Undergraduate Research Projects
Ruthenium Nitrosyl Compounds in Anticancer therapy.
Cancer cells are cells which have acquired mutations in their genome that allow them to behave differently to normal cells and survive in conditions in which normal cells would not. These capabilities are commonly referred to as the hallmarks of cancer, and they may include limitless replicative ability, evasion of growth suppressors and avoidance of immune destruction which are tightly regulated by cancer cells to ensure cell survival. Therefore, the most desirable anticancer drugs would target the deregulation of one or more of these hallmarks to cause cancer cell death.
Ruthenium nitrosyl complexes exhibit lower unselective toxicity than classical platinum-based chemotherapy drugs such as cisplatin (i.e. they have less toxic side effects). This is hypothesised to be due to ruthenium’s ability to mimic iron (an abundant intracellular metal) and bind to various biomolecules. While there had been a significant amount of synthetic studies of ruthenium nitrosyl compounds and subsequent chemical characterisation, there lacked significant biological studies to examine their physiological mechanisms of action. Of the studies that had reported in vitro effects, there had been contradicting conclusions, which demonstrated the requirement for study in a biological setting to determine how these compounds act on cancer cells.
While on exchange in Singapore in 2016, Tara worked with Dr Wee Han Ang (Chemistry, NUS). Tara’s research sought to understand the biological mechanism of action of two novel ruthenium nitrosyl complexes in several cancer cells lines. Her work contributed towards two publications.
Relevant Publications:
NO Releasing and Anticancer Properties of Octahedral Ruthenium–Nitrosyl Complexes with Equatorial 1H-Indazole Ligands
Ewelina Orlowska, Maria V. Babak, Orsolya Dömötör, Eva A. Enyedy, Peter Rapta, Michal Zalibera, Lukáš Bučinský, Michal Malček,
Chinju Govind, Venugopal Karunakaran, Yusuf Chouthury Shaik Farid, Tara E. McDonnell, Dominique Luneau, Dominik Schaniel,
Wee Han Ang, and Vladimir B. Arion
Inorganic Chemistry 2018 57 (17), 10702-10717
DOI: 10.1021/acs.inorgchem.8b01341
Pt-Ni Nanoparticles for the oxygen reduction reaction
Platinum is heavily used in industry, where it is used as a catalytic converter in combustion engines, as a reformer in the petroleum industry and as a catalyst for hydrogenation and oxygen reduction reactions in fuel cells. The oxygen reduction reaction is one of the two reactions that occur in next-generation fuel cells aimed at replacing those currently in cars that consume fossil fuels. One of the key issues with developing these fuel cells is the high energy barrier (or overpotential) required for the oxygen reduction. Platinum nanoparticles are currently the best known catalyst for this reaction because platinum metal has the highest overpotential of all metals (meaning it requires the least input to make this reaction happen).
While monometallic platinum nanoparticles are the currently best option for the oxygen reduction reaction, there are still many limitations, particularly the relatively high cost of platinum, and the strong binding properties to oxygen, inhibiting release of a reaction intermediate (i.e. during the reaction, sometimes things get stuck to the nanoparticles and both slow the reaction and block binding of new reactants).
In an effort to reduce costs, and increase reaction efficiency, research focus shifted towards combining platinum with non-precious metals. Since catalytic reactions only occur on the surface of nanoparticles, replacing the nanoparticle core with a non-precious metal means less precious platinum is wasted where it does not partake in the reaction. Additionally, when one metal coats another, due to differences in atomic size between the two metals, nanoparticle strain arises (think about this like if you were to force an item into a cardboard box with slightly different dimensions - you might still be able to squeeze it in, but there is uneven pressure on both the items and the box due to physical constraints). This allows the tweaking of the binding efficiency of the reactant molecules to improve overall reaction efficiency.
During her third year, Tara worked with Dr Richard Tilley (Chemistry, UNSW) to design and generate a synthetic paradigm for nickel-platinum (Ni-Pt) core-shell nanoparticles. This work paved the way for a new PhD project in the lab.
Protein-Protein Interactions
During Tara’s first two research projects, she studied aspects of protein-protein interactions. The direct interaction between two proteins occurs due to many biochemical factors, and these interactions drastically dictate protein function. Some interactions are transient, occurring only for a short time, maybe to transfer a group from one protein to another to activate or deactivate it. Some occur on much longer timescales, where either many of the same protein, or multiple different proteins come together to form multi-protein complexes to execute their function. Understanding how two proteins interact with one another can provide information on their relationship and role, as well as shed light on potential relationships with other proteins or biomolecules that may share similar features.
In the summer of 2016, working with Dr Richard Edwards (BABS, UNSW), Tara completed a bioinformatics-based project. She looked at short linear motif (SLiM) enrichment in the protein-protein interaction (PPI) partners of 14-3-3 proteins, which was part of ongoing work assessing how well the lab’s current PPI data captured SLiM-mediated interactions. She also investigated whether there was any evidence of phosphomimicry in 14-3-3 ligand binding. In the next semester, she joined Dr Rob Yang’s lab (BABS, UNSW) to examine the physical mechanisms of interaction between two proteins involved in lipolysis: hormone sensitive lipase and seipin.
