation Solution
Development of peptides with a specific structure comprising one or more cationic domains and two hydrophobic domains positioned at the N- and C-terminus, enhancing cell penetration and efficacy while reducing toxicity by allowing lower dose administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If high doses of existing cell-penetrating peptides are used to enhance therapeutic delivery, then cell penetration and therapeutic efficacy are improved, but toxicity increases
Solution Approach 1:
The patent modifies the chemical structure of cell-penetrating peptides by incorporating D-amino acids instead of L-amino acids, and by changing the side chain compositions (using Dab, Dhb, DPr residues instead of traditional amino acids). These parameter changes in molecular structure enable the peptides to achieve effective cell penetration and therapeutic delivery at lower doses, thereby reducing toxicity while maintaining or improving efficacy
Solution Approach 2:
The patent creates composite peptide structures combining multiple D-amino acid residues with specific hydrophobic and hydrophilic side chains in defined sequences. These composite structures exhibit enhanced cell-penetrating capabilities and improved pharmacokinetic properties compared to natural peptides, allowing effective therapeutic delivery at reduced doses with lower toxicity profiles
2Productivity
If existing CPPs are used at sufficient doses to achieve therapeutic effects, then delivery efficiency is improved, but side effects and toxicity worsen
Solution Approach 1:
By changing the stereochemistry from L-amino acids to D-amino acids and modifying side chain compositions, the patent creates peptides with altered pharmacokinetic properties including improved stability, enhanced cell penetration efficiency, and reduced immunogenicity. These parameter changes enable effective therapeutic delivery without requiring high doses that cause side effects
Solution Approach 2:
The patent develops peptides with improved stability and efficacy that can achieve therapeutic effects at lower, safer doses. The modified D-amino acid peptides exhibit resistance to proteolytic degradation and improved pharmacokinetic profiles, allowing effective single or repeated administrations at doses that do not cause significant side effects
3Stability of the object's composition
If natural amino acid sequences are used in CPPs, then biological compatibility is maintained, but cell penetration efficiency and serum stability are insufficient
Solution Approach 1:
The patent systematically changes the stereochemical configuration from L-amino acids to D-amino acids throughout the peptide sequence. This parameter change confers resistance to proteolytic degradation by natural enzymes, dramatically improving serum stability while simultaneously enhancing cell penetration efficiency through altered membrane interaction properties
Solution Approach 2:
The patent employs specific combinations of D-amino acids with particular side chain properties (hydrophobic, hydrophilic, charged) at different positions in the peptide sequence. This local optimization of amino acid residues creates regions with specific functions for membrane interaction, stability, and cellular uptake, achieving both high serum stability and efficient cell penetration
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 peptides achieve high levels of exon skipping and dystrophin protein restoration in skeletal muscles, demonstrating improved therapeutic efficacy with reduced toxicity compared to existing CPPs.
Implementation Method 1
the peptide comprising: One or more cationic domains; and Two or more hydrophobic domains
Implementation Method 2
Two or more hydrophobic domains each comprising at least 3 amino acid residues
Data Source
AI summary
the present invention relates to peptides, in particular cell-penetrating peptides, having a first hydrophobic domain positioned at the C-terminus of the peptide and a second hydrophobic domain positioned at the N-terminus of the peptide, and to conjugates of such cell-penetrating peptides with a therapeutic molecule. 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 muscular dystrophies such as Duchenne muscular dystrophy.