D-amino acid polypeptides for efficient intracellular cargo delivery
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Solution Overview
Problem
Current methods for delivering macromolecules such as proteins, peptides, and oligonucleotides into cells face challenges including high elimination rates, off-target uptake, immune response, and inefficient intracellular delivery, particularly for therapeutic and diagnostic applications, with existing cell-penetrating peptides (CPPs) often requiring high concentrations that can cause toxicity and membrane disruption.
Innovation Solution
Development of polypeptides with at least 85% sequence identity to specific sequences, incorporating D-amino acids and derivatized amino acids, which can form conjugates with therapeutic agents or nucleic acids, facilitating efficient cellular internalization and reduced cytotoxicity, and antimicrobial peptides capable of disrupting microbial membranes with improved hemocompatibility.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If high concentrations of cell-penetrating peptides are used to achieve efficient cargo delivery, then delivery efficiency is improved, but membrane disruption and cytotoxicity increase
Solution Approach 1:
The patent modifies the chemical parameters of CPPs by incorporating D-amino acids and derivatized amino acids, which fundamentally changes the peptide's interaction with cell membranes. This allows achieving efficient cargo delivery at lower concentrations, thereby avoiding the cytotoxicity associated with high concentrations of conventional L-amino acid-based CPPs
Solution Approach 2:
The patent creates composite peptide structures by combining D-amino acids, derivatized amino acids, and cargo molecules into integrated conjugates. These composite structures achieve both efficient cellular internalization and reduced cytotoxicity simultaneously, resolving the contradiction between delivery efficiency and safety
2Ease of operation
If conventional CPPs are used to deliver macromolecules into cells, then cellular internalization is achieved, but the cargo gets trapped in endosomal pathways leading to lysosomal degradation
Solution Approach 1:
The patent changes the chemical parameters of the CPP structure by using D-amino acids and derivatized amino acids, which fundamentally alters the internalization mechanism. These modified peptides facilitate direct translocation into the cytosol while minimizing endosomal trapping, thereby improving cargo delivery reliability to the cytosol while maintaining cellular internalization capability
3Reliability
If peptide drugs are administered to target intracellular ligands, then therapeutic effect is improved, but elimination rates and off-target uptake must be overcome
Solution Approach 1:
The patent applies local quality modification by incorporating specific D-amino acids and derivatized amino acids at particular positions within the peptide sequence. This localized modification strategy optimizes the peptide's pharmacokinetic properties, reducing elimination rates and off-target uptake while maintaining or enhancing therapeutic effect
Solution Approach 2:
The patent changes the chemical parameters of the peptide drug by incorporating D-amino acids and derivatized amino acids, which fundamentally alters the peptide's stability, cellular uptake, and elimination characteristics. These parameter changes enable the peptide to achieve better therapeutic effects with reduced off-target effects and slower elimination rates
Data Source
AI summary
Described herein are membrane permeabilizing peptides and antimicrobial peptides, polynucleotides encoding the peptides, and compositions containing the peptides. Furthermore, described herein are methods for using the peptides, polynucleotides, and compositions for research, diagnosis, and therapy.