A Photoelectrocatalytic Platform for Sequence-Unrestricted Modification of Oligonucleotide Backbones

Area of Science:

• Medicinal Chemistry
• Oligonucleotide Therapeutics
• Chemical Biology

Background:

• Oligonucleotide therapeutics offer promise for genetic disorders but face challenges like nuclease instability and poor cellular uptake.
• Chemical backbone modifications, particularly neutral alkyl phosphonates, are key to improving oligonucleotide drug properties.
• Existing methods for installing diverse alkyl groups at specific backbone positions are limited, especially for complex motifs.

Purpose of the Study:

• To develop a general and programmable method for site-specific installation of diverse alkyl groups onto oligonucleotide backbones.
• To create enhanced oligonucleotide analogs with improved stability and therapeutic efficacy.
• To demonstrate the translational potential of these modified oligonucleotides in preclinical models.

Main Methods:

• A modular photoelectrochemical strategy utilizing photoredox and electrochemical activation to generate alkyl radicals from carboxylic acids.
• Radical-mediated C(sp3)─P bond formation for direct alkyl modification of oligonucleotide backbones.
• Synthesis of phosphoramidite monomers from modified oligonucleotides and incorporation via automated solid-phase synthesis.

Main Results:

• The method successfully installed a broad range of alkyl groups, including sterically demanding ones, in a sequence-unrestricted manner.
• Modified oligonucleotides retained duplex hybridization and exhibited enhanced nuclease resistance.
• Incorporation into an antisense drug candidate (Prexigebersen) significantly improved anti-leukemic efficacy in cellular and patient-derived models.

Conclusions:

• The developed photoelectrochemical strategy provides a versatile platform for creating next-generation oligonucleotide therapeutics.
• This approach overcomes limitations of existing modification techniques, enabling enhanced stability and efficacy.
• The enhanced Prexigebersen demonstrates significant therapeutic potential for treating leukemia.