Imogen McNeill
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PROJECT SUMMARY
Dinogunellins are a class of four toxic phospholipids found in the roe of four fish with a unique and modular structure. To date, they have only been extracted rather than synthesised, resulting in small quantities of compound and limiting the ability to test their properties. This project aims to build on ongoing research in the Green group by utilising a click-chemistry approach to synthesise a library of dinogunellin analogues and subsequently test their biological activity. As numerous other toxic natural compounds have demonstrated biological activity and drug-like properties, dinogunellins and analogues are anticipated to behave similarly, and therefore show serious promise as a starting point for developing drugs to fight infectious diseases.
RESEARCH IMPACT
New Zealand will always have to face serious infectious disease threats and will therefore require a range of effective drugs for these situations. Dinogunellins have a unique structure, especially with regard to the phosphoramidate bond, that strongly suggests that analogues will be biologically active and possess drug-like properties. Synthesis of a variety of analogues with the aim of finding a drug lead is a critical step in developing our understanding of these compounds. Moreover, the widespread availability of the starting materials necessary means that synthesis of dinogunellin analogues will not be limited by rarity or expense of the required building blocks. Combined with the straightforward click chemistry approach, the synthesis of these potentially very useful compounds is uncomplicated, easily replicated, and therefore remarkably useful for New Zealand's ability to respond to infectious disease threats.
RESEARCH PERSONNEL
- Dr Nick Green | Supervisor
Myles Landon
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PROJECT SUMMARY
Malonyl-CoA Decarboxylase (MCD) is a crucial enzyme in the initial step of fatty acid biosynthesis. MCD is responsible for the breakdown of malonyl-CoA to acetyl-CoA, which can be synthesised into new fatty acids and ultimately energy production. Fatty acids can be conjugated to drugs, increasing their half-life within the bodily environment and subsequently, increasing their absorption into cells. Historically, fatty acid biosynthesis has been difficult in situ, with only recent developments having some success. Fatty acids have the potential to be manufactured into therapeutical agents and help deliver drugs such as steroids and hormones into cells, and if their synthesis can be controlled, more effective therapeutics can be produced.
Coacervates, which are droplets formed by liquid-liquid phase separation, acting as membrane-less organelles that compartmentalise cellular contents, can either localise enzymes and their substrates or sequester components of the reaction, altering their relative concentrations and altering catalytic activity. Incorporating MCD and malonyl-CoA inside a coacervate may increase the reaction rate, increasing the fatty-acid biochemical pathways.
This project will express and purify MCD and the coacervate-forming Ddx4 protein. Then incorporate the enzyme into the coacervates and test the catalytic kinetics of this modulated reaction compared to the unaltered reaction outside of a coacervate.
RESEARCH IMPACT
This project will define how coacervates can alter catalytic reactivity to be used in further health research. Fatty-acid synthesis is a key area of research as altering reactions could help better synthesise supplements and drugs that are related to this pathway such as steroids and hormones.
RESEARCH PERSONNEL
- Prof Renwick Dobson | Primary Supervisor
- Dr Amy Yewdall | Supervisor