Dr. Creina Slator (senior postdoctoral researcher)

Funder: Novo Nordisk Foundation

Title: Image and Destroy: New Radionuclides for Cancer Theranostics (ID-Cancer)

This project seeks to develop a new class of metallodrug-hybrid materials as radionuclide diagnostic and therapeutic (theranostic) agents. This involves developing oligonucleotide vectors that specifically target DNA (antigene) and RNA (antisense) that will be incorporated into metal-chelating hybrid constructs. Unique therapeutic action and underpinning mechanisms will be evaluated through a range of biophysical and molecular biological techniques.

Dr. Georgia Menounou (postdoctoral researcher)

Funder: Synthesis and Solid-State Pharmaceutical Centre (SSPC) and co-funded by Merck Sharp & Dohme

Title: Design of Highly specific Gene Knockout Agents

Genome editing and nucleic acid (NA) therapies are expected to play a key role in next-generation personalized medicine by correcting the underlying genetic causes of disease with precision. However, state-of-the-art gene editing technologies including CRISPR-Cas suffer from a number of unresolved issues that preclude their clinical application. This project seeks to extend the boundaries of today`s gene editing technologies through the production of an innovative chemistry-based gene editing methodology and the generation of a unique class of advanced site-selective bio-compatible hybrid materials as gene knockout therapeutics. These hybrids are consisted of a triplex forming oligonucleotide (TFO) loaded with a copper- or zinc-based artificial metallo-nuclease (AMN). The AMN is capable to induce a unique oxidative DNA cleavage mediated by reactive oxygen species (ROS). To conjugate AMNs to TFOs cutting-edge “click chemistry” methodologies are explored with or without copper catalysis. We seek to establish an efficient, fast and one-pot chemoselective methodology to improve the yield and facilitate scalable generation of AMN-TFO hybrid libraries. Hybrid constructs with optimal sequence discrimination and suitable cellular targeting properties will progress to in vivo analysis. The project has received funding by the SSPC ‘Molecules 3’ Scheme and MSD Carlow.

Dr. Bríonna McGorman (Postdoctoral Researcher)

Funder: Irish Research Council (IRC) Government of Ireland Postgraduate scheme

Title: Multiple nucleotide incorporation-primer extension (MNI-PEX for the synthesis of novel nucleic acid therapeutics.

There is major interest in targeting the human genome with directed nucleases for genetic engineering and knock-out applications. CRISPR/Cas 9 is currently considered the gold-standard for gene-editing, but artificial metallo-nucleases (AMNs) offer an intriguing alternative as they provide greater flexibility and offer multiple avenues for gene-silencing. Extensive research has been performed to direct AMNs to specific genetic targets. Triplex-forming oligonucleotides (TFOs) are short strands of nucleotides that can hybridise to specific sequences of dsDNA and form stable triple helical structures. Thereby, tethering an AMN to a TFO enables delivery of AMNs to their desired genetic target. Within this project I aim to develop new enzymatic protocols for the synthesis of novel AMN-TFO hybrids that will overcome the limitations of solid-phase oligonucleotide synthesis and result in the generation of new gene-targeted therapeutics.

Dr. Joseph Hennessy (Postdoctoral Researcher)

Funder: Irish Research Council (IRC) Government of Ireland Postgraduate scheme

Title: Mitchondrial Targeted Copper Complexes: New Agents for Site Selective Therapeutic Intervention

The development of targeted strategies in the design of therapeutic agents for human cancer is now a major driving force of inorganic medicinal chemistry research. This project seeks to develop a new class of targeted chemotherapeutic agents that are specific for mitochondrial DNA (mtDNA). We believe that mtDNA could be a unique target to exploit in the search for successful metallodrug lead agents that offer unique mechanism compared with cisplatin and related agents.

