Modified Nucleotides in Bifunctional Antisense Oligonucleotides: Exploring their Anticancer Potential

Area of Science:

• Molecular Biology
• Biochemistry
• Cancer Research

Background:

• Bifunctional antisense oligonucleotides (BASOs) are splice-switching tools targeting pre-messenger RNA.
• Alternative splicing of the pyruvate kinase M1/2 gene is crucial in cancer development.
• Understanding nucleotide modifications can enhance BASO therapeutic efficacy.

Purpose of the Study:

• To investigate the impact of modified nucleotides on pyruvate kinase M1/2 gene alternative splicing.
• To evaluate the anticancer potential of modified BASOs in cancer cells.
• To identify chemical modifications that improve BASO therapeutic properties.

Main Methods:

• Synthesis and application of variously modified BASOs.
• Real-time measurement of cancer cell proliferation and motility.
• Analysis of alternative splicing regulation by BASOs.

Main Results:

• Specific chemical modifications significantly enhanced BASO therapeutic properties.
• Modified BASOs reduced cancer cell proliferation, induced cell death, and decreased motility.
• β-L-RNA and unlocked nucleic acid modifications showed potent splicing regulatory and anticancer effects.

Conclusions:

• Chemical modifications, particularly β-L-RNA and unlocked nucleic acid, improve BASO efficacy in splicing regulation and cancer therapy.
• These modifications offer a promising strategy for developing novel oligonucleotide-based cancer treatments.
• The study proposes efficient modifications for protein-binding oligonucleotides to enhance therapeutic outcomes.