Aminopyridinyl-Pseudodeoxycytidine Derivatives Selectively Stabilize Antiparallel Triplex DNA with Multiple CG...

Area of Science:

• Molecular Biology
• Chemical Biology
• Genetics

Background:

• Triplex DNA formation is a promising genome-targeting strategy.
• Natural nucleosides cannot recognize inverted CG and TA base pairs, limiting triplex DNA applications.
• Developing modified nucleosides is crucial for expanding triplex-forming technologies.

Purpose of the Study:

• To design and synthesize novel pseudo-deoxycytidine (ΨdC) derivatives.
• To achieve selective recognition of the CG base pair for triplex DNA formation.
• To explore the potential of these derivatives in genome-targeting applications and gene regulation.

Main Methods:

• Synthesis of aminopyridine-bearing ΨdC derivatives.
• Assessment of binding selectivity and affinity towards CG base pairs.
• Formation of triplex DNA with a target gene promoter sequence.
• Evaluation of transcriptional inhibition in human cancer cells.

Main Results:

• Aminopyridine-ΨdC derivatives demonstrated high selectivity and affinity for CG base pairs across various sequence contexts.
• 3-methyl-2-aminopyridinyl-ΨdC ((Me) AP-ΨdC) successfully formed stable triplex DNA with the hTERT gene promoter.
• The (Me) AP-ΨdC containing triplex effectively inhibited hTERT gene transcription in human cancer cells.

Conclusions:

• Novel ΨdC derivatives, particularly (Me) AP-ΨdC, enable selective CG base pair recognition for triplex DNA formation.
• These modified nucleosides significantly expand the scope of triplex-forming oligonucleotides for genome targeting.
• (Me) AP-ΨdC holds potential for developing new therapeutic strategies against cancer by inhibiting specific gene transcription.