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Peptide-Oligonucleotide Conjugates (POCs) for Oligonucleotide Delivery

Peptide-Oligonucleotide conjugates (POCs) are synthetic molecules, in which a peptide is conjugated to an oligonucleotide, for example, a linear or cyclic peptide linked by a covalent bond or linker to an oligonucleotide or its analogs.

Peptide-oligonucleotide conjugates (POCs) combine peptides with oligonucleotides through a covalent bond or a linker molecule, combining the unique properties of each to enhance biological or therapeutic applications. This combination leverages the binding specificity of oligonucleotides with the diverse functionality of peptides to improve cellular targeting, cellular uptake, and stability.

 

Peptide   -   Linker  -  Oligonucleotide

 

Peptide Design, Synthesis, and Conjugation

Linear or cyclized peptides can be designed and synthesized via solid-phase peptide synthesis. Non-standard amino acids can be incorporated during synthesis or post-synthesis as desired. In general peptide range between 5 to 25 amino acids in length.

Linkers and conjugation

A variety of activated linkers is commercially available for conjugation. Alternatively, standard bioconjugation techniques allow the synthesis of simple and complex conjugates. Non-cleavable, cleavable, and self-immolating linkers allow the design of specific complex POCs.

Oligonucleotide Design and Synthesis

Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) can be designed based on target genes. Single and double-stranded RNA or DNA oligonucleotides can be used for conjugation.

Modifications

Optimized synthesis and conjugation methods allow the incorporation of base, sugar, and backbone modifications for increased stability and efficiency.

Fluorescence and Dye Labeling

In addition, selected conjugation methods, such as click chemistries, enable the addition of fluorescent or dye moieties to POCs.

Synthesis

The synthesis of POCs generally involves the chemical conjugation of a peptide to an oligonucleotide through a variety of linkers. These linkers can be stable or cleavable under certain conditions, such as pH-sensitive or enzymatically degradable linkers, to release the oligonucleotide within specific cellular compartments.

Potential use of POCs

Enhancing Targeting and Delivery: Specific peptides can target specific cell types or tissues, improving the delivery of the oligonucleotide component to desired locations. For example, cell-penetrating peptides (CPPs) like TAT or R9 are often used to shuttle oligonucleotides across cell membranes.

Improving Stability and Bioavailability

Conjugation of oligonucleotides to peptides stabilizes and protects them from nucleases in the bloodstream or cellular environments, extending the conjugate's half-life, especially beneficial for therapeutic applications.

Broader Therapeutic Applications

Various therapeutic uses, including gene silencing, gene editing, and cancer therapy, demand specific designs of POCs. POCs enable targeting particular genes or molecular targets by linking therapeutic oligonucleotides, such as antisense oligonucleotides (ASOs), siRNAs, or aptamers, with targeting peptides.

Diagnostic and Research Tools

POCs are powerful probes for molecular imaging and diagnostics. Conjugating fluorescently labeled peptides with oligonucleotides can help visualize molecular interactions, monitor gene expression, or detect specific nucleic acid sequences within cells.

Customizable Design

The synthesis of designed sequences, with controlled lengths of both the peptide and oligonucleotide components, allows customization to fit various biochemical and cellular conditions.

Reference and Links

Fàbrega C, Aviñó A, Navarro N, Jorge AF, Grijalvo S, Eritja R. Lipid and Peptide-Oligonucleotide Conjugates for Therapeutic Purposes: From Simple Hybrids to Complex Multifunctional Assemblies. Pharmaceutics. 2023 Jan 18;15(2):320. [PMC]

Klabenkova K, Fokina A, Stetsenko D. Chemistry of Peptide-Oligonucleotide Conjugates: A Review. Molecules. 2021 Sep 6;26(17):5420. [PMC]

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Bio-Synthesis provides custom morpholinos including Phosphorodiamidate Morpholino, and Thiomorpholino Oligonucleotides.

Bio-Synthesis provides a full spectrum of high quality custom oligonucleotide modification services including 5'-triphosphate and back-bone modifications, conjugation to fatty acids, biotinylation by direct solid-phase chemical synthesis or enzyme-assisted approaches to obtain artificially modified oligonucleotides, such as BNA antisense oligonucleotidesmRNAs or siRNAs, containing a natural or modified backbone, as well as base, sugar and inter-nucleotide linkages.

Bio-Synthesis also provides biotinylated mRNA and long circular oligonucleotides.

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