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

Overview

Journal Angew Chem Int Ed Engl

Specialty Chemistry

Date 2021 Oct 15

PMID 34652881

Citations 10

Authors

Joseph Hennessy

Brionna McGorman

Zara Molphy

Nicholas P Farrell

Daniel Singleton

Tom Brown

Andrew Kellett

Affiliations

Soon will be listed here.

Abstract

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

Citing Articles

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Thiazole orange-carboplatin triplex-forming oligonucleotide (TFO) combination probes enhance targeted DNA crosslinking.

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