Selective photo-cross-linking of 2'-O-psoralen-conjugated oligonucleotide with RNAs having point mutations

Area of Science:

• Molecular Biology
• Medicinal Chemistry
• Genetics

Background:

• Point mutations in genes are a significant cause of various cancers.
• Selective regulation of gene expression is crucial for developing novel anticancer therapeutics.

Purpose of the Study:

• To present a novel antisense molecule capable of sequence-specific photo-cross-linking to mutated oligonucleotide sites.
• To investigate the efficacy of a 2'-O-psoralen-conjugated antisense molecule compared to a 5'-O-psoralen-conjugated counterpart.

Main Methods:

• Synthesis of a 2'-O-psoralen-conjugated adenosine molecule in four steps.
• Introduction of the psoralen-conjugated adenosine into an oligodeoxyribonucleotide (2'-Ps-oligo).
• Comparative analysis of photo-cross-linking selectivity between 2'-Ps-oligo and 5'-O-psoralen-conjugated oligodeoxyribonucleotide (5'-Ps-oligo).

Main Results:

• The synthesized 2'-O-psoralen-conjugated adenosine was successfully incorporated into an oligodeoxyribonucleotide.
• The 2'-Ps-oligo demonstrated more selective photo-cross-linking compared to the 5'-Ps-oligo.
• Selective cross-linking occurred at the pyrimidine base within the mutated site (purine to pyrimidine alteration) in the target oligoribonucleotide.

Conclusions:

• The 2'-O-psoralen-conjugated oligodeoxyribonucleotide is a promising tool for sequence-specific targeting of mutated genes.
• This approach offers a potential new avenue for developing targeted anticancer drugs through precise gene expression regulation.