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NATURE-ETN ESRs publish review on DNA triplexes

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A collaborative review by ESRs Ahmad Abdullrahman from the Department of Pharmacy, Chemistry and Pharmacy Building, University of Reading (UK), and Maria Dalla Pozza from Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences (France) was published in Chemical Science in August 2022.

In this review, entitled Three’s a crowd – stabilisation, structure, and applications of DNA triplexes, the ESRs put their efforts together in proficient teamwork supervised by Dr. James Hall, Prof. Christine Cardin from the University of Reading, and Prof. Gilles Gasser from Chimie ParisTech, PSL University.

They describe the main characteristics of triplex DNA structures, focusing on their application and interaction with metal compounds, highlighting the need for additional structure characterization and biological studies.

The DNA triplex may be formed naturally, during homologous recombination, or can be formed by the introduction of a synthetic triplex-forming oligonucleotide (TFO) to a DNA duplex. Among others, the most interesting feature of TFOs is their sequence specificity in binding a duplex DNA. The authors first compare the triplex structure with the canonical B-DNA structure. Subsequently, they report the main modifications at the base, sugar and phosphate backbone levels currently available to obtain a more stable structure, considering the potential in vivo conditions.

There is significant interest in developing TFOs with potential therapeutic applications, including their use as a delivery mechanism for compounds able to modify or damage DNA. However, to combine triplexes with functionalised compounds, a full understanding of triplex structure and chemical modification strategies is essential, stress the authors. In the review, these areas are discussed. Moreover, the possible use of photoactive Ruthenium polypyridyl complexes as a suitable photophysical payload for a TFO system is presented in this scientific paper. With the hope that future research will harness the peculiar characteristics of DNA triplexes.

New publication examines the multi-modal activity of copper(II) and silver (I)-phendione complexes on DNA scission within P. aeruginosa

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Recent collaborative work from NATURE-ETN has been published in the Journal of Biological Inorganic Chemistry by researchers in the Kellett lab at DCU. Co-authors include NATURE-ETN coordinator Dr. Andrew Kellett, co-supervisor Dr. Georgia Menounou, and ESR Conor Bain. The paper investigated the multi-modal activity of copper(II) and silver(I) complexes with the N,N-coordinating ligand, 1,10-phenanthroline-5,6-dione, with particular focus on DNA damage within Pseudomonas aeruginosa.

The emergence of microbial drug-resistance in recent decades has given rise to the need for novel antimicrobial therapeutics. The metal-based complexes [Ag(1,10-phenanthroline-5,6- dione)2]ClO4 (Ag-phendione) and [Cu(1,10-phenanthroline-5,6-dione)3](ClO4)2.4H2O (Cu-phendione) have previously demonstrated efficient antimicrobial action against multidrug-resistant species. The focus of the study was to understand the binding potential of these complexes with double-stranded DNA using a combination of in silico and in vitro approaches. Promising results arising from this work revealed a potentially new class of antimicrobial drug candidate with a distinct therapeutic mechanism against the multidrug-resistant pathogen P. aeruginosa.

Molecular docking studies showed both complexes elicit a multi-mechanistic approach to DNA-binding via hydrogen bonding, hydrophobic and electrostatic interactions, with both complexes favouring minor groove binding. Of the two complexes, Cu-phendione achieved the highest binding affinity for both major and minor grooves with nearly 10x greater affinity to DNA than Ag-phendione and nearly 20x greater affinity than the phendione ligand alone. Cu-phendione achieved DNA scission through free radical oxidative damage, as well as DNA-nicking and relaxation of supercoiled plasmid DNA. It was concluded that both complexes elicit a dose-dependent effect, with successful DNA fragmentation within multi-drug resistant pathogen P. aeruginosa when treated with a single dose of Cu-phendione. This work proposes a novel dose-regulated class of metal-based antimicrobial therapeutics.

Reference:

Galdino, A.C.M., Viganor, L., Pereira, M.M., Devereux, M., McCann, M., Branquinha, M.H., Molphy, Z., O’Carroll, S., Bain, C., Menounou, G., Kellett, A., Dos Santos, A.L.S. Copper(II) and silver(I)-1,10-phenanthroline-5,6-dione complexes interact with double-stranded DNA: further evidence of their apparent multi-modal activity towards Pseudomonas aeruginosa. J Biol Inorg Chem (2022). https://doi.org/10.1007/s00775-021-01922-3

Global Tech Company Biotage acquires ATDBio

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On 20 October 2021, one of NATURE-ETN’s partners, ATDBio has announced that it has been acquired by Swedish multinational life sciences company Biotage for approximately £ 45 million. The acquisition will bring many years of experience and expertise in highly complex DNA and RNA production to Biotage. As a new part of the Biotage Group, the ATDBio founders will continue to work on these technologies with existing and new customers. While ATDBio is undergoing major changes, R&D projects such as the ones that are ongoing as part of NATURE-ETN – with early-stage researcher Diallo Traore on CRISPR-Cas 9 in live-cell imaging – will continue as planned.

“ATDBio is very proud to become part of the Biotage family, which shares our passion for innovation, customer focus and sustainability. With our deep understanding of nucleic acid chemistry, we can ensure superior quality oligonucleotide synthesis, and supply highly pure products. We make oligonucleotides for a broad range of academic and commercial customers, including some of the most significant biotech and pharma companies globally. We will now be able to scale up even further thanks to the global presence and world-leading separation science expertise of Biotage.  We will continue to innovate, helping our customers to bring the next generation of nucleic acid molecular diagnostics, vaccines and therapeutics to the market”, said Dr Tom Brown Jr, Director of ATDBio.

ATDBio was founded in 2004 by Professor Tom Brown (Snr), one of the world’s leading nucleic acids chemists, Dr Dorcas Brown, an expert in oligonucleotide synthesis, Dr Tom Brown (Jnr) and Dr Asha Brown. It has laboratories in Oxford and Southampton, UK. As a leader in complex oligonucleotide synthesis, ATDBio has been working on molecular diagnostics, nucleic acid-based therapeutics and vaccines in addition to a new generation of DNA and RNA sequencing technologies.

Press release (Biotage)

Press release (ATDBio)

Successful NATURE-ETN check meeting

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The NATURE-ETN check meeting with our European Commission Research Executive Agency (REA) Project Officer took place online on the 5th of October 2021. Our Coordinator reported on the progress of the project and the COVID-19- and Brexit-induced challenges encountered and successfully solved through effective mitigation measures and collaboration. On their side, our 15 ESRs introduced themselves, their project objectives and training ambitions. The discussions on the next steps and upcoming milestones with the REA Project Officer were both fruitful and informative.

This meeting was the occasion to highlight our appreciation for the REA’s flexibility and support in these uncertain times and our gratitude for being part of the Marie-Skłodowska-Curie Actions community. A community that now counts two Nobel Prize winners in Chemistry for the second year in a row.

First ESRs recruited

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Seven out of the 15 ESRs have started their position in Germany, United Kingdom, France and Czech Republic.

The NATURE- ETN intersectorial training programme will provide them  with unique multidisciplinary scientific training  in the fields of chemical synthesis, biochemistry and cell biology as well as transferable and business skills, thanks notably to the contribution of the industry partners.

You can read about their project and background in the “People” section.