Dr. Raphael de Paiva (Postdoctoral Researcher)

Funder: Irish Research Council (IRC) Government of Ireland Postgraduate scheme

Title: Click and Crosslink: A Click Chemistry Approach to Developing Gene-Targeted Platinum(II) Therapeutics

By using small pieces of modified nucleic acids, scientists have discovered exciting new gene therapies that can treat human diseases such as cancer. This type of treatment can target either RNA or DNA and is known as antisense or antigene therapy. Current antigene therapies have limitations as they can be easily degraded in the human body, bind poorly with their targets, and cannot appropriately reach their intended targets to switch them off. This project will develop an exciting new class of gene therapy that will direct platinum drugs to specific cancer-causing genes. Their construction relies on a ground-breaking click chemistry approach that has the potential to improve the stability and genetic targeting effects of antigene therapies. The target molecules are composed of two elements: 1) a guide that recognises and binds sequence specifically with human genes of interest, and 2) a platinum(II) drug that will ‘harpoon’ or tightly bind with DNA at this specific point to silence its activity.

Sinéad O’Carroll (PhD candidate)

Funder: PPtBio – Science Foundation Ireland

Title: Polynuclear Platinum(II) Antisense Nucleic Acid Discovery

This PhD project aims to investigate the targeted binding affinity of polynuclear platinum(II) materials and to develop new, programmable, materials that act as in situ hybridisation probes for genetic detection. The development of new probes will be achieved through the use of heavily alkyne-modified Triplatin-PNA oligomers. The project involves nucleic acid chemistry, chemical synthesis, biophysical analysis, and molecular biology.

Conor Bain (PhD candidate)

Funder: H2020 Marie Skłodowska-Curie Action — Nature-ETN

Title: Oligonucleotide-linked artificial metallonucleases bearing intercalative phenanthrene ligands for targeted oxidative cleavage of mRNA.

Therapeutic nucleic acids often rely on the recruitment of endonucleases such as RNase H for the cleavage of mRNA in antisense therapy. Directed cleavage can be achieved by conjugation to oligonucleotide probe strands, and phenanthrene ligands have been shown to convey outstanding thermal stabilization properties to these probes through intercalative pi-stacking. This project will focus on the engineering of catalytic RNA hybrids bearing intercalative phenanthrene ligands linked to redox active artificial metallonucleases (AMNs) that recognise and oxidatively cleave therapeutically relevant mRNA. These RNA-metal ion hybrids will be constructed through the incorporation of alkyne-modified nucleotides followed by click chemistry with phenethrene-azide ligands and catalytic metal ion binding.

Anna Ziemele (PhD candidate)

Funder: Irish Research Council (IRC) Government of Ireland Postgraduate scheme

Title: Development of Mitochondrial Gene-Editing Ruthenium Hybrid Materials

The primary focus of this project is the development of ‘click chemistry’ probes to direct biologically active materials within the mitochondrial matrix. Up to this point, the delivery of probes to the mitochondria has been limited by the use of mitochondrial-targeted proteins. This approach is costly and time consuming and is limited by the preparation of new materials. A possible solution to this problem is the application of copper-catalysed ‘click chemistry’ and this project proposes new chemistry to explore this opportunity. The project involves the synthesis of Ru(II) polypyridyl probes with intrinsic fluorescence and functionality containing mitochondrial targeting moieties.

Seán O’Halloran (PhD candidate)

Funder: CÚRAM Centre for Research in Medical Devices – Science Foundation Ireland

Title: Photoswitchable Biomaterials for Personalised Gene Therapy (Photo-Gene)

This project will develop biocompatible medical device coatings with the aim to reduce inflammation, both acute and chronic by the targeting of iron and copper ions. While copper and iron are used extensively in vivo as metalloproteins, responsible for transport and detoxification of reactive oxygen species (ROS), their free ion forms can catalyse the formation of ROS and cause acute tissue toxicity. This will be achieved using a Nanoscribe Photonic Professional Gt 3D Laser Lithography System, to achieve sub micro-meter resolution of a novel surface, azide modified and capable of “Click” chemistry for the coupling of designer chelating ligands. These ligands will be specific to iron (II/III) and copper (II/I) and once coordinated to a metal ion, will act as Superoxide Dismutase (SOD) catalysts.

Simon Poole (PhD candidate)

Funder: CÚRAM Centre for Research in Medical Devices – Science Foundation Ireland

Title: Development of Holliday junction-stabilising di-nuclear complexes via click chemistry: a new gene targeting strategy for metal-based drugs

The Holliday junction (HJ) is a four-way non-canonical DNA structure with known functions in recombination and repair. The development of new synthetic agents that recognise and stabilise HJ assembly is an important goal and yet only a limited number of synthetic agents can recognise and stabilise the HJ including a bis-acridine C6 ligand capable of binding noncovalently at the junction crossover region. This project will develop new di-copper(II) and di-ruthenium(II) complexes using a breakthrough click chemistry approach whereby aliphatic linkers will ‘click’ to azide chelated ligands coordinated to metal complexes bearing designer intercalators.

Alex Gibney (PhD candidate)

Funder: Synthesis and Solid-State Pharmaceutical Centre (SSPC) and co-industry funded by Merck Sharp & Dohme

Title: Design of Processive, Gene-targeted DNA Molecular Scissors Using ‘Click’ Chemistry

Since its discovery, the copper-catalysed alkyne-azide click (CuAAC) reaction has seen widespread use in synthetic settings as a linkage tool and in biological fields for labelling and bioconjugations. This project focuses on the development of novel multidentate ligands to form multinuclear complexes, intended as artificial metallonucleases. This project has also been designed to induce properties of naturally occurring enzymes, such as processivity and sequence selectivity, on these multinuclear complexes through bioconjugation to targeting vectors and processivity factors.

Giuseppe Avella (PhD candidate)

Funder: H2020 Marie Skłodowska-Curie Action, ITN — ClickGene

Title: Investigating the role of fatty acids in CHO cell culture and the development of novel genome engineering tools.

Enhancing Chinese Hamster Ovary (CHO) cells productivity of recombinant proteins has been an area of intense research over the last two decades to meet the rising global market demand. The most common approach has been to adapt the media formulation and the bioprocess design to boost large scale production. The project focuses on engineering CHO cells lipids metabolism pathways while growing in lipids rich media formulations evaluating possible recombinant biotherapeutic protein production enhancements. The modulation of gene expression allows to regulate the activity of a protein directly before its transcription. Most of the genome engineering tools are based on the Watson-Crick base pairing. In this project, we focus as well on possible alternatives based on the combination of Hoogsteen base pairing and different DNA modifications to avoid their degradation by nucleases in the cells, while preserving the binding stability.

Malou Coche (PhD candidate)

Funder: H2020 Marie Skłodowska-Curie Action — Nature-ETN

Title: Development of synthetic molecular scissors for artificial gene editing.

Antigene technology will be developed by hybridising a probe strand (e.g. a TFO) with specific metal complexes that can either damage DNA through oxidative processes or through crosslinking.

Beth Searle (PhD candidate)

Funder: H2020 Marie Skłodowska-Curie Action — Nature-ETN

Title: Development of on DNA oxidation catalysts for the efficient oxidation of 5-methyl- and 5- hydroxymethyl-dC to 5-formyldC for sequencing.

5-methylcytosine has long been known as an omnipresent epigenetic base in the genome. Since the discovery of oxidised derivatives 5-hydroxymethyl-, 5-formyl-, 5-carboxyl- cytosines it has become imperative to develop efficient and selective methods for their detection and base resolution sequencing in order to elucidate their biological implications. This project focusses on developing an oxidation catalyst selective for 5-methyl- and 5-hydroxymethyl- cytosine, with a view to employing these in the base resolution sequencing of these epigenetic bases. Metal complexes will be explored as a means of accomplishing this in conjunction with directing probes.

Dr Shubhanjan Mitra (Organic Synthesis)

Funded by IRC GOI Postdoctoral Fellowship (2019-present) for project entitled ‘Catalytic Asymmetric Synthesis of Cyclopentanones and Application to the Synthesis of Prostaglandin Pharmaceuticals.’

Sophie Connolly (Organic Synthesis)

MSc studies funded by School of Chemical Sciences (2019-present) for a project entitled ‘Asymmetric synthesis of pharmaceutically important lactones.’