Total stepwise solid-phase synthesis of oligonucleotide-(3'-->N)-peptide conjugates

Area of Science:

• Oligonucleotide chemistry
• Peptide synthesis
• Bioconjugation

Background:

• Oligonucleotide-peptide conjugates are valuable tools in molecular biology and medicine.
• Previous methods for synthesizing these conjugates have limitations in efficiency and scope.
• Developing robust synthetic routes is crucial for advancing therapeutic applications.

Purpose of the Study:

• To establish an efficient solid-phase synthesis for oligonucleotide-peptide conjugates.
• To create a versatile platform for conjugating various peptides and oligonucleotide modifications.
• To enable the incorporation of labels for studying cellular uptake.

Main Methods:

• Stepwise solid-phase synthesis utilizing controlled pore glass or macroporous polystyrene beads.
• Employing a homoserine linker approach for conjugate formation.
• Synthesizing conjugates with different cell-penetrating peptides and oligonucleotide backbones (phosphodiesters, phosphorothioates).

Main Results:

• Demonstrated an efficient and stepwise solid-phase synthesis of oligonucleotide-peptide conjugates.
• Successfully prepared a range of conjugates with diverse peptide and oligonucleotide components.
• Showcased the ability to incorporate fluorescent labels for cellular uptake analysis.

Conclusions:

• The described solid-phase synthesis provides an efficient route to oligonucleotide-peptide conjugates.
• This method supports the conjugation of various peptides and modified oligonucleotides.
• The platform facilitates the development of novel oligonucleotide-based therapeutics and research tools.