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

• DOI: 10.1002/ange.202110455
• Publication Date: 2021-10-15T22:05:03Z
• Authors: Joseph Hennessy; Bríonna McGorman; Zara Molphy; Nicholas P. Farrell; Daniel Singleton; Tom Brown; Andrew Kellett
• Keywords: Nucleobase

Abstract Limitations of clinical platinum(II) therapeutics include systemic toxicity and inherent resistance. Modern approaches, therefore, seek new ways to deliver active discrete nucleic acid targets. In the field antigene therapy, triplex‐forming oligonucleotides (TFOs) have attracted interest for their ability specifically recognise extended duplex DNA Here, we report a click chemistry based approach that combines alkyne‐modified TFOs with azide‐bearing cis ‐platinum(II) complexes—based on cisplatin, oxaliplatin, carboplatin motifs—to generate library Pt II ‐TFO hybrids. These constructs can be assembled modularly enable directed crosslinking purine nucleobases target sequence under guidance TFO. By covalently incorporating modifications thiazole orange—a known DNA‐intercalating fluorophore—into ‐TFOs constructs, enhanced binding discrimination between off‐target sequences was achieved.