Peptide Conjugate-Based Delivery Systems

Unlike small-molecule drugs, oligonucleotides are macromolecules, and their physicochemical properties, in particular, their polarity and polyanionic nature of the ribose phosphate backbone, essentially hinder passive diffusion through the phospholipid bilayer of a biological membrane. Thus, overcoming the challenge of delivering oligonucleotides selectively to the correct organ or tissue after systemic or local administration is crucial for the success of oligonucleotide therapeutics.

Cell-penetrating peptides (CPPs) are cationic and/or amphipathic peptides, usually up to 30 amino acids in length, that are characterized by their remarkable ability to deliver different cargo molecules into cells and tissues. Recent studies have shown that conjugates of CPPs with various oligonucleotides and, more often, their analogs demonstrate excellent efficiency in the delivery of oligonucleotide therapeutics.

Common CPPs Used in Peptide-Oligonucleotide Conjugates

The CPPs commonly used in peptide-oligonucleotide conjugates include: polycationic peptides, amphipathic peptides, and hydrophobic peptides. Here are some examples.

Mechanism of Peptide Conjugate-Based Delivery

Mechanisms of peptide conjugate-based delivery are internalization modes that may be divided into two groups: energy-independent (direct translocation) and energy-dependent (endocytosis) modes^[1]. It is believed that direct translocation occurs when CPPs form nanocomplexes with oligonucleotides (non-covalent strategy) at high peptide concentrations. However, most CPPs and their conjugates seem to be taken up by cells via endocytosis, which is a natural and energy-dependent process. Endocytosis involves a variety of pathways, broadly classified as macropinocytosis, endocytosis mediated by clathrin or caveolin, and clathrin/caveolin-independent endocytosis.

Synthetic Approaches of Peptide-Oligonucleotide Conjugates

There are two main synthetic approaches for peptide-oligonucleotide conjugates at Alfa Chemistry. One is the stepwise solid-phase synthesis, and another is post-synthetic conjugation. Their advantages are as follows.

Stepwise solid-phase synthesis

• No excess of either peptide (P) or oligonucleotide (O) fragments.
• Absence of time-consuming isolation/purification of both P and O fragments.
• It is convenient for peptide-oligonucleotide conjugation due to the compatibility of protecting group.

Post-synthetic conjugation

• Many suitable conjugation procedures are available.
• No incompatibility issue with the two chemistries.

How We Do?

Alfa Chemistry is proficient in the drug delivery technology of oligonucleotide therapeutics and provides solutions to improve the delivery efficiency and security of oligonucleotide therapeutics. You can also contact us directly to customize peptide-oligonucleotide conjugates to speed up your project.

Our products and services are for research use only and cannot be used for any clinical purposes.

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