Stapled Cell-Penetrating Peptides for Oligonucleotide Delivery
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Solution Overview
Problem
Current methods for delivering biologically active compounds, such as oligonucleotides, face challenges in penetrating cells due to their uncharged nature and toxicity issues associated with positively charged peptides, which limits their effectiveness and clinical translation.
Innovation Solution
The development of stabilized cell-penetrating peptides (CPPs) through stapling or stitching, forming stapled or stitched peptides, which are conjugated to biologically active compounds via a bi-functional linker, enabling efficient cellular uptake while reducing toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If positively charged peptides are used to deliver biologically active compounds, then cellular uptake is improved, but toxicity increases
Solution Approach 1:
The patent applies parameter changes by modifying the charge state of peptides from positively charged to neutral or negatively charged, while maintaining cell-penetrating capability through structural stabilization (stapling/stitching). This resolves the contradiction by changing the charge parameter to reduce toxicity while preserving delivery function.
Solution Approach 2:
The patent creates composite structures by combining stabilized peptide scaffolds with biologically active compounds (oligonucleotides, proteins) through conjugation. The stabilized peptide acts as a delivery vehicle that protects the cargo and facilitates cellular uptake without the toxic side effects of traditional charged peptides.
2Object-affected harmful factors
If neutral oligonucleotides are used as biologically active compounds, then toxicity is reduced, but cellular penetration ability deteriorates
Solution Approach 1:
The patent introduces stabilized peptides as intermediary carriers that mediate the delivery of neutral oligonucleotides into cells. The peptide-conjugate acts as a bridge, providing the cell-penetrating function that neutral oligonucleotides lack, while maintaining the low toxicity advantage of the neutral cargo.
Solution Approach 2:
The patent segments the delivery system into distinct functional components: a stabilized peptide carrier (for cellular uptake) and a neutral oligonucleotide cargo (for therapeutic action). This segmentation allows each component to optimize its specific function while working together as an integrated delivery system.
3Stability of the object's composition
If cell-penetrating peptides are stabilized through stapling or stitching, then structural stability is improved, but molecular complexity increases
Solution Approach 1:
The patent applies preliminary action by pre-stabilizing the peptide structure through stapling or stitching modifications before conjugation to the biologically active compound. This pre-stabilization ensures structural integrity and cell-penetrating capability are established in advance, simplifying the overall conjugation process and improving reproducibility.
Data Source
AI summary
The invention relates to improvements in drug delivery and more particularly to the use of Cell Penetrating Agents (CPA's) or Cell Penetrating Peptides (CPP's) which have been stabilized by, for example: i) stapling two amino acids to form Stapled CPP's (StaP's) or ii) stitching three or more amino acids to form stitched CPP's (StiP's). These stabilized CPP's are conjugated to a drug or Biologically Active Compound (BAC) directly or via a Bi-Functional Linker (BFL) so that the BAC can be carried though a cell membrane by the CPP. The resulting molecules are referred to as Drug Carrying Cell Penetrating Molecules (DCCPM's). The preferred BAC is an electrically low charge carrying oligonucleotide such as a phosphorodiamidate morpholino oligonucleotide (PMO). The invention also relates to a method of facilitating the uptake of a BAC into a cell, the use of a DCCPM in the treatment of a disease requiring alteration of an endogenous or exogenous gene, a method of improving the bioavailability of a drug or BAC, a method of introducing a drug or BAC to a site which is refractory to the drug or BAC in its native state, a method of treating a subject comprising administering the DCCPM's of the invention and to a pharmaceutical composition comprising the DCCPM and one or more pharmaceutically acceptable excipients.