A Click Chemistry Approach to Targeted DNA Crosslinking with cis‐Platinum(II)‐Modified Triplex‐Forming Oligonucleotides

Abstract

Limitations of clinical platinum(II) therapeutics include systemic toxicity and inherent resistance.M odern approaches,t herefore,s eek new ways to deliver active platinum(II) to discrete nucleic acid targets.I nt he field of antigene therapy, triplex-forming oligonucleotides (TFOs) have attracted interest for their ability to specifically recognise extended duplex DNAtargets.Here,wereport aclickchemistry based approach that combines alkyne-modified TFOs with azide-bearing cis-platinum(II) complexes-based on cisplatin, oxaliplatin, and carboplatin motifs-to generate al ibrary of Pt II -TFO hybrids.T hese constructs can be assembled modularly and enable directed platinum(II) crosslinking to purine nucleobases on the target sequence under the guidance of the TFO.B yc ovalently incorporating modifications of thiazole orange-a knownD NA-intercalating fluorophore-into Pt II -TFOs constructs,e nhanced target binding and discrimination between target and off-target sequences was achieved.

Enzymatic Synthesis of Chemical Nuclease Triplex-Forming Oligonucleotides with Gene-Silencing Applications

“…An internally modified 31 nucleotide poly-pyrimidine parallel-binding TFO was produced by solid-phase synthesis in a similar manner to earlier reported TPMA-TFOs. ( 35 ) This TFO was selected as previous studies have reported thermal stability > 37°C ( 35 , 38 ) and increased target discrimination for internally modified AMN-TFO hybrids. ( 35 )…”

Triplex-forming oligonucleotides as an anti-gene technique for cancer therapy

“…Two TFO motifs are possible: pyrimidine-rich TFOs bind in a parallel manner, while purine-rich TFOs bind in an anti-parallel orientation. The pyrimidine-rich TFOs consisting primarily of thymines (T) or protonated cytosines (C + ) bind to DNA with AT and GC base pairs to form the canonical base triads T:AT and C + :GC with duplex DNA ( Beal and Dervan, 1991 ; Hennessy et al, 2022 ). Typically, pyrimidine-rich TFOs can only form the triple-helix formation under acidic conditions.…”

Site-specific covalent metalation of DNA oligonucleotides with phosphorescent platinum(ii) complexes

“…A similar approach was recently reported in the context of (non-luminescent) cis -Pt(II)-modified triplex-forming oligonucleotides. 36 …”