Cover Feature: Polypyridyl‐Based Copper Phenanthrene Complexes: Combining Stability with Enhanced DNA Recognition (Chem. Eur. J. 3/2021)

Fantoni, Nicolò Zuin; Molphy, Zara; O'Carroll, Sinead; Menounou, Georgia; Mitrikas, George; Krokidis, Marios G.; Chatgilialoglu, Chryssostomos; Colleran, John; Banasiak, Anna; Clynes, Martin; Roche, Sandra; Kelly, S.; McKee, Vickie; Kellett, Andrew

doi:10.1002/chem.202003314

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“…The first discovered AMN [Cu(1,10‐phenanthroline) 2 ] 2+ (Cu‐Phen) was shown to semi‐intercalate and oxidise DNA from the minor groove in the presence of a reductant (e. g., ascorbate) [7,11] . More recently, polypyridyl and macrocyclic copper‐binding AMN architectures have been identified [12–16] . Copper AMNs have so far been used in DNA footprinting, [7] recombinant protein production, [17] chemotherapy, [18] and for nucleobase discrimination [19] …”

Section: Introductionmentioning

confidence: 99%

Development of Gene‐Targeted Polypyridyl Triplex‐Forming Oligonucleotide Hybrids

et al. 2020

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In the field of nucleic acid therapy there is major interest in the development of libraries of DNA-reactive small molecules which are tethered to vectors that recognize and bind specific genes. This approach mimics enzymatic gene editors, such as ZFNs, TALENs and CRISPR-Cas, but overcomes the limitations imposed by the delivery of a large protein endonuclease which is required for DNA cleavage. Here, we introduce a chemistrybased DNA-cleavage system comprising an artificial metallonuclease (AMN) that oxidatively cuts DNA, and a triplex-forming oligonucleotide (TFO) that sequence-specifically recognises duplex DNA. The AMN-TFO hybrids coordinate Cu II ions to form chimeric catalytic complexes that are programmable-based on the TFO sequence employed-to bind and cut specific DNA sequences. Use of the alkyne-azide cycloaddition click reaction allows scalable and high-throughput generation of hybrid libraries that can be tuned for specific reactivity and gene-ofinterest knockout. As a first approach, we demonstrate targeted cleavage of purine-rich sequences, optimisation of the hybrid system to enhance stability, and discrimination between target and off-target sequences. Our results highlight the potential of this approach where the cutting unit, which mimics the endonuclease cleavage machinery, is directly bound to a TFO guide by click chemistry.

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