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click chemistry

New Publication: Thiazole Orange-Carboplatin TFO Combination Probes for Enhanced DNA Crosslinking

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A group of researchers from the Kellett group at Dublin City University (including our ESR Malou Coche), the Brown group at the University of Oxford, and the company ATDBio, along with the member of our Scientific Advisory Board Nicholas P. Farrell (Virginia Commonwealth University) co-authored a new publication in the journal RSC Medicinal Chemistry.

Titled “Thiazole Orange-Carboplatin Triplex-Forming Oligonucleotide (TFO) Combination Probes Enhance Targeted DNA Crosslinking”, this study reports a new class of Carboplatin-TFO hybrid that incorporates a bifunctional alkyne-amine nucleobase monomer called AP-C3-dT that enables dual ‘click’ platinum(II) drug conjugation and thiazole orange fluorophore coupling.

It is available in Open Access on the journal’s website.

A new publication from the collaboration between LMU and baseclick

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Our ESR Eva Schönegger, together with colleagues from the company baseclick GmbH and the Carell group at LMU Münich, just published a new paper titled “Orthogonal end labelling of oligonucleotides via dual incorporation of Click reactive NTP analogues” on ChemBioChem.

The paper introduces a modular method for modifying DNA and RNA strands at both ends with click-modifiable functional groups using γ-modified ATP analogues and T4 PNK catalysis for 5′-modification, compatible with TdT-catalyzed 3′-elongation using 3′-Azido-2′,3′-ddGTP. The approach is demonstrated to be suitable for oligo-oligo ligations and ssDNA-circularization, potentially enhancing the utility of oligonucleotides in therapeutic and diagnostic applications, particularly in next-generation sequencing.

The list of publications originating from the network can be found on our Dissemination page.

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.

The 4th training week – In the core of NATURE-ETN

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Early-stage researchers (ESRs) and principal investigators have been invited to attend the 4th training week at Dublin City University where this EU-funded research consortium was born.

Prof. Andrew Kellett first gave an update on the project before introducing Prof. Nicholas Farrell from Virginia Commonwealth University (US), who is one of the scientific advisors of NATURE-ETN and is interested in Glycosaminoglycans as signalling molecules. He talked about his latest results and joked about how retiring is difficult when you can’t stop looking for more results.

Each ESR presented their results obtained so far followed by questions, comments, and discussions for future ideas. On Thursday, a team from the German biophysical instrument manufacturer NanoTemper delivered training on the Monolith technologies in Andrew Kellett’s lab to ESRs who had the opportunity to prepare the samples, learn how to read the results, and think about how this technology can be applied to their projects.

Finally, on the last day of the training week, ESRs were hosted by Prof. Niall Barron at the National Institute for Bioprocessing Research and Training (NIBRT). Prof. Barron explained the advanced therapy medicinal products, emphasizing the need to keep in mind the patient delivery process while obtaining basic research results. ESRs conducted a complete tour guided by Dr Adam Pritchard who showed and explained the technologies behind the bioproduction of recombinant proteins, vaccines, and cell and gene therapies.

Before saying goodbye, the ESRs decided to go for a walk together. This time down to the lighthouse at Dún Laoghaire, a small town outside the busy Dublin. Prof. Barron mentioned Emerson who said, “Science does not know its debt to imagination”, and isn’t the sea the best place to clear the mind and fire the imagination?

In this training week, new collaborations were created between ESRs, wrapping up before departing to their different locations in Europe, where they will bring home new ideas to apply in their labs and Irish souvenirs!

By Ahmad Abdullrahman (ESR4)

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

Second training week – Entrepreneurship, IP and ESR updates

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From the 13th to the 15th of September 2021, the ESRs took part in the second online NATURE-ETN training week.

In the first two days, the ESRs updated each other on their progress and receive valuable feedback from their peers and PIs. Potential opportunities for collaboration and secondments were also explored.

On the third day, Dr. Thomas Frischmuth, CEO of baseclick GmbH, provided two training sessions on entrepreneurship and Intellectual Property (IP). Using the leading biotechnological company and NATURE-ETN beneficiary baseclick as a basis, Dr. Frischmuth shared his experience and perspectives in terms of business models and company growth. During the IP session, the ESRs were introduced to internal vs. external IP, patent filing strategies, and examples of European and national patenting processes.

First training week – combining soft and technical skills

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From the 18th to the 22nd of June 2021, the ESRs took part in the first NATURE-ETN training week, which covered a mix between soft and technical skills. The training was held virtually due to the COVID-19 pandemic and subsequent travel limitations.

During the first day, the ESRs were introduced to Hugh Kearns’ (ThinkWell) Seven Secrets of Highly Successful Research Students.

In this workshop, Kearns described key habits that help PhD students complete their research project efficiently, ensuring appropriate work-life balance and overcoming issues such as writer’s block and imposter syndrome.  
 
The second day started with a training session on Research Project Management from the partner organisation accelopment Switzerland Ltd.
 
The training covered aspects such as project planning, project monitoring, reporting, risk management, and project communication.

The scientific training consisted of both live and pre-recorded (asynchronous) lectures and the materials will remain available to the ESRs for future references.

Prof Tom Brown from the University of Oxford gave introductory and advanced lectures on the Synthesis of Biomolecules. This training notably covered nucleic acid structures, as well as oligonucleotide synthesis and their use as drugs in genetic and forensic analyses.
 
Dr Tom Brown Jnr from the oligonucleotide synthesis company ATDBio provided additional insights from more applied and commercial perspectives, and an introduction to ATDBio’s activities.
 
On the third and last day, Prof Andrew Kellett, Coordinator of NATURE-ETN, and his team at the Dublin City University (DCU) introduced the ESRs to artificial gene editing systems and molecular methods.

Prof Andrew Kellett discussed in detail metallodrug-DNA interactions, chemical nucleases, and advanced hybrid biomaterials for gene editing using click chemistry. Pre-recorded lectures with the principles of novel methodologies, techniques, and biophysical assays developed within the Kellett group were followed by high-quality virtual laboratory sessions recorded at the exceptionally well-equipped facilities at DCU.

This was the first of a series of training events that will be held both online and in-person throughout the project duration.

Open position in Oxford, UK

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The research group of Prof. Tom Brown from the Oxford University Department of Chemistry is looking for an Early-Stage Researcher (ESR) for a period of three years. The ESR will work on a project entitled “chemically modified CRISPR systems for improved gene editing”, which aims to use cutting-edge nucleic acid chemistry to radically alter the mechanism by which the CRISPR-Cas9 system functions.

Deadline for application: 10 March 2021

Job description and application details

Picture: Bodleian Library, Oxford / Author: Zhushenje

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.