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Dissemination

Tayler presents his work around the world

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Our ESR Tayler David Prieto from the University of Reading presented his work on synthetic and structural studies of ruthenium complexes as DNA major groove binders at different conferences.

He first presented a poster at the 16th  International Symposia of Applied Bioinorganic Chemistry (ISABC), which took place in Ioannina, Greece from the 11th to the 14th of June 2023. On the 7th of July, he did an oral presentation about it at the 19th Royal Society of Chemistry’s Nucleic Acid Forum in London, UK. His journey continued in Adelaide, Australia, for the 20th International Conference on Biological Inorganic Chemistry (ICBIC20), where he gave another oral presentation.

The poster can be found here.

The aim of his project, in collaboration with Diamond Light Source and the Kellett group at Dublin City University, is to provide the first crystallographic evidence of a ruthenium polypyridyl complex binding from the DNA major groove; potentially, as one component of a DNA-binding triplex-forming oligonucleotide (TFO) assembly.

DCU and LMU publish review on Third Generation Sequencing of Epigenetic DNA

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The Kellett (DCU) and Carell (LMU) groups recently published a collaborative review titled ‘Third Generation Sequencing of Epigenetic DNA’ in Angewandte Chemie. The review is open access and covers the latest developments in sequencing techniques adapted and developed for ‘third generation’ sequencing platforms, which promise to provide the fastest and most convenient means of DNA sequencing to date.

Cytosine modifications have been shown to influence gene regulation, in turn effecting disease and development, thus facile methods for sequencing these base modifications by exploiting the chemistries of these new devices is an active area of research. Despite extensive reviews covering sequencing technologies and base modifications independently, to our knowledge, this is the first publication to highlight the emerging potential of third generation sequencing technologies to expedite epigenetic research.

During the first in-person NATURE-ETN training week organised in the Institute for Chemical Epigenetic – Munich (ICE-M), Dr Markus Müller and Dr. Pascal Giehr delivered seminars focused on epigenome sequencing which provided valuable background in techniques developed to facilitate the decoding of this secondary information layer in DNA. Work Package 3 in NATURE-ETN aims to generate new techniques for sequencing and imaging epigenetic bases. DCU and LMU have access to third generation sequencing devices, so this review will provide a helpful reference point for researchers in the network.  

Eva publishes about click chemistry-based library preparation for long-read third-generation sequencing

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The communication paper of ESR Eva Schönegger and Dr. Antony Crisp from baseclick GmbH in collaboration with the LMU Munich, Institute for Chemical Epigenetics Munich was published in September 2022 in Bioconjugate Chemistry.

In this communication paper, entitled Click Chemistry Enables Rapid Amplification of Full-Length Reverse Transcripts for Long-Read Third Generation Sequencing, Eva, Dr. Antony Crisp, Dr. Markus Müller and coworkers describe the development of a novel click chemistry-based method for the generation and amplification of full-length cDNA libraries from total RNA.

In this work, supervised by Prof. Thomas Carell (LMU) and Dr. Thomas Frischmuth (baseclick), the use of click chemistry circumvents the need for the problematic template-switching reaction.

The use of PCR primers containing two overhanging 3′-nucleotides is one essential modification of the described workflow resulting in a significantly improved read-through compatibility of the 1,4-disubstituted 1,2,3-triazole-containing cDNA, where these modifications normally hinder amplification. This enables to use an insert size which is twice as large compared to the state-of-the art click chemistry-based technique, PAC-seq.

Taking the known advantages of PAC-seq, such as suppression of PCR artefacts, into consideration, the described library preparation method could enable various applications, including improved analyses of mRNA splicing variants and fusion transcripts.

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 on the cytotoxic activity of organometallic di-iron complexes in cancer cell lines

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Recent collaborative work from NATURE-ETN and the University of Pisa has been published in Organometallics by ESR Maria Dalla Pozza from the group of Gilles Gasser at Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences (France), in collaboration with the team of Prof. Fabio Marchetti at the University of Pisa (Italy). The scientists investigated the anticancer activity of some di-iron compounds functionalised with sugar moieties to increase their cellular uptake and possibly their selectivity for cancer cells. The compounds, synthesised by Marchetti’s group, were tested against a panel of cancerous cells by ESR Maria Dalla Pozza.

Among the different categories of metal drug candidates, iron complexes based on the ferrocene scaffold have aroused notable interest. The antiproliferative activity of these compounds is ascribable to the redox chemistry of the ferrocenyl iron(II) center, which undergoes oxidation to Fe(III) in the tumour cells. This enhances the formation of toxic metabolites that lead to cell death. Di-iron compounds have been less investigated, however recent studies have disclosed a promising anticancer potential. In this study, the sugar functionalisation was performed on di-iron complexes to optimise the cytotoxic properties by exploiting the Warburg effect. Specifically, the anticancer activity of the compounds was evaluated using the resazurin assay and the scratch assay. Overall, this study pointed out that the antiproliferative activities of the new complexes correlate with their lipophilicity, ranging from moderate cytotoxicity to inactivity, and showing an absence of appreciable selectivity with respect to a non-cancerous cell line. On the other hand, analogous diiron complexes without the sugar moiety functionalisation, analysed as references, performed better in the same conditions. This confirms the potential of the present category of organometallics in the medicinal field.

Reference:
Schoch, S., Iacopini, D., Dalla Pozza, M., Di Pietro, S., Degano, I., Gasser, G., Di Bussolo, V., and Marchetti, F. Tethering Carbohydrates to the Vinyliminium Ligand of Antiproliferative Organometallic Diiron Complexes. 
Organometallics (2022). https://doi.org/10.1021/acs.organomet.1c00519

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