CPP–Carbohydrate Conjugates for Hepatocyte Oligonucleotide Targeting
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Solution Overview
Problem
Existing nucleic acid therapies face challenges in achieving efficient intracellular delivery, particularly to liver cells such as hepatocytes, due to limited access when administered systemically, and current carrier systems provide low intracellular delivery efficiency.
Innovation Solution
Compounds comprising a cell penetrating peptide (CPP), a therapeutic oligonucleotide (TO), and a carbohydrate targeting moiety (CTM), optionally with an exocyclic peptide (EP), enhance delivery to target cells, particularly liver cells, by forming specific structures like cyclic peptides and using linkers to connect these components.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If carrier systems such as polymers, cationic liposomes or chemical modifications are used to facilitate intracellular delivery of nucleic acid therapeutics, then delivery capability is improved, but intracellular delivery efficiency remains low
Solution Approach 1:
The patent creates a composite delivery system combining multiple functional components: a cell-penetrating peptide (CPP) for membrane transduction, a carbohydrate targeting moiety (CTM) for hepatocyte-specific targeting, and a therapeutic oligonucleotide (TO) for therapeutic effect. This multi-component composite structure resolves the contradiction by integrating both delivery capability (via CPP) and delivery efficiency (via CTM-mediated targeted accumulation in liver cells)
Solution Approach 2:
The carbohydrate targeting moiety (CTM) acts as an intermediary between the delivery system and hepatocyte surface receptors (such as asialoglycoprotein receptors). This intermediary component enables specific recognition and binding to target cells, thereby improving intracellular delivery efficiency without compromising the overall delivery capability provided by the CPP
2Reliability
If GalNAc is used to target therapeutic oligonucleotides to liver cells, then targeting capability is improved, but further improvement in intracellular targeting to hepatocytes is limited
Solution Approach 1:
The patent merges two targeting functionalities: the GalNAc moiety (providing baseline liver cell targeting) with an enhanced carbohydrate targeting moiety (CTM) designed for superior hepatocyte specificity. This merging creates a synergistic effect where the combined targeting system achieves both reliable liver cell binding and enhanced hepatocyte intracellular delivery efficiency
Data Source
AI summary
Compounds are provided include a cell penetrating peptide, a therapeutic oligonucleotide, and a carbohydrate targeting moiety. The compounds may also include an exocyclic peptide. The compounds may be targeted to liver cells. The therapeutic oligonucleotide may be an oligonucleotide for treating a disease or disorder associated with a liver cell